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“STUDIES ON CHEMICAL ENTITIES OF
THERAPEUTIC INTEREST”
A THESIS
SUBMITTED TO THE
SAURASHTRA UNIVERSITY
FOR THE DEGREE OF
Doctor of Philosophy IN
THE FACULTY OF SCIENCE (CHEMISTRY)
BY Bhavesh L. Dodiya
UNDER THE GUIDANCE
OF
Prof. H. S. Joshi DEPARTMENT OF CHEMISTRY
(DST-FUNDED, UGC-SAP SPONSORED),
SAURASHTRA UNIVERSITY
(Re-Accredited Grade B by NAAC, CGPA 2.93),
RAJKOT - 360 005
(GUJARAT) INDIA
MAY-2011
Gram: UNIVERSITY Phone: (R) 0281-2584221 Fax: 0281-2577633 (O) 0281-2578512
SAURASHTRA UNIVERSITY University Road Rajkot - 360 005
Prof. H. S. Joshi Residence: M.Sc., Ph.D., F.I.C.S. B-1, Amidhara Appartment, Professor, 2- Jalaram Plot, Department of Chemistry University Road, Rajkot - 360 005 No. GUJARAT (INDIA) Date: - -2011 Statement under O. Ph. D. 7 of Saurashtra University The work included in the thesis is my own work under the supervision of Prof. H.
S. Joshi and leads to some contribution in chemistry subsidized by a number of
references.
Date: - -2011 (Bhavesh L. Dodiya) Place: Rajkot This is to certify that the present work submitted for the Ph. D. Degree of
Saurashtra University by Bhavesh L. Dodiya his own work and leads to advancement in
the knowledge of chemistry. The thesis has been prepared under my supervision.
Date: - -2011 Prof. H. S. Joshi Place : Rajkot Professor Department of Chemistry Saurashtra University
Rajkot-360005
ACKNOWLEDGEMENT
First and foremost, I wish to pay my sincere homage to the Lord Shiva for
making me capable of doing all that I propose, the work leading to my Ph. D. thesis
submission is one of them.
I would like to express my sincere gratitude to my supervisor Prof. H. S. Joshi
for accepting me as his research student and who made this research a success. It is
with Dr. Joshi’s enthusiasm and integral view on research combined with his
willingness to provide quality chemistry and not less that kept me going and I wish to
say thank you sir. Besides being a wonderful Supervisor, Dr. Joshi is as close as family
and a very good friend and I am deeply honored to have wonderful person like him in
my life. I wish to say thank you so much again for all the help you offered over the
years both in and out of my academic life.
I also owe to Dr. P. H. Parsania, Professor and Head, Department of
Chemistry, Prof. Anamik Shah and Dr. Y. T. Naliapara as I have been constantly
benefited with their lofty research methodology and the motivation as well as their
affectionate. I am thankful to the all staff members of the Department of Chemistry
for their relevant support to me. I am also thankful to Mr. Harshadbhai Joshi for
their kind support. I express my grateful tribute to Department of Chemistry,
Saurashtra University for providing me the excellent laboratory facilities for
accomplishing this work. I also thanks to University Grants Commission for finding
me as Meritorious Research Fellow which is really an achievement and helpful task for
me.
From bottom of heart I specially thanks to my seniors Dr. N. M. Dodiya, Dr.
D. H. Purohit, Dr. Paresh Zalavadiya, Dr. Vijay Ram, Dr. Satish Tala, Dr. Jignesh
Akbari, Dr. Kapil Dubal and Tejas Parmar for their selfless help, moral support and
guidance during my Ph. D. work. I heartily express special thanks to Dr. Govind &
Ila, Mr. Piyush Vekariya and Mr. Gaurang Pandya, for their unlimited help to me.
An endeavor such as a Ph. D. is impossible to accomplish without the generous
help and support of seniors and colleagues Dr. Kaushik Joshi, Haresh Ram, Ramesh
Nandaniya and Ranjit Pada by whom I was inspired for my doctoral work.
Words are inadequate to thank my most beloved friend and colleagues Renish
Ghetiya, Dr. Mehul Bhatt, Abhay Bavishi and Vipul (Odich) who was always helping
me in all situations.
I am very much thankful to him for his technical guidance and comprehensive
exchange of ideas during the course of my research work. I am very much thankful to
Dr. Shailesh, Dr. Shrey, Dr. Amit, Dr. Nayan, Dr. Rahul, Dr. Ravi, Ashish, Jignesh,
Suresh, Ritesh, Pooja, Rizwan, Leena, Bharat, Bhavin, Ravi, Dhiru, Hardev,
Harshad, Manisha, Ashish(Master), Hitesh, Mrunal, Ramani, Ladwa, Mahesh, Anil,
P.P., Gami, Naimish, Rakesh, Deepti, Chintan, Bipin, Vipul and Dangar.
I get this achievement with tremendous support and cooperation of my friends
Karshanbhai, Hiren, Yogesh, Anil, Jayesh, Nilesh, Gatur, Sidhu, Pravin, Mepal,
Pedu, Nikhil, Bipin, Rakesh, Dinesh, Pankaj and Joshi thank you so much to be such
a wonderful friend and fill my life with full of joy and stay with me whenever I
needed.
First and foremost I want to pay all my homage and emotions to my beloved
grandmother late. Kurayben and Bhabhu Raniben. Most venerated my elder bhai &
bhabhi Arjanbhai-Kamarabhabhi, whose blessing this task would not have been
accomplished. I bow my head with utter respect to them for their continuous source of
inspiration, motivation and devotion to me.
Who have given us everything that we possess in this life? The life itself is their
gift to us, so I am at loss of words in which to own my loving mother Smt. Kariben
and most esteemed father Shri Lakshmanbhai and most venerated brother
Narsinhbhai-Lasubhabhi, Kalubhai-Nathibhabhi. I am very much grateful to My
Sister Maniben, Rasilaben and Harshaben for their love, affectionate and caring. I am
also obliged to my younger brother Rahul and my cute nephews & nice Rushi, Rohit,
Hiren, Keval, Dhaval, Hetal, Kajal, Kinjal. Through the stress and strain of this
study, my friend and wife Mital has encouraged me to reach my destination.
(Bhavesh L. Dodiya)
CONTENTS
SYNOPSIS……………………………………………………………………………………..1 STUDIES ON CHEMICAL ENTITIES OF THERAPEUTIC INTEREST PART-A: STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES
1. Introduction………………..............................................................................................8
2. Therapeutic Importance……………………………………………………………...…13
3. References………………………………………………………………………………19
PART-I: STUDIES ON INDOLE-3-YL-GLYOXYLAMIDE DERIVATIVES
1. Introduction……………………………………………………………………………..24
2. Therapeutic Importance………………………………………………………………...28
Section-I
Synthesis and biological evaluation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-propyl-1H-indole-
2-carboxylic acids
1. Reaction scheme………………………………………………………………………...32
2. Experimental section…………………………………………………………………....33
3. Analytical data………………………………………………….………………………35
4. Spectral study…………………………………………………………………………...37
5. Antimicrobial activity………………………………………………………………...…42
6. References….……………………………………………………………………….…..45
PART-II: STUDIES ON IMIDAZOLONE DERIVATIVES
1. Introduction……………………………………………………………………….…….48
2. Therapeutic Importance……………………………………………………………...…49
Section-I
Synthesis and biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-
imidazol-1-yl]-1H-indole-2-carboxamides.
1. Reaction scheme…………………………………………………………………..…….52
2. Experimental section…………………………………………………………………....53
3. Analytical data……………………………………………………………………….…55
4. Spectral study…………………………………………………………………………...57
5. Antimicrobial activity………………………………………………………………...…62
6. References……………………………………………………………………….….......63
PART-III: STUDIES ON OXADIAZOLE DERIVATIVES
1. Introduction……………………………………………………………………….…….65
2. Therapeutic Importance……………………………………………………………...…67
Section-I
Synthesis and biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indoles.
1. Reaction scheme……………………………………………………………………..….70
2. Experimental section………………………………………………………………...….71
3. Analytical data……………………………………………………………………….…73
4. Spectral study…………………………………………………………………………...75
5. Antimicrobial activity…………………………………………………………...………80
6. References………………………………………………………………………………81
PART-B: STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES
1. Introduction……………………………………………………………………….…….84
2. Therapeutic Importance………………………………………………………………...87
3. References………………………………………………………………………………91
PART-I: STUDIES ON IMIDAZO[1,2-a]PYRIDINE-3-YL-GLYOXYLAMIDE
DERIVATIVES
1. Introduction……………………………………………………………………….…….94
2. Therapeutic Importance…………………………………………………………………95
Section-I
Synthesis and biological evaluation of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-
3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.
1. Reaction scheme………………………………………………………………………...96
2. Experimental section……………………………………………………………………97
3. Analytical data……………………………………………………………………….…100
4. Spectral study…………………………………………………………………………...102
5. Antimicrobial activity………………………………………………………………...…107
6. References………………………………………………………………………………108
PART-II: STUDIES ON MANNICH BASE DERIVATIVES
1. Introduction……………………………………………………………………….…….109
2. Therapeutic Importance……………………………………………………………...…111
Section-I
Synthesis and biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-
ylmethyl)imidazo[1,2-a]pyridines.
1. Reaction scheme………………………………………………………………………...114
2. Experimental section………………………………………………………………...….115
3. Analytical data ………………………………………………………………………....117
4. Spectral study…………………………………………………………………………...119
5. Antimicrobial activity………………………………………………………………...…124
6. References………………………………………………………………………………125
PART-III: STUDIES ON BIS-IMIDAZO[1,2-a]PYRIDIN DERIVATIVES
3. Introduction…………………………………………………………………….……….127
4. Therapeutic Importance……………………………………………………………...…129
Section-I
Synthesis and biological evaluation of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-methylH-
imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]pyridines.
1. Reaction scheme………………………………………………………………………...132
2. Experimental section…………………………………………………………………....133
3. Analytical data……………………………………………………………………….…135
4. Spectral study………………………………………………………………………..….137
5. Antimicrobial activity………………………………………………………………...…142
6. References………………………………………………………………………………143
PART-C: STUDIES ON THIOPHENE DERIVATIVES
1. Introduction……………………………………………………………………………..145
2. Therapeutic Importance……………………………………………………………...…146
3. References………………………………………………………………………………149
PART-I: STUDIES ON PYRAZOLINE DERIVATIVES
1. Introduction……………………………………………………………………….…….151
2. Therapeutic Importance……………………………………………………………...…154
Section-I
Synthesis and biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-yl)-
4,5-dihydro-1H-pyrazol-1-yl]methanones.
1. Reaction scheme………………………………………………………………………...159
2. Experimental section…………………………………………………………………....160
3. Analytical data……………………………………………………………………….…163
4. Spectral study………………………………………………………………………..….167
5. Antimicrobial activity………………………………………………………………...…172
6. References………………………………………………………………………………173
PART-II: STUDIES ON PYRIMIDINE DERIVATIVES
1. Introduction……………………………………………………………………….…….178
2. Therapeutic Importance……………………………………………………………...…181
Section-I
Synthesis and biological evaluation of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-
yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.
1. Reaction scheme………………………………………………………………………...184
2. Experimental section…………………………………………………………………....185
3. Analytical data……………………………………………………………………….…187
4. Spectral study…………………………………………………………………………...191
5. Antimicrobial activity………………………………………………………………...…196
6. References………………………………………………………………………………197
List of publication…………………………………………………………………………………….....199
SYNOPSIS
Studies on chemical…
Synopsis 1
The research work incorporated in the thesis with the title “STUDIES ON
CHEMICAL ENTITIES OF THERAPEUTIC INTEREST” has been described as
under.
PART-A : STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES
PART-B : STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES
PART-C : STUDIES ON THIOPHENE DERIVATIVES
PART-A : STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES
Nowadays, the entire pharmaceutical industry is faced with the challenge of
increasing productivity and innovation. The major hurdles are the increasing costs of
research and development and a simultaneous stagnating number of new chemical entities
(NCEs). So the primary goal of the our research work is to find and develop new
chemical entities (NCEs)
Indole nucleus possesses remarkable pharmaceutical importance and biological
activities, some of their derivatives occur as natural products, amino acid, hormones etc.
In animals serotonin is a very important neurotransmitter in the central nervous system
and also plays a vital role in the cardiovascular and gastrointestinal system. Many indole
derivatives are used as pharmaceuticals and highly selective medicines which are in
current use. In view of our on going interest in the synthesis of some new potentially
bioactive indole derivatives have been described as under.
PART-I: STUDIES ON INDOLE-3-YL-GLYOXYLAMIDE DERIVATIVES
The synthesis of compounds incorporating indole-3-yl-glyoxylamide has been
attracted widespread attention due to their diverse pharmacological properties like
anticancer, anti-inflammatory, antibiotic, antifungal, herbicidal, antitubercular etc. To
approach this goal syntheses of some indole-3-yl-glyoxylamides have been undertaken,
which have been described as under.
SECTION-I: Synthesis and biological evaluation of 3-[N,N-Dialkylamine(oxo)
acetyl]-1-propyl-1H-indole-2-carboxylic acids.
Studies on chemical…
Synopsis 2
N
O
OH
OOR
CH3 R = Seco. amine
Type (I)
Indole-3-yl-glyoxylamide derivatives of Type (I) have been synthesized by the
condensation of 1-propyl-1H-indole-2-carboxylic acid with oxalyl chloride and different
secondary amine in the presence of DCM.
PART-II: STUDIES ON IMIDAZOLONE DERIVATIVES
The discovery of imidazolone as potent biologically active agent has led to the
exploration of large number of structural variants, containing imidazolone moiety as an
invariable ingredient. Its derivative have shown various biologically activities such as
anathematic, antimicrobial, antihistamine, anti-inflammatory, antibacterial etc. in order to
develop therapeutically important compounds, it was consider of interest to synthesize
some imidazolones shown as under.
SECTION-I: Synthesis and biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-
phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-carboxamides.
NH
NH
O
NN
OR
R= Aryl
Type (II)
The synthesis of imidazolones of Type (II) have been under taken by the reaction
of 1H-indole-2-carbohydrazide with substituted azalactone which in turn have been
prepared by well known Erlenmeyer azalactone synthesis.
Studies on chemical…
Synopsis 3
PART-III: STUDIES ON OXADIAZOLE DERIVATIVES
1,3,4-Oxadiazoles are associated with broad spectrum of pharmacological activity
like anesthetic, hypnotic, antibacterial, hypoglycemic and antifungal. These valid
observations promoted us to synthesize 1,3,4-oxadiazole derivatives with better
therapeutic value which have been described as under.
SECTION-I: Synthesis and biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-
1-propyl-1H-indoles.
N
CH3
N
O
N
R
R=Aryl
Type (III)
The oxadiazole derivatives of Type (III) have been synthesized by the
condensation of 1-propyl-1H-indole-2-carbohydrazide with various aromatic acids in the
presence of POCl3.
PART-B : STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES
Heterocyclic compounds bearing imidazo[1,2-a]pyridine ring system are endowed
with variety of biological activities. Our strategy is based on to develop a new bioactive
entity especially with pharmacological activities bearing heterocyclic ring system.
Literature survey reveals that nitrogen containing heterocyclic compounds like
imidazo[1,2-a]pyridines have received considerable attention in medicinal science due to
their biological and pharmacological activities like anti-inflammatory, antitumor, calcium
channel blocker, hypnotic, sedative, antimicrobial, antitubercular, CNS depressant,
antithyroid and many other therapeutic activities.
These valid observations led us to design and synthesize some heterocycles like
glyoxylamide, mannich bases, bis-imidazo[1,2-a]pyridine etc., bearing imidazo[1,2-
a]pyridine nucleus, which have been described as under.
PART-I: STUDIES ON IMIDAZO[1,2-a]PYRIDINE-3-YL-GLYOXYLAMIDE
DERIVATIVES
Studies on chemical…
Synopsis 4
Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives have been found to be
potent drug in pharmaceutical and possess a wide range of pharmacological activities
such as anticancer, anticonvulsant, hypnotic, antithyroid, anti-inflammatory etc. It
appeared of interest to design and synthesize imidazo[1,2-a]pyridine-3-yl-glyoxylamide
derivative, which have been describe as under.
SECTION-I: Synthesis and biological evaluation of 1-[2-(4-Fluorophenyl)-6-
methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.
N
NF
CH3O
R
O
R= Seco. amine
Type (IV)
Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives of Type (IV) have been
synthesized by the condensation of 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine
with oxalyl chloride and different secondary amine in the presence of DCM.
PART-II: STUDIES ON MANNICH BASE DERIVATIVES
Compound containing bridge N-atom exhibit pronounced pharmacological
activities. Mannich base derivatives with bridge N-atom have been found to potent drug
in medicine science and possess a wide range of therapeutic activities like
antihypertensive, antidepressant, anticholestemic, antifungal etc. by consideration this
valid observations, to approach this goal we have synthesize some new mannich bases,
which have been shown as under.
SECTION-I: Synthesis and biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-
(N,N-dialkylamine-4-ylmethyl)imidazo[1,2-a]pyridines.
N
N
CH3
F
R R= Seco. amine
Type (V)
Studies on chemical…
Synopsis 5
Mannich bases of Type (V) have been synthesized by the condensation of 2-(4-
fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different secondary amines and
formaldehydes in the presence of acid catalyst.
PART-III: STUDIES ON BIS-IMIDAZO[1,2-a]PYRIDIN DERIVATIVES
Bis imidazo[1,2-a]pyridine derivatives are important intermediates in organic
synthesis, especially in the synthesis of biologically active and medicinally useful agents.
For instance, they are widely used in the synthesis of cyclin-dependent kinases (CDK)
inhibitors, sleep inducers, anticonvulsant agents, antiviral agents etc. The synthesis of
some new potentially bioactive bis imidazo[1,2-a]pyridine derivatives have been
undertaken.
SECTION-I: Synthesis and biological evaluation of 2-(4-Flurophenyl)-3-((2-(4-
flurophenyl)-6-methylH-imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-
imidazo[1,2-a]pyridines.
N
N
CH3
F
N
NF
CH3R
R=Aryl
Type (VI)
Bis imidazo[1,2-a]pyridine derivatives of Type (VI) have been synthesized by the
condensation of the 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different
aryl aldehyde and sodium acetate.
PART-C : STUDIES ON THIOPHENE DERIVATIVES
Thiophen nucleus represents important building blocks in both natural and
synthetic bioactive compounds, which have been shown to possess diverse therapeutic
activities. Our works are paying attention on introduction of chemical multiplicity in the
molecular frame work, in order to synthesizing active molecules of widely different
composition. Literature assessment reveals that sulfur containing heterocyclic compounds
has been shown to have a broad range of important biological and pharmacological
activities such as anti-HIV, antitubercular, antimicrobial, anticonvulsant, anticancer,
Studies on chemical…
Synopsis 6
antiviral etc. Considering the increasing importance of thiophene nucleus, we have
undertaken the synthesis of some new pyrazoline and pyrimidine derivatives bearing
thiophene nucleus, which have been described as under.
PART-I: STUDIES ON PYRAZOLINE DERIVATIVES
In the present chapter, the efforts have been made for the synthesis of pyrazoline
derivatives. Substituted pyrazoline derivatives have drawn considerable attention of the
chemist due to their good pharmacological activities like antibacterial, anticonvulsant,
analgesic etc. with a view to getting better therapeutic agent and to evaluate
pharmacological profile, different types of pyrazoline derivatives have been prepared
which have been described as under.
SECTION-I: Synthesis and biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-
5-(thiophen/aryl-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.
NN
ONH
R1
R
R = thiophene/aryl
R1 = aryl/thiophene
Type (VII)
Pyrazoline derivatives of Type (VII) have been synthesized by the
cyclocondensation of the 1H-indole-2-carbohydrazide and different substituted chalcones
under acidic condition.
PART-II: STUDIES ON PYRIMIDINE DERIVATIVES
The chemistry of pyrimidine and its derivatives has been studied for over a
century due to their diverse biological activities. Due to formal isoelectronic relationship
with purines, the pyrido[2,3-d]pyrimidine ring system is of special biological interest. It
has numerous pharmacological and medicinal applications viz, antitumour,
immunodilator, tuberculosis, antiallergic and radioprotective.
Studies on chemical…
Synopsis 7
SECTION-I: Synthesis and biological evaluation of 2-Methyl-5-aryl/thiophen-7-
(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.
N R1
R
NH
N
O
CH3 R = thiophen/aryl
R1 = aryl/thiophen
Type (VIII)
The synthesis of pyrido[2,3-d]pyrimidines of Type (VIII) was achieved by acid
catalysed cyclocondensation of 2-amino-6-aryl/thiophene-4-(thiophene/aryl-2-
yl)pyridine-3-carbonitrile with glacial acetic acid.
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR and 13C NMR spectroscopy and further
supported by mass spectroscopy. Purity of all the compounds have been checked on thin
layer chromatographic plate and HPLC technique.
All the compounds have been evaluated for their antibacterial activity towards
Gram +ve and Gram -ve bacterial strains and antifungal activity towards Aspergillus
niger at a concentration 40 µg/ml. The biological activities of the synthesized compounds
have been compared with standard drugs.
Part – A
Introduction
Studies on Indole-2-carboxylic acid Derivatives
Studies on chemical…
Indole derivatives… 8
INTRODUCTION
Indole (2,3-benzopyrrole, ketole, 1-benzazole; C8H7N) is an aromatic heterocyclic
organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring
fused to a five-membered nitrogen-containing pyrrole ring. The participation of the
nitrogen lone pair electron in the aromatic ring means that indole is not a base, and it does
not behave like a simple amine.
Indole is a solid at room temperature. It can be produced by bacteria as a
degradation product of the amino acid tryptophan. It occurs naturally in human faces and
has an intense facial odor. At very low concentrations, however, it has a flowery smell,
and is a constituent of many flower scents (such as orange blossoms) and perfumes. It
also occurs in coal tar.
NH1
2
345
67
(1)
Indole compounds include the plant hormone Auxin (indolyl-3-acetic acid), the
anti-inflammatory drug indomethacin, the betablocker pindolol, and the naturally
occurring hallucinogen dimethyltryptamine.
The name indole is a portmanteau of the words indigo and oleum, since indole
was first isolated by treatment of the indigo dye with oleum. Indole chemistry began to
develop with the study of the dye indigo. Indigo can be converted to isatin and then to
oxindole. Then, in 1866, Adolf von Baeyer reduced oxindole to indole using zinc dust.1 In
1869, he proposed a formula for indole.2
Certain indole derivatives were important dyestuffs until the end of the 19th
century. In the 1930, interest in indole intensified when it became known that the indole
nucleus is present in many important alkaloids, as well is in tryptophan and auxins, and it
remains an active area of research today.3
The indole skeleton is one of the most attractive frameworks with a wide range of
biological and pharmacological activities.4 This physiologically important nucleus is
abundantly found in therapeutic agents5,6 as well as in natural products. Many researchers
have described synthesis of indole and its derivatives along with its applications in
literature.7
Studies on chemical…
Indole derivatives… 9
SYNTHETIC ASPECT
Various methods for the preparation of indole derivatives have been cited in
literature, some of them are as under.
1. B. George8 has reported one-pot microwave assisted synthesis of indole from
phenylhydrazine and pyruvic acid.
NHNH2 O
HOOC
CH3
ZnCl2PCl5 N
H
+
2. N. Sakai et al.9 have cyclized 2-ethynylanilines by indium as catalyst and
produced various indole derivatives in good yields for substrates having an alkyl
or aryl group on the terminal alkyne.
NH
R3
R1
R2
5 mol -% in Br3
toluene, reflux 5-20 hR
1
NR
3
R2
3. Rhodium (II) perfluorobutyrate-mediated decomposition of vinyl azides
allows rapid access to a variety of complexes of indole was prepared by B.
J. Stokes et al.10
N3
O
OCH3
R1 R
1
NH
O CH3
O
3-5 mol-%
toluene, 60 oC, 16 h
Rh2(OCOC3F7)4
4. Y. Du and coworkers11 have been synthesized various N-arylated and N-alkylated
indoles and pyrrole-fused aromatic compounds by a phenyliodine
bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization.
R3
NHR
1
R2
EWG
R1
NR
3
R2
EWG
1.3 eq. PhI(O2CCF3)2(PIFA)
CH2Cl2, RT, 30 min
Studies on chemical…
Indole derivatives… 10
5. Microwave-assisted synthesis of indole derivatives in water via
cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by A.
Carpita et al.12,13
NH2
R2
R1 H2O, 200 oC
MW, base/acid saltR
1
NH
R2
6. Synthesis of 2-substituted indoles via palladium-catalyzed domino Heck reaction
with 71 % yield was given by H. Mao et al.14
I
N R1 N
H
R1Pd(OAc)2, PPh3, 120oC
KOBu-t, DMSO
7. D. K. Whelligan and coworkers15 have synthesized two-step aza- and diazaindoles
from chloroamino-N-heterocycles using ethoxyvinylborolane.
NH2
OEtR
1 AcOHR
1
NH
8. One-pot synthesis of indole derivatives from nitroarenes under hydrogenation
condition with supported gold nanoparticles was reported by Y. Yamane et al.16
NO2
R1
NH
R1H2
Au/Fe2O3
9. A mild preparation of substituted indole from simple aromatic precursors using
(trimethylsilyl)diazomethane was reported by L. Zhu et al.17
NHNH2
OTMSCHN2, CS2CO3
MeOH, 60oC
Studies on chemical…
Indole derivatives… 11
10. E. V. Sadanandan et al.18 have synthesized 4,6,7-trimethoxyindol marine
alkaloids.
OMe
OMeMeO
COOMe
N3
xylenereflux
OMe
OMeMeO N
H
COOMe
11. S. Wagaw et al.19 have reported novel fischer indole synthesis.
NHN
PhPhR
3+
R1
O R2
TsOH.H2O, EtOH
refluxR
3
NH
R1
R2
12. G. A. Kraus and coworkers20 have synthesized indole derivatives under
microwave-assisted conditions with high yields in one-pot reaction.
+PPH3
-Br
N R1
t-BuoKTHF, 25 oC N
H
R1
13. Gold(III)-catalyzed indole derivatives from 2-alkynylanilines in EtOH annulations
at room temperature in good yields was reported by A. Arcadi et al.21
R1
NH2
R2
4 mol-% NaAuCl4.2H2O
EtOH, rtR
1
NH
R2
14. Copper(II)-catalyzed cyclization of 2-ethynylaniline derivatives to indoles can be
carried out in a MeOH was given by K. Hiroya et al.22
NH
R3
SO2R1
R2 Cu(OCOCF3)2
MeOH, rtR
2
N
SO2R1
R3
Studies on chemical…
Indole derivatives… 12
15. A. Dobbs et al.23 have synthesized indole derivatives from ortho-
bromonitrobenzenes with various vinyl grignard reagents in THF.
BrNO2
R1
+R
2
R3
MgBrTHF, -40 oC
Br
R1
NH
R2
R3
16. One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-
iodoanilines and aldehydes under mild ligandless conditions in DMF was reported
by Y. Jia et al.24
R1
NH
I
R2
+O
R3
H5 mol-% Pd(OAc)2 R
1
N
R3
R2
DABCO, DMF, 85 oC
17. Suzuki-Miyaura coupling of ortho-gem-dihalovinylanilines with boronic acids, of
a Pd(OAc)2 catalyst in the presence of K3PO4·H2O was doccumented by Y. Q.
Fang et al.25
NH2
R1
R2
Br
Br
+ R1
NH
Ar
R2
Ar-B(OH)2
1-5 mol-% Pd(OAc)2
K3PO4.H2O, toluene, 90 oC
18. V. Sridharan et al.26 have synthesized microwave assisted 2-arylindoles in good
yields.
NHR
1
O ArMW
DMFR
1
NH
Ar
19. Lewis acids catalyzed cyclization of methyl phenyldiazoacetates was reported by
L. Zhou et al.27
Studies on chemical…
Indole derivatives… 13
N R1
COOCH3
N2
Zn(OTf)2
MDC, rt NH
R1
COOCH3
REACTION MECHANISM
The reaction of phenyl hydrazine with an aldehyde or ketone initially forms
phenylhydrazone which isomerizes to the respective enamine. After protonation, a cyclic
sigmatropic rearrangement occurs producing an imine. The resulting imine forms a cyclic
aminoacetal, which under acid catalysis eliminates NH3, resulting in the energetically
favorable aromatic indole.
NHN
NHNH
NHNH
H
NH2NH
H+
NH2NH2- +N
HNH2
HH
-H+H
+
NH
NH3
HH
+-H
+
-NH3NH
Phenylhydrazone Enamine Imine
AminoacetalIndole THERAPEUTIC IMPORTANCE
The indole ring system represents a privileged structure in drug discovery. The
number of bioactive compounds containing this ring system is so vast that the complete
range of their biological activities can be hardly classified.28-30
1. Analgesic31
2. Antiallergic32
3. Antibacterial33
4. Anticonvulsant34
5. Antifungal35
6. Antihistaminic36
7. Anti-inflammatory37
8. Antitumor38
Studies on chemical…
Indole derivatives… 14
9. Antiviral39
10. β-adrenergic40
11. Diuretic41
12. Insecticidal42
13. Anticancer43
14. Anti HIV44
15. Anti hypertensive45
16. Cardiovascular46
17. Antioxidant47
B. Pelcman et al.48 have synthesized marine sponge pigment fascaplysin (2) from
indole and reported their antimicrobial activity.
NH
N
(2)
M. C. Pirrung et al.49 have synthesized indolylquinones (3) and checked their
activity on the human insulin receptor by demethylasterriquinone B1 (DAQ B1) and its
consequent oral insulin mimetic activity tested in mice by B. Zhang and coworkers.50
DAQ B1 was also subsequently shown to activate the TrkA nerve growth factor receptor
was reported by N. Wilkie and coworkers. 51
O
ONH
NH
OH
OH
(3)
Activities of asterriquinones (4) against HIV protease and HIV reverse
transcriptase have been disclosed by A. Fredenhagen et al.52 and K. Ono et al.53 and also
activity against serine proteases given by U. Mocek et al.54
Studies on chemical…
Indole derivatives… 15
NH
NH
O
O
OO
RR
R = H, CH3(4)
S. Pasquini et al.55
prepared library of 1,5-disubstituted-3-indole-N-
alkylacetamides as CB2 receptor ligands. Some representatives of CB2 agonists are
compounds AM1241, GW405833, JWH-015 and AM630 possess an indole structure
reported by K. Mackie et al.56 and C. Manera et al.57
N
O
I
NO2
N
N
N
O
O
O
Cl Cl
N
O
N
O
I
N
O
O
AM1241 GW405833 JWH-015 AM630
J. B. Blair et al.58 have synthesized fluorinated indole (5) derivatives.
NH
NR
1
R2
R3
R4
R1 = OH, H, F R2 = H, OCH3
R3 = H, F R4 = H, F(5)
P. Diana et al.59 have synthesized 3,5-bis(3’-indolyl)pyrazoles (6) by cyclization
of diketones and hydrazine monohydrate and evaluated their antitumor properties. The
interest in this class of compounds has been stimulated by both their unique chemical
structure and the wide range of biological properties including antiviral, antimicrobial,
and antitumor activity was given by V. M. Dembitsky et al.60
Studies on chemical…
Indole derivatives… 16
NH
BrN
NH N
H
Br
(6)
H. Sard et al.61 have synthesized psilocybin analogs (7) and discoved a selective
5-HT2C agonist.
NH
OR N
R = H, P(O)(OH)2
(7)
E. J. Glamkowski et al.62 have synthesized 3-(4-acylaminopiperazin-1-
ylalky1)indoles (8) as potential anti hypertensive agents.
NH
N
NNH
R1
O
R1 = aryl
(8)
M. Banerjee et al.63 have synthesized indole derivatives, such as HIV-1
nonnucleoside reverse transcriptase inhibitor. D. C. Cole et al.64 have tested 5-HT
receptor agonists or antagonists. Q. Shi et al.65 and H. D. H. Showalter et al.66 have
synthesized and tested peroxisome proliferator-activated receptor (PPAR) agonists and
protein tyrosine kinase inhibitors. G. Primofiore and coworkers67 and K. L. Lee et
al.68 have prepared and tested benzodiazepine receptor (BzR) ligands. Human cytosolic
phospholipase A2R inhibitor and blood coagulation factor Xa inhibitor have also been
presented by H. Matter et al.69
J. Holenz et al.70 prepared medicinal chemistry driven approaches toward novel
and selective serotonin 5-HT6 receptor ligands (9).
Studies on chemical…
Indole derivatives… 17
N
NR
2R
1
R3
NHSR
4O
O
(9)
Preparation and antibacterial activities of indole containg compounds reported by
Y. Yasuo et al.71 T. Bhawana et al.72 have synthesized and tested antimicrobial activity
of indole derivatives. Synthesis and biological screening of some new indole
derivatives doccumented by D. S. Mehta et al.73 and G. S. Gadaginamath et al.74 Potent
antimicrobial activity of indole derivatives against methicillin-resistant Staphylococcus
aureus investigated by R. A. Al-Qawasmeh et al.75 Regioselective synthesis and
biological evaluation of bis(indolyl)methane derivatives as anti-infective agents given
by M. Damodiran et al.76
Discovery of indole inhibitor of cytosolis phospholipase A2α reported by K. L.
Lee et al.77 Y. Kawashima et al.78 have studied structure activity of indole derivatives
with analgesic and anti-inflammatory activities. Synthesis and anti-inflammatory
activity of heterocyclic indole derivatives reported by R. Preeti et al.79 Amido indole
derivatives used in cannabinoid receptor modulators discovered by H. John et al.80
M. G. Bursavich et al.81 have synthesized indole derivatives and tested for PI3
kinase-α and the mammalian target. Synthesis and evaluation of indole derivatives as
antagonists of Wnt/β-catenin, signaling and CLL cell survival reported by J. Guangyi
et al.82 D. A. James and coworkers83 synthesized conjugated indole-imidazole
derivatives, displaying cytotoxicity against multidrug resistant cancer cell lines. C.
Girolamo et al.84 have synthesized derivatives of the new ring system indole with
potent antitumor and antimicrobial activity. B. Emile et al.85 have synthesized
substituted indole derivatives as new class of antineoplastics agent.
Studies on chemical…
Indole derivatives… 18
Endogenous substances and marketed drugs with indole substructures
NH
NH2
O
OHNH
NH2
OH
NH
NH
O
O
N
O
O
OH
O Cl N
O
O NN
NH
NS
NH OO
Tryptophan 5 - HT Melatonin
Indometacin OndansetronSumatriptan
NH
NHS
S
Brassinin
Thus the important role displayed by indole and its derivatives for various
therapeutic and biological activities prompted us to synthesize some Glyoxylamide,
Imidazolone and Oxadiazole derivatives bearing indole moiety in order to achieve
compounds having better therapeutic activities described as in the following parts.
STUDIES ON INDOLE-2-CARBOXYLIC ACID DERIVATIVES
PART-I: STUDIES ON INDOLE-3-YL-GLYOXYLAMIDE DERIVATIVES
PART-II: STUDIES ON IMIDAZOLONE DERIVATIVES
PART-III: STUDIES ON OXADIAZOLE DERIVATIVES
Studies on chemical…
Indole derivatives… 19
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75. R. A. Al-Qawasmeh, M. Huesca, V. Nedunuri, R. Peralta, J. Wright, Y. Lee, A. Young,
Bioorg. Med. Chem. Lett., 20(12), 3518-3520 (2010).
76. M. Damodiran, D. Muralidharan, P. T. Perumal, Bioorg. Med. Chem. Lett., 19(13), 3611-
3614 (2009).
Studies on chemical…
Indole derivatives… 23
77. K. L. Lee, M. A. Foley, L. Chen, M. L. Behnke, F. E. Lovering, S. J. Kirincich, W.
Wang, J. Shim, S. Tam, M. W. H. Shen, J. Med. Chem., 50(6), 1380-1400 (2007).
78. Y. Kawashima, F. Amanuma, M. Sato, S. Okuyama, Y. Nakashima, K. Sota, I.
Moriguchi, J. Med. Chem., 29(11), 2284-2290 (1986).
79. R. Preeti, V. K. Srivastava, A. Kumar, Eur. J. Med. Chem., 39(5), 449-452 (2004).
80. H. John, L. Katerina, W. Hong, P. Chennagiri, C. Ping, N. J. Derek, C. Bang-Chi, Z.
Rulin, K. A. Peter, X. Chen, Bioorg. Med. Chem. Lett., 12(17), 2399-2402 (2002).
81. M. G. Bursavich, N. Brooijmans, L. Feldberg, I. Hollander, S. Kim, S. Lombardi, K.
Park, R. Mallon, A. M. Gilbert, Bioorg. Med. Chem. Lett., 20(8), 2586-2590 (2010).
82. J. Guangyi, L. Desheng, Y. Shiyin, C. N. Christina, J. X. Liu, C. A. Dennis, C. B.
Howard, Bioorg. Med. Chem. Lett., 19(3), 606-609 (2009).
83. D. A. James, K. Koya, H. Li, S. Chen, Z. Xia, W. Ying, Y. Wu, L. Sun, Bioorg. Med.
Chem. Lett., 16(19), 5164-5168 (2006).
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Chiara, P. Alessandra, M. Paola, M. Carla, J. Med. Chem., 42(14), 2561-2568 (1999).
85. B. Emile, N. C. Hung, P. Alain, P. Odile, D. Paul, G. Pierre, J. Med. Chem., 31(2), 398-
405 (1988).
Part – A
(Part – I)
Studies on Indole-3-yl-glyoxylamide Derivatives
Studies on chemical…
Glyoxylamide derivatives… 24
INTRODUCTION
Indole-3-yl-glyoxylamide derivatives are potent biologically active agent has led
to the exploration of large number of structural variants, containing indole-2-carboxylic
moiety as an invariable ingredient so the synthesis of these compounds has become an
important target in current years. The diversity, efficiency and rapid access to small and
highly functionalized organic molecules makes this approach of central current interest in
the construction of compounds library and optimization in drug discovery process.1,2
NH
O
O
N R2R
1
(1)
A new class of indole-3-yl-glyoxylamide derivatives is high affinity agonists at
the benzodiazepine binding site receptors. It has proved a rich source of clinically
effective drugs, particularly anxiolytics, hypnotics and anticonvulsants.
SYNTHETIC ASPECT
Various methods for the preparation of 3-oxoacetamide-1H-indole derivatives and
alkylation of indole have been cited in literature, some of the methods are as under.
ALKYLATION
1. K. T. Potts et al.3 have synthesized 1-methylindole from indole, CH3I and NaNH2
in diethyl ether solution.
NH
CH3I
NaNH2, Et2O NCH3
2. R. S. Davidson et al.4 have reported N-alkylation of indole using phase transfer
catalyst with ultrasound.
Studies on chemical…
Glyoxylamide derivatives… 25
NH
N
C6H5CH2Br
PEG methyl ether
3. Potassium carbonate as a base for the N-alkylation of indole in ionic liquid was
prepared by Y. R. Jorapur et al.5
NH
+ Br Ph[bmim][BF4], CH3CN
K2CO3, 110 oC N
Ph 4. Alkylation of indole from potassium hydroxide, alkyl/aryl halide in acetone was
reported by C. A. Marlic et al.6
NH
NR
1
KOH, R1Xacetone
5. Synthesis of N-alkyl substituted indole in presence of sodium hydride in DMF was
documented by S. Roy et al. 7
NH
N
NC
NaH, DMFBr CN
6. Dual nucleophilic catalysis with DABCO for the N-methylation of indoles was
synthesized by W. Shieh et al.8
NH
R1 DABCO, DMF
MDC, 95 oC NR
1
CH3
Studies on chemical…
Glyoxylamide derivatives… 26
7. B. Sebastian et al.9 have synthesized selective Ruthenium-catalyzed N-alkylation
of indole by using alcohol.
NH
R1
+ R2
OH 24 h, toluene N
R1
R2
Shvo, PTSA
GLYOXYLAMIDE
8. The use of (NHC)CuI complex in combination with a N-heterocyclic carbene
precursor as catalyst for the double carbonylation of aryl iodides and secondary
amines solves the problem of using the precious metal Pd and phosphine ligands
was reported by J. Liu et al.10
IR
1+ CO + NH
R2
R2
NHC-Cu-ICS2CO3
R1
O
O
N
R2
R2
9. J. Zhua and coworkers11 have given one-pot synthesis of nitrogen-containing
heteroaryl α-keto amides from heteroaryl halides.
R1
Cl + NNC
O R1
O
ON(1) Base, THF
(2) CH3COOH
10. I. Bennacefa et al.12 have synthesized halogenated N,N-dialkylel-(2-phenyl-1H-
indol-3-yl)glyoxylamide derivatives.
NH
NH
O
O
R1
(1) (COCl)2, THF, 0OC
(2) Amine, THF, 0OC
11. R. Gitto et al.13 have synthesized glyoxylamide derivatives containing N-
substituted isoquinoline nucleus.
Studies on chemical…
Glyoxylamide derivatives… 27
N
OCH3
OCH3
R1
OOH
ON
OCH3
OCH3
R1
OR
2
Ocycloalkylamines,HBTU
DMF, TEA, rt
12. One-step synthesis of N-alkyl-2-aryl-2-oxoacetamide derivatives was given by I.
Yavari et al.14
R1
N+
C-
+
CHO
OH
X
OH
XO
O
NHR
2
13. M. Takhi et al.15 have synthesized 3-indolylglyoxamide derivatives.
NH
NH
O
O
Cl
NH
O
O
R1
(COCl)2
THF, 0OCsecondary amine
THF, 0OC
REACTION MECHANISM
NR
..N
+
R
H-
O
Cl O
Cl
N+
R
HO
-
Cl O
Cl
N+
R
H
O
ClO
R1
NHR
2
NR
OCl
O..
NR
OClN
+
O
R2
R1
H-
NR
ON
O
R2
R1
Studies on chemical…
Glyoxylamide derivatives… 28
THERAPEUTIC IMPORTANCE
Indole-3-yl-glyoxylamide derivatives have been tested for various
pharmacological activities, which have been summarized as under.
1. Anticancer16
2. Antitumor17
3. Anxiolytic18
4. Anti-HIV19
5. Antiviral20
6. Antimicrobial15
7. Antileishmanial21
8. GABA-A receptor22
9. Antihypertensive23
10. Cardiovascular24
F. D. Settimo et al.25 have studied anxiolytic effects of N,N-dialkyl-2-phenylindol-
3-ylglyoxylamides (2) by modulation of translocator protein promoting neurosteroid
biosynthesis. M. Gavish et al.26 and P. Casellas et al.27 have synthesized indole-3-
glyoxamide derivatives in a variety of biological processes, including calcium
homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation,
apoptosis induction, and regulation of immune functions. G. Primofiore et al.28 have
synthesized N,N-dialkyl-2-phenylindol-3-ylglyoxylamides a new class of potent and
selective ligands at the peripheral benzodiazepine receptor.
NH
N R2R
1
R3
O
OR4
R5
R1 = R2 = (CH2)2CH3
R3 = NO2, CF3, H, F
R4 = H, NO2, OCH3, F, Cl
R5 = H, Cl, CH3(2)
N. A. Meanwell et al.29 have described the discovery of indole-3-glyoxamide (3)
derivatives as the first small molecule inhibitors of the gp120-CD4 interaction (HIV-1
attachment inhibition) that demonstrate potent antiviral activity in cell culture.30
Studies on chemical…
Glyoxylamide derivatives… 29
NH
FO
O
N
N
O
(3)
Antibacterial activities of 3-indolylglyoxamide substituent have been explored in
an effort to improve the spectrum and potency of this class of agents by M. Takhi et al.15
X
N
O
ON N
R1
F
NO
O
R4R
3R2
R1 = H, CN, NO2, OCH3, Br
R2 = H, CH3
R3 = H, CH3
X = CH, N(4)
A series of marine alkaloid 8,9-dihydrocoscinamide, (5) its analogues and
indolylglyoxylamide derivatives have been synthesized and screened for their in vitro
antileishmanial activity profile in promastigote and amastigote models by L. Gupta et al.21
N
O
O
NH
N
R1
R2
R1 = R
2 = CH3 = SO2Ph
(5)
I. Collins et al.31 have synthesized new class of N-(indol-3-ylglyoxylyl)piperidines
(6) are high affinity agonists at the benzodiazepine binding site of human GABA-A
receptor ion-channels, with modest selectivity for receptors containing the α1.
Studies on chemical…
Glyoxylamide derivatives… 30
NH
O
O
NO
R1
R1 = OCH2Ph, NHCH2Ph, N(CH3)CH2Ph
(6)
G. Primofiore and coworkers32 have synthesized N-(arylalkyl)indol-3-
ylglyoxylylamides (7) targeted as ligands of the benzodiazepine receptor, as well as
biological evaluation and molecular modeling analysis of the structure activity
relationships reported by them.
NH
R1
O
O
NHR
2
R3
(7)
V. W. Pike et al.33 have evaluated novel N-methyl-2-phenylindol-3-ylglyoxyl-
amides (8) as a new chemo type of 18 kDa translocator protein-selective ligand suitable
for the development of positron emission tomography radioligands.
NCH3
NO2
O
O
NnPr
nPr
(8)
Preparation of 2-[5-[[(6-chloroimidazo[2,1-b]thiazol-5-yl)sulfonyl]amino]-1H-
indol-3-yl]-N,N-dimethyl-2-(oxo)acetamide (9) compounds as 5-HT6 receptor modulators
for use in medicaments was reported by M. V. Ramon et al.34
Studies on chemical…
Glyoxylamide derivatives… 31
NH
O
O
NCH3 CH3
NHSO
ON
NCl
S
(9) W. Tao and coworkers35 have evaluated indole to azaindoles leading to the
discovery of 1-(4-Benzoylpiperazin-1-yl)-2-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-
yl)ethane-1,2-dione as a antiviral activity in HIV-1 infected subjects. J. Wang and
coworkers36 have modified structure-activity relationship of a small molecule HIV-1
inhibitor targeting the viral envelope glycoprotein gp120. M. Pascal et al.37 have
synthesized N-aryl(indol-3-yl)glyoxamides as antitumor agents.
Literature survey reveals that the compounds bearing glyoxamides moiety possess
potential drug activity. Looking to the diversified biological activities we have
synthesized some glyoxamides derivatives in order to achieving better therapeutic agents.
These studies are described in following section.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-[N,N-
DIALKYLAMINE(OXO)ACETYL]-1-PROPYL-1H-INDOLE-2-
CARBOXYLIC ACIDS.
Studies on chemical…
Glyoxylamide derivatives… 32
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-[N,N-
DIALKYLAMINE(OXO)ACETYL]-1-PROPYL-1H-INDOLE-2-CARBOXYLIC
ACIDS.
Heterocyclic compounds bearing Indole-3-yl-glyoxylamide ring system are
endowed with variety of biological activities. Our strategy is based on to develop a new
bioactive entity especially with pharmacological activities bearing heterocyclic ring
system. In view of our ongoing interest in the synthesis of some new Indole-3-yl-
glyoxylamide derivatives, we have under taken the condensation of 1-propyl-1H-indole-
2-carboxylic acid with oxalyl chloride and different secondary amine in the presence of
DCM.
REACTION SCHEME
NH
O
OH N
O
OH
CH3
N
O
OH
CH3
O
R
O
DMFN-Propylbromide
K2CO3 MDC, TEA(ii) Sec. amine
(i) (COCl)2
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Glyoxylamide derivatives… 33
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR
and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Preparation of 1-Propyl-1H-indole-2-carboxylic acid.
To a stirred suspension of K2CO3 (2.72 g, 0.02 mol) and 1H-indole-2-carboxylic
acid (1.61 g, 0.01 mol) in dry DMF (10 ml), 1-bromopropane (1.18 ml, 0.013 mol) was
added dropwise after 5 minute. The resultant solution was stirred for 5 hour at room
temperature, and then poured onto crushed ice, the product was isolated and washed with
water and hexane to give pure product. Yield: 93 %, mp 80-83 oC.
[B] General procedure for the preparation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-
propyl-1H-indole-2-carboxylic acids.
To a stirred cooled (ice bath) solution of 1-propyl-1H-indole-2-carboxylic acid
(2.03 g, 0.01 mol) in dry DCM (15 ml), oxalyl chloride (1.27 ml, 0.015 mol) was added
dropwise in solution. The obtained solution was stirred at 0-5 oC for 10-15 minute then
add TEA (1.68 ml, 0.012 mol) dropwise. The resulting solution was stirred at 0-5 oC for
30.0 minute and then at 25-30 oC for 1 hour. Dark yellow colored was formed. The
solvent was removed in vacuo, the residue was dissolved in dry DCM (12 ml) and
different secondary amine (0.012 mol) dropwise. The reaction mixture was stirred at 0-
5 oC for 30.0 minute and then 25-30 oC for another 30.0 minute (monitored by TLC). The
solvent was removed in vacuo. The product was dissolved in water and extracted with
ethylacetate (25 ml × 3). The combined organic layers were washed with water followed
by brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the
solid was triturated with hexane and resulting precipitate was filtered, washed with
hexane and dried to give analytical pure product. The physical constants of the product
are recorder in Table-1a.
Studies on chemical…
Glyoxylamide derivatives… 34
Table-1a: Physical constant of 3-[N,N-Dialkylamino(oxo)acetyl]-1-propyl-1H-indole-
2-carboxylic acids.
N
O
OH
O
R
O
CH3
Sr. No. Substitution R M. F. M. W. Yield (%) Rf value
1a N O
C18H20N2O5
344.36 83 0.46
1b NCH3
CH3 C18H22N2O4 330.37 80 0.51
1c N N
C24H25N3O4 419.47 79 0.64
1d N
C19H22N2O4
342.38 89 0.38
1e N N CH3
C19H23N3O4
357.40 85 0.47
1f N NCH3
C20H25N3O4
371.43 76 0.39
1g NCH3
CH3
CH3
CH3
C20H26N2O4
358.43 80 0.53
1h N
C18H20N2O4
328.36 82 0.51
1i N
CH3
C20H24N2O4 356.41 84 0.48
1j N CH3
C20H24N2O4
356.41 78 0.60
TLC solvent system:- E.A. : Hexane = 6 : 4
Studies on chemical…
Glyoxylamide derivatives… 35
ANALYTICAL DATA
3-[Morpholin-4-yl(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1a). mp 168-
170 °C; Purity by HPLC: 94 %; IR (KBr): 3446 (O-H, str), 3023 (Ar, C-H str), 2947 (C-H
str), 2805 (C-H str), 1706 (acid, C=O str), 1633 (amide, C=O str), 1528 (Ar, C=C str),
1440 (Ar, C=C str), 1256 (C-H ban), 1152 (C-O str) cm-1; 1H NMR (400 MHz, CDCl3): δ
ppm 0.92-0.96 (t, J=7.32 Hz, 3H, CH3), 1.07-1.25 (m, 2H, CH2), 1.63-1.75 (m, 4H,
2CH2), 3.62-3.66 (t, J=7.08 Hz, 2H, CH2), 3.77-3.87 (m, 4H, 2CH2), 7.30-7.45 (m, 3H,
ArH), 8.30-8.31 (d, J=7.92 Hz, 1H, ArH), 9.77 (s, 1H, OH). 13C NMR (100 MHz,
CDCl3): δ ppm 10.28, 21.81, 41.89, 46.36, 66.27, 112.36, 116.38, 123.07, 123.85,
126.41, 127.48, 129.99, 135.13, 159.00, 166.94, 187.66; MS: m/z = 344 [M]+; Anal.
Calcd for C18H20N2O5: C, 62.78; H, 5.85; N, 8.13. Found: C, 62.67; H, 5.47; N, 8.09%.
3-[(Diethylamino)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1b). mp 133-
134 °C; Purity by HPLC: 91 %; IR (KBr): 3412, 3044, 2983, 2861, 1710, 1673, 1552,
1444, 1287, 1175 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.86-0.89 (t, J=7.4 Hz, 3H,
CH3), 1.29-1.34 (m, 6H, 3CH3), 1.51-1.60 (m, 2H, CH2), 3.41-3.44 (t, J=7.08 Hz, 2H,
CH2), 3.55-3.61 (m, 4H, 2CH2), 7.28-7.30 (m, 1H, ArH), 7.32-7.36 (m, 1H, ArH), 7.45-
7.47 (d, J=8.2 Hz, 1H, ArH), 8.31-8.33 (d, J=8.0 Hz, 1H, ArH), 10.11 (s, 1H, OH). 13C
NMR (100 MHz, CDCl3): δ ppm 10.17, 12.50, 13.73, 21.66, 39.35, 42.72, 66.95, 112.71,
116.09, 122.99, 123.54, 125.99, 127.59, 130.06, 135.24, 158.88, 167.89, 188.32; MS: m/z
= 330 [M]+; Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.36;
H, 6.61; N, 8.37%.
3-[(4-Phenylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1c).
mp 153-155 °C; IR (KBr): 3502, 3101, 2961, 2852, 1708, 1678, 1533, 1456, 1248, 1156
cm-1; MS: m/z = 419 [M]+; Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02.
Found: C, 68.59; H, 5.89; N, 9.95%.
3-[Oxo(piperidin-1-yl)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1d). mp 189-190
°C; IR (KBr): 3432, 3513, 3033, 2988, 2857, 1700, 1689, 1578, 1482, 1252, 1162 cm-1;
MS: m/z = 343 [M+1]+; Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found:
C, 66.53; H, 6.31; N, 8.06%.
3-[(4-Methylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1e).
mp 128-130 °C; IR (KBr): 3501, 3055, 2971, 2868, 1711, 1693, 1561, 1483, 1291, 1158
Studies on chemical…
Glyoxylamide derivatives… 36
cm-1; MS: m/z = 357 [M]+; Anal. Calcd for C19H23N3O4: C, 63.85; H, 6.49; N, 11.76.
Found: C, 63.77; H, 6.45; N, 11.70%.
3-[(4-Ethylpiperazin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1f). mp
136-138 °C; IR (KBr): 3522, 3033, 2999, 2905, 1715, 1694, 1499, 1432, 1240, 1160 cm-
1; MS: m/z = 371 [M]+; Anal. Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found:
C, 64.63; H, 6.72; N, 11.28%.
3-[(N,N-Diisopropylamino)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1g).
mp 171-172 °C; IR (KBr): 3488, 3097, 2986, 2971, 1718, 1701, 1497, 1422, 1285, 1178
cm-1; MS: m/z = 358 [M]+; Anal. Calcd for C20H26N2O4: C, 67.02; H, 7.31; N, 7.82.
Found: C, 66.97; H, 7.28; N, 7.78%.
3-[Oxo(pyrrolidin-1-yl)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1h). mp 201-
203 °C; IR (KBr): 3489, 3098, 2978, 2891, 1706, 1681, 1499, 1488, 1280, 1171 cm-1;
MS: m/z = 328 [M]+; Anal. Calcd for C18H20N2O4: C, 65.84; H, 6.14; N, 8.53. Found: C,
65.79; H, 6.09; N, 8.47%.
3-[(2-Methylpiperidin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1i).
mp 191-193 °C; IR (KBr): 3569, 3099, 2966, 2898, 1720, 1696, 1583, 1467, 1281, 1184
cm-1; MS: m/z = 356 [M]+; Anal. Calcd for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86.
Found: C, 67.35; H, 6.70; N, 7.83%.
3-[(4-Methylpiperidin-1-yl)(oxo)acetyl]-1-propyl-1H-indole-2-carboxylic acid (1j).
mp 149-150 °C; IR (KBr): 3546, 3084, 2997, 2951, 1717, 1687, 1576, 1455, 1279, 1187
cm-1; MS: m/z = 356 [M]+; Anal. Calcd for C20H24N2O4: C, 67.40; H, 6.79; N, 7.86.
Found: C, 67.27; H, 6.73; N, 7.81%.
Studies on chemical…
Glyoxylamide derivatives… 37
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 1a
Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60 : 40, v/v)
Flow rate : 1.0 ml/min
Minutes0 1 2 3 4 5 6 7 8
0
500
10001
.81
3 5
91
6 0
.05
2.4
64
1
03
40
43
4 9
4.5
6
2.8
69
4
35
78
9 3
.98
3.4
13
4
34
74
0
.40
4.0
43
6
05
24
0
.55
4.5
87
1
84
08
0
.17
5.0
24
4
01
0 0
.04
5.3
76
2
58
74
0
.24
7.0
61
1
37
0 0
.01
IR spectra of compound 1a
5007501000125015001750200025003000350040001/cm
30
45
60
75
90
105
%T
3491
.27
3446
.91
3345
.64
3096
.82
3023
.52
2947
.33
2805
.56
1706
.09
1633
.76
1528
.64
1440
.87
1386
.86
1300
.07
1256
.67
1207
.48
1152
.51
1104
.28
992.
4193
8.40
817.
8577
5.41
695.
3662
6.89
537.
1951
3.08
Reaction-90 p1
N
O
OH
OO
CH3
N
O
Studies on chemical…
Glyoxylamide derivatives… 38
Mass spectrum of compound 1a
Mass spectrum of compound 1c
N
O
OH
OO
CH3
N
O
M.Wt. = 344.36
N
O
OH
OO
CH3
N
N
M.Wt. = 419.47
Studies on chemical…
Glyoxylamide derivatives… 39
1H NMR spectrum of compound 1a
Expanded spectrum of compound 1a
N
O
OH
OO
CH3
N
O
Studies on chemical…
Glyoxylamide derivatives… 40
1H NMR spectrum of compound 1b
Expanded spectrum of compound 1b
N
O
OH
OO
CH3
N
CH3 CH3
Studies on chemical…
Glyoxylamide derivatives… 41
13C NMR spectrum of compound 1a
13C NMR spectrum of compound 1b
N
O
OH
OO
CH3
N
O
N
O
OH
OO
CH3
N
CH3 CH3
Studies on chemical…
Glyoxylamide derivatives… 42
ANTIMICROBIAL ACTIVITY
Biological evaluation of 3-[N,N-Dialkylamine(oxo)acetyl]-1-propyl-1H-indole-2-
carboxylic acids.
All of the synthesized compounds (1a-j) were tested for their antibacterial and
antifungal activity (MIC) in vitro by broth dilution method38-40 with two Gram-positive
bacteria Staphylococcus aureus MTCC-96 and Streptococcus pyogenes MTCC 442, two
Gram-negative bacteria Escherichia coli MTCC 443 and Pseudomonas aeruginosa
MTCC 1688 and three fungal strains Candida albicans MTCC 227, Aspergillus Niger
MTCC 282 and Aspergillus clavatus MTCC 1323 taking gentamycin, ampicillin,
chloramphenicol, ciprofloxacin, norfloxacin, nystatin and greseofulvin as standard drugs.
The standard strains were procured from the Microbial Type Culture Collection (MTCC),
Institute of Microbial Technology, Chandigarh, India.
The minimal inhibitory concentration (MIC) values for all the newly synthesized
compounds, defined as the lowest concentration of the compound preventing the visible
growth, were determined by using micro dilution broth method according to NCCLS
standards.38
Minimal Inhibition Concentration [MIC]
The main advantage of the Broth Dilution Method for MIC determination lies in
the fact that it can readily be converted to determine the MIC as well. 1. Serial dilutions were prepared in primary and secondary screening.
2. The control tube containing no antibiotic is immediately subcultured (before
inoculation) by spreading a loopful evenly over a quarter of plate of medium
suitable for the growth of the test organism and put for incubation at 37 0C
overnight.
3. The MIC of the control organism is read to check the accuracy of the drug
concentrations.
4. The lowest concentration inhibiting growth of the organism is recorded as the
MIC.
5. The amount of growth from the control tube before incubation (which represents
the original inoculums) is compared.
Studies on chemical…
Glyoxylamide derivatives… 43
Methods used for primary and secondary screening
Each synthesized compounds was diluted obtaining 2000 μg mL-1 concentration,
as a stock solution. Inoculum size for test strain was adjusted to 108 cfu (colony forming
unit) per milliliter by comparing the turbidity.
Primary screen: In primary screening 1000 μg mL-1, 500 μg mL-1 and 250 μg mL-
1 concentrations of the synthesized compounds were taken. The active synthesized drugs
found in this primary screening were further tested in a second set of dilution against all
microorganisms.
Secondary screen: The compounds found active in primary screening were similarly
diluted to obtain 200 μg mL-1, 100 μg mL-1, 50 μg mL-1, 25 μg mL-1, 12.5 μg mL-1, and
6.250 μg mL-1 concentrations.
Reading Result: The highest dilution showing at least 99 % inhibition zone is taken as
MIC. The result of this is much affected by the size of the inoculums. The test mixture
should contain 108 organism/mL.
The results obtained from antimicrobial susceptibility testing are depicted in
Table 1b.
Studies on chemical…
Glyoxylamide derivatives… 44
Table-1b: Antimicrobial activity of 3-[N,N-Dialkylamino(oxo)acetyl]-1-propyl-1H-
indole-2-carboxylic acids.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
1a 250 250 500 500 1000 1000 1000 1b 250 100 250 500 200 500 500 1c 62.5 100 500 500 >1000 250 250 1d 100 500 250 250 250 500 200 1e 100 250 100 250 500 250 250 1f 500 200 200 100 1000 250 500 1g 200 100 62.5 100 500 500 250 1h 50 100 100 200 500 250 1000 1i 250 500 200 500 250 200 1000 1j 100 500 100 200 250 500 500
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Glyoxylamide derivatives… 45
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Part – A
(Part – II)
Studies on Imidazolone Derivatives
Studies on chemical…
Imidazolones derivatives… 48
INTRODUCTION
Imidazolinone, a five membered heterocycle having 2-nitrogen atoms at the 1 and
3-positions and C=O group at following positions: 2-oxo-imidazoline (1), 4-oxo-
imidazoline (2), 5-oxo-imidazoline (3). Imidazolines are structurally related to guanidines
and amidines.
Imidazolinone has been used extensively as a corrosion inhibitor of certain
transition metals, such as copper. Preventing copper corrosion is important, especially in
aqueous systems, where the conductivity of the copper decreases due to corrosion.
NH
NH
O NH
NHO
NH
NH
O
(1) (2) (3)
The discovery of the 2-substituted-5-imidazolines dates back to the year 1888,
when A. W. Hoffmann1 for the first time discovered 5-oxo-imidazoline by heating N1-
diacetyl ethylene diamine in a stream of dry hydrogen chloride and moreover the same
compound was prepared by A. Ladenburg2 by the fusion of two equivalents of sodium
acetate with one equivalent of ethylene diamine dihydrochloride.
SYNTHETIC ASPECT
Various methods have been reported for the synthesis of imidazolinones in
literature.3 Aminolysis of oxazolone with amines led to the formation of imidazolinones
which has been reported in literature.4
1. Saxena et al.5 have synthesized new imidazolinone derivatives (4) by the reaction
of hydrazide with azalactone in dry pyridine.
N
O
Ar
O O
NHNH2Cl
dry pyridineN
N NH
OAr O
Cl
(4) 2. X. Huang et al.6 have synthesized some new imidazolinone derivatives (5) by the
reaction of halide with acetonitrile in presence of K2CO3.
Studies on chemical…
Imidazolones derivatives… 49
Cl
COOEt
N=C=S
R1NH2
CH3CN
Cl
NHN
O
R1
S
R2X,CH3CN
K2CO3
Cl
NN
O
SR2
R1
R1=n-Pr,R2=Aryl (5) 3. A. V. Patel et al.7 have synthesized new Imidazolinone derivatives by
conventional method.
4. Z. Han et al.8 have synthesized 5-imidazolinone derivatives with 2-bromo- acetic
acid as a starting material.
REACTION MECHANISM
Azalactone reacts with variety of compounds such as water, alcohols, amines and
hydrogen halides. Amides of α-acylamino acrylic acids obtained from the condensation of
azalactone and primary amine can be converted to imidazolinone as shown under.
N O
OR
X XO
NH NH
OR
R'R'-NH2 POCl3 N N
R
X
R'
R' = NH2, Dry C5H5N/Abs.C2H5OH, K2CO3
The ring closer can be affected under a variety of conditions. Substituted anilides
have been converted to imidazolinone derivatives by the action of POCl3.
THERAPEUTIC IMPORTANCE
Naphazoline hydrochloride, xylometazoline hydrochloride etc. are various
imidazolinone derivatives which have been used as adrenergic stimulants and tolazoline
and phentolamine as adrenergic blocking agents. Various imidazolinones are known to
exhibit a broad spectrum of biological activities such as:
1. Antitubercular9
2. Anti cancer10
Studies on chemical…
Imidazolones derivatives… 50
3. Insecticidal11
4. Antiviral12
5. Hypertensive13
6. Antiinflammatory14
7. Glucagon antagonists15
8. Antimicrobial16
9. Antihistaminic17
10. Antidiabetic18
P. Sah and coworkers19 have prepared some new imidazolinones and reported
their antimicrobial and antileishmanial activities. K. M. Khan et al.20 have reported
antibacterial and fungicidal activity of 5-oxo-imidazolines. Herbicidal activity of
imidazolinone derivatives have been reported by Wang Ying et al.21 Y. Zhou et al.22 and
A. Pai et al.23 have reported anticancer active analogues of 5-oxo-imidazolines.
Imidazolinone derivatives which possess antifungal activity have been reported by M. D.
Shah et al.24 Some new 5-oxoimidazolines as antimicrobial agents have been
investigated P. S. Patel et al.25 V. Leroy and coworkers26 have prepared substituted
imidazolone derivatives and reported their pharmaceutical use as inhibitors of protein
kinases, particularly CDC7 and antiproliferative agents. N. Xue et al.27 have synthesized
and evaluated imidazol-2-one derivatives (6) as potential antitumor agents.
H3CO
H3CO
H3CO
NN CH3
OO
(6) Work done from our laboratory
A. M. Vyas28 have synthesized 1-aryl-2-methyl-4-(8-hydroxyquinolin-7-yl
methine)-5-imidazolones. Synthesis of some new imidazolones and 1,2,4-triazoles
bearing benzo[b]thiophene nucleus as antimicrobial agents have been reported by K. M.
Thakar.29 1-N-substituted benzalaminothiocarbonyl-2-methyl-4-(8'-hydroxyquinolin-7'-
yl)methine-5-imidazolones have been reported by A. M. Vyas.30
Studies on chemical…
Imidazolones derivatives… 51
Literature survey reveals that the compounds bearing imidazolones moiety
possess potential drug activity. Looking to the diversified biological activities we have
synthesized some imidazolinone derivatives in order to achieving better therapeutic
agents. These studies are described in following section.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF N-[(4Z)-4-
ARYLIDENE-5-OXO-2-PHENYL-4,5-DIHYDRO-1H-IMIDAZOL-1
-YL]-1H-INDOLE-2-CARBOXAMIDES.
Studies on chemical…
Imidazolones derivatives… 52
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF N-[(4Z)-4-ARYLIDENE-5-
OXO-2-PHENYL-4,5-DIHYDRO-1H-IMIDAZOL-1-YL]-1H-INDOLE-2-
CARBOXAMIDES.
Various imidazolinone have resulted in many potential drugs and are known to
possess a broad biological spectrum. In view of getting better therapeutic agents and
considering the association of various biological activities with Indole-2-carbohydrazide
nucleus, the preparation of imidazolone have been undertaken by the condensation of 1H-
indole-2-carbohydrazide with substituted azalactones which in turn have been prepared by
well known Ertenmeyer azalactone synthesis.
REACTION SCHEME
NH
O
OH NH
O
O CH3 NH
O
NH NH2
ON
H5C6
R O
Pyridine
MeOH
Con. H2SO4
MeOHHydrazine Hydrate
NH
N
O
NN
OR
H
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Imidazolones derivatives… 53
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned. [A] Synthesis of 1H-Indole-2-carbohydrazide.31
Methyl 1H-indole-2-carboxylate (1.75 g, 0.01 mol) in absolute ethanol (25 ml)
was refluxed with 1.0 ml of hydrazine hydrate for 2 hour. After the completion of the
reaction checked by TLC, the reaction mixture was cooled to room temperature. The
separated solid was filtered, washed with cold ethanol and recrystallized from ethanol.
Yield 98%, m.p 247-248 °C. [B] Synthesis of 4-Arylidene-2-phenyl-5-oxazolinones.
These were prepared by the condensation of substituted benzaldehyde with
benzoyl glycine in presence of sodium acetate and acetic anhydride as described by
Vogel.32
[C] General procedure for the preparation of N-[(4Z)-4-Arylidene-5-oxo-2-
phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-carboxamides.
To a mixture of 1H-indole-2-carbohydrazide (1.75 g, 0.01 mol) and different 4-
arylidene-2-phenyl-5-oxazolinones (0.01 mol) in a pyridine (15 ml) was refluxed for 8-10
hour (monitoring by TLC). The excess of solvent was removed under reduced pressure
and reaction mixture was poured on crushed ice. The product was isolated and
crystallized from methanol to give analytical pure product. The physical constants of the
product are recorded in Table-2a.
[D] Biological evaluation of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-
imidazol-1-yl]-1H-indole-2-carboxamides.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-2b.
Studies on chemical…
Imidazolones derivatives… 54
Table-2a: Physical constant of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-1H-
imidazol-1-yl]-1H-indole-2-carboxamides.
NH
N
O
NN
RO
H
Sr. No Substitution R M. F. M. W. Yield (%) Rf value
2a
O CH3
C26H20N4O3 436.36 73 0.39
2b N+
O-
OC25H17N5O4 451.43 68 0.43
2c CH3 C26H20N4O2 420.46 74 0.53
2d
C25H18N4O2 406.43 78 0.36
2e Cl
C25H17ClN4O2 440.88 71 0.47
2f N
+O-
O
C25H17N5O4 451.43 70 0.62
2g OH C25H18N4O3 422.43 68 0.66
2h F
C25H17FN4O2 424.42 65 0.38
2i OCH3
C26H20N4O3 436.46 81 0.48
2j
O
O
CH3
CH3
C27H22N4O4 466.48 76 0.44
TLC solvent system:- E.A. : Hexane = 3 : 7
Studies on chemical…
Imidazolones derivatives… 55
ANALYTICAL DATA
N-[(4Z)-4-(2-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-
1H-indole-2-carboxamide (2a). mp 236-238 °C; Purity by HPLC: 99 %; IR (KBr): 3338
(N-H str), 3059 (Ar, C-H str), 2926 (C-H str), 2847 (C-H str), 1647 (amide, C=O str),
1591 (C=N str), 1570 (Ar, C=C str), 1508 (Ar, C=C str), 1271 (C-H ban), 1026 (C-N str),
810 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 3.92 (s, 3H, OCH3), 6.84-
6.98 (m, 2H, ArH), 6.99-7.09 (m, 2H, ArH), 7.14-7.21 (m, 3H, ArH), 7.39-7.50 (m, 3H,
ArH), 7.52-7.60 (m, 1H, ArH), 7.74-7.79 (m, 1H, ArH), 7.98 (s, 1H, C=CH), 8.05-8.07
(d, J=7.12 Hz, 2H, ArH), 8.54 (s, 1H, NH), 10.75 (s, 1H, NH). 13C NMR (100 MHz,
CDCl3): δ ppm 55.66, 115.20, 124.06, 124.21, 124.42, 126.10, 127.20, 127.29, 127.95,
128.10, 128.95, 129.27, 129.40, 129.99, 130.08, 130.74, 137.27, 141.20, 157.35, 159.57,
189.06; MS: m/z = 437 [M+1]+; Anal. Calcd for C26H20N4O3: C, 71.55; H, 4.62; N, 12.84.
Found: C, 71.29; H, 4.47; N, 12.61%.
N-[(4Z)-4-(4-Nitrobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-
indole-2-carboxamide (2b). mp 213-215 °C; Purity by HPLC: 96 %; IR (KBr): 3443,
3068, 1697, 1591, 1522, 1445, 1260, 1040, 820 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm
7.42-7.52 (m, 3H, ArH), 7.54-7.63 (m, 3H, ArH), 7.65-7.75 (m, 1H, ArH), 7.84-7.85 (d,
J=7.08 Hz, 1H, ArH), 8.09-8.13 (m, 2H, ArH), 8.24-8.27 (d, J=11.84 Hz, 2H, ArH), 8.35
(s, 1H, C=CH), 8.52 (s, 1H, NH), 8.78-8.86 (m, 2H, ArH), 10.73 (s, 1H, NH). 13C NMR
(100 MHz, CDCl3): δ ppm 115.72, 127.60, 127.80, 128.00, 129.74, 130.20, 130.41,
130.65, 131.02, 131.72, 132.10, 132.40, 133.27, 133.62, 134.10, 137.60, 141.10, 157.48,
160.12, 191.16; MS: m/z = 451 [M]+; Anal. Calcd for C25H17N5O4: C, 66.51; H, 3.80; N,
15.51. Found: C, 66.25; H, 3.76; N, 15.42%.
N-[(4Z)-4-(4-Methylbenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-
indole-2-carboxamide (2c). mp 179-180 °C; IR (KBr): 3466, 3075, 1681, 1613, 1499,
1402, 1261, 1025, 840 cm-1; MS: m/z = 420 [M]+; Anal. Calcd for C26H20N4O2: C, 74.27;
H, 4.79; N, 13.33. Found: C, 73.95; H, 4.70; N, 13.21%.
N-[(4Z)-4-Benzylidene-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-indole-2-
carboxamide (2d). mp 163-165 °C; IR (KBr): 3469, 3076, 1706, 1646, 1576, 1466,
1281, 1021, 746 cm-1; MS: m/z = 406 [M]+; Anal. Calcd for C25H18N4O2: C, 73.88; H,
4.46; N, 13.78. Found: C, 73.58; H, 4.40; N, 13.67%.
Studies on chemical…
Imidazolones derivatives… 56
N-[(4Z)-4-(4-Chlorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-
indole-2-carboxamide (2e). mp 225-224 °C; IR (KBr): 3459, 3077, 1694, 1634, 1597,
1464, 1261, 1013, 866 cm-1; MS: m/z = 440 [M]+; Anal. Calcd for C25H17ClN4O2: C,
68.11; H, 3.89; N, 12.71. Found: C, 67.82; H, 3.81; N, 12.54%.
N-[(4Z)-4-(3-Nitrobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-
indole-2-carboxamide (2f). mp 183-184 °C; IR (KBr): 3492, 3064, 1705, 1625, 1599,
1406, 1242, 1039, 723 cm-1; MS: m/z = 452 [M+1]+; Anal. Calcd for C25H17N5O4: C,
66.51; H, 3.80; N, 15.51. Found: C, 66.18; H, 3.75; N, 15.39%.
N-[(4Z)-4-(4-Hydroxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-
1H-indole-2-carboxamide (2g). mp 151-153 °C; IR (KBr): 3469, 3003, 1691, 1589,
1565, 1482, 1250, 1044, 716 cm-1; MS: m/z = 422 [M]+; Anal. Calcd for C25H18N4O3: C,
71.08; H, 4.29; N, 13.26. Found: C, 70.84; H, 4.18; N, 13.08%.
N-[(4Z)-4-(4-Fluorobenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-1H-
indole-2-carboxamide (2h). mp 138-139 °C; IR (KBr): 3454, 3086, 1712, 1602, 1546,
1445, 1016, 747 cm-1; MS: m/z = 425 [M+1]+; Anal. Calcd for C25H17FN4O2: C, 70.75; H,
4.04; N, 13.20. Found: C, 70.21; H, 3.98; N, 13.07%.
N-[(4Z)-4-(4-Methoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl]-
1H-indole-2-carboxamide (2i). mp 173-174 °C; IR (KBr): 3394, 3074, 1688, 1592,
1572, 1465, 1028, 727 cm-1; MS: m/z = 436 [M]+; Anal. Calcd for C26H20N4O3: C, 71.55;
H, 4.62; N, 12.84. Found: C, 71.16; H, 4.51; N, 12.63%.
N-[(4Z)-4-(2,5-Dimethoxybenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-
yl]-1H-indole-2-carboxamide (2j). mp 201-202 °C; IR (KBr): 3386, 3056, 1690, 1587,
1585, 1464, 1024, 723 cm-1; MS: m/z = 467 [M+1]+; Anal. Calcd for C27H22N4O4: C,
69.52; H, 4.75; N, 12.01. Found: C, 69.27; H, 4.63; N, 11.94%.
Studies on chemical…
Imidazolones derivatives… 57
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 2a
Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 2a
Minutes0 1 2 3 4 5 6 7 8 9 10
mA
U
0
250
500
750
1.46
1 1
484
0.0
21.
664
197
0.0
01.
909
347
4 0
.05
2.53
9 2
378
0.0
3
2.95
5 1
063
0.0
13.
200
263
0.0
03.
381
199
0.0
03.
701
598
6 0
.08
4.39
5 7
3548
94 9
9.72
5.08
8 1
145
0.0
2
5.95
2 3
56 0
.00
6.49
6 2
382
0.0
3
7.77
6 1
616
0.0
2
5007501000125015001750200025003000350040001/cm
20
40
60
80
100
%T
3543
.35
3392
.90
3338
.89 32
38.5
930
59.2
029
26.1
128
47.0
3
1647
.26
1591
.33
1570
.11
1548
.89
1508
.38
1406
.15
1340
.57
1271
.13
1224
.84
1168
.90
1026
.16
837.
1381
0.13 55
7.45
507.
3044
7.50
KAJ-CHAL-OME
NH
N
O
NN
OO
CH3
H
Studies on chemical…
Imidazolones derivatives… 58
Mass spectrum of compound 2a
Mass spectrum of compound 2c
NH
N
O
NN
OO
CH3
H
M. Wt. = 436.46
NH
N
O
NN
O
H CH3
M. Wt. = 420.46
Studies on chemical…
Imidazolones derivatives… 59
1H NMR spectrum of compound 2a
Expanded spectrum of compound 2a
NH
N
O
NN
OO
CH3
H
Studies on chemical…
Imidazolones derivatives… 60
1H NMR spectrum of compound 2b
Expanded spectrum of compound 2b
NH
N
O
NN
O
HN
+
O-
O
Studies on chemical…
Imidazolones derivatives… 61
13C NMR spectrum of compound 2a
13C NMR spectrum of compound 2b
NH
N
O
NN
OO
CH3
H
NH
N
O
NN
O
HN
+
O-
O
Studies on chemical…
Imidazolones derivatives… 62
Table-2b: Antimicrobial activity of N-[(4Z)-4-Arylidene-5-oxo-2-phenyl-4,5-dihydro-
1H-imidazol-1-yl]-1H-indole-2-carboxamides.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
2a 100 50 62.5 100 200 500 250 2b 200 200 100 250 500 200 500 2c 100 100 250 250 500 1000 1000 2d 500 250 500 100 250 250 500 2e 500 500 100 100 500 1000 1000 2f 250 500 100 500 1000 250 500 2g 250 100 200 200 >1000 200 250 2h 200 250 100 500 500 1000 250 2i 500 500 500 250 500 500 500 2j 200 500 250 250 250 500 200
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Imidazolones derivatives… 63
REFERENCES
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2. A. Ladenburg, Ibid., 27, 2952 (1894).
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Gaikwad, R. P. Tripathi, Eur. J. Med. Chem., 44(8), 3350-3355 (2009).
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Pal-Bhadra, Bioorg. Med. Chem. Lett., 20(16), 4865-4869 (2010). 11. C. Gary, S. Thomas, M. Casandra, D. David, B. Kristy, B. Annette, D. William, C.
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McCormick, J. J. Piwinski, R. E. West, J. C. Anthes, S. M. Williams, W. Ren-Long, S. H.
Susan, M. A. Rivelli, J. C. Mutter, M. R. Corboz, J. A. Hey, F. Leonard, Bioorg. Med.
Chem. Lett., 16(2), 395-399 (2006).
18. K. S. Shia, C. H. Wu, T. K. Yeh, Y. S. Chao, U.S. Pat. Appl.
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Drug Design & Discovery, 6(1), 69-77 (2009).
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22. Y. Zhou, Y. Li, J. Zhu, J. Lv, Y. Li, C. Zheng, H. Tang, Faming Zhuanli Shenqing
Gongkai Shuomingshu CN 101691357 A 20100407 (2010).
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Part – A
(Part – III)
Studies on Oxadiazole Derivatives
Studies on chemical…
Oxadiazole derivatives… 65
INTRODUCTION
Oxadiazoles belong to an important group of heterocyclic compounds
having –N=C-O- linkage. It is well documented that oxadiazole system contains
the following members which are numbered by designating the hetero atoms at
particular position.
NN
ON
O
NN
ON
N
O
N
(1) (2) (3) (4)
1,3,4-Oxadiazole is a heterocyclic molecule with oxygen atom at 1 and two
nitrogen atoms at 3 and 4 position. 1,3,4-Oxadiazole is a thermally stable aromatic
molecule.1 They have been known for about 80 years it is only in the last decade
that investigations in this field have been intensified. This is because of large number
of applications of 1,3,4-oxadiazoles in the most diverse areas viz. drug
synthesis, dye stuff industry, heat resistant materials, heat resistant polymers and
scintillators. Reviews of the relevant literature prior to 1965 are available.2
SYNTHETIC ASPECT
Most 1,3,4-oxadiazoles are best obtained by synthesis from acyclic precursors.
Such reactions are ‘one bond’ or ‘two bond’ cyclization. Different methods for the
synthesis have been cited in literature.3-8 1. B. Chandrakantha et al.9 have synthesized oxadiazoles (5) by the reaction of
hydrazide and aromatic acid in presence of POCl3.
O
NH
ONH2
F
O
F N
O
NRPOCl3 + R-COOH
110 oC
(5)
2. D. Ramesh and B. Sreenivasan10 have synthesized 1,3,4-oxadiazoles (6) from
semicarbazide in presense of POCl3.
Studies on chemical…
Oxadiazole derivatives… 66
N N
NH O
NHNH
O
POCl3Ref. 4 h. N N
NH N
ON
R(6)
3. K. Mogilaiah and B. Sakram11 have prepared 1,3,4-oxadiazoles (7) from
acetophenone-2-trifluoromethyl-1,8-naphthyridine-3-carbonyl hydrazone in
presence of acetic anhydride.
N N
NH
O
CF3
N
Ar
AC2O
N N CF3
N
O
N
O
Ar
(7) 4. Yu Yuve have reported microwave-assisted synthesis protocol of oxadiazoles (8)
with 91 % of the yield.12
R NH
ONH2
R1
O
OH O
N N
R R1
(8)
POCl3MW, 12 min
+
5. L. Somogyi13 synthesized 1,3,4-oxadiazoles (9) from several steps, from aryl
hydrazides and aryl aldehydes.
RNH
O
NH2
R1
OAc Cl
O
N N
R R1
(9)
+ +
6. Silica sulfuric acid catalyst used for the rapid and ecofriendly synthesis of 1,3,4-
oxadiazoles (10) at ambient temperature reported by M. Dabiri et al.14
R C(OEt)3 R1
NH
O
NH2O
N N
R R1
Silica, H 2SO4
MW,10min
(10)
+
7. Green chemistry and one-pot, solvent-free using microwave mediated synthesis of
Studies on chemical…
Oxadiazole derivatives… 67
1,3,4-oxadiazoles (11) were reported by V. Polshettiwar.15
R C(OEt)3 R1
NH
O
NH2 O
N N
R R1
(11)
MW80
oC, 10 min
+
REACTION MECHANISM
N
CH3
O
NH NH2
Cl CR
O+
..
N
CH3
O
NH N+H
C
H
O-
R
Cl
N
CH3
O
NH N+H
C
H
OR-Cl
N
CH3
O
NH N
H
CO
R
-H+
N
CH3
O+
N N
H
C
O-
R
H
N
CH3
N+
O
N
HH
O-
R
N
CH3
N
O
NH
OH
R N
CH3
N
O
N
R-H 2O
THERAPEUTIC IMPORTANCE
2,5-Disubstituted-1,3,4-oxadiazole derivatives have been tested for various
pharmacological activities, which have been summarized as under.
1. Antibacterial16
2. Antiinflammatory17
3. Analgesic18
4. Antiviral and anticancer19
5. Antihypertensive20
6. Anticonvulsant21
7. Antiproliferative22
8. Antifungal23
9. Cardiovascular24
Studies on chemical…
Oxadiazole derivatives… 68
10. Herbicidal25
11. Hypoglycemic26
12. Hypnotic and Sedative27
13. MAO inhibitor28
14. Insecticidal29
S. R. Bishnoi et al.30 have screened oxadiazoles for their antimicrobial activity.
A. El-Azzouny et al.31 have synthesized 1,3,4-oxadiazole derivatives and evaluated for
their analgesic, anti-inflammatory, ulcerogenic effects and inhibitory activity on
plasma prostaglandin E2 (PGE2) Level.
S. V. Bhandari et al.32 have reported 1,3,4-oxadiazoles for their anti-
inflammatory activity. Song Cao et al.33 have investigated some oxadiazoles possessing
insecticidal activity. G. V. Suresh Kumar et al.34 have discovered oxadiazole derivatives
and reported their antimycobacterial activity. Ali Almasired et al.35 have prepared 1,3,4-
oxadiazoles of type (12) as anticonvulsant agent. Meria Grazia Mamolo et al.36 have
synthesized 3-substituted-5-(pyridine-4-yl)-3H-1,3,4-oxadiazole-2-ones of type (13)
and studied their antimycobacterial activity.
O
N N
ONH2
F
(12)
NO
N NX
O
(13)
Krishna Kant Jha et al.37 have reported antimicrobial activity of oxadiazole
derivatives. J. A. Christopher et al.38 have documented human immunodeficiency virus
(HIV) infection of 1,3,4-oxadiazole derivatives. S. J. Gilani et al.39 have synthesized
some oxadiazoles as anti-inflammatory and analgesic agents. K. Subrahmanya Bhat et
al.40 have prepared new fluorine containing 1,3,4-oxadiazoles (14) and reported them as
potential antibacterial and anticancer agents. T. P. Mohan et al.41 have synthesized
2,5-disubstituted-1,3,4-oxadiazole derivatives (15) and screened for their insecticidal
activity.
Studies on chemical…
Oxadiazole derivatives… 69
(14)
O
CH3 CH2O
N N
R
(15)
N
O
N
ClCl
F R
Ronald Kim et al.42 have discovered oxadiazole derivatives useful as protease
inhibitors. Mohd Amir and Kumar Shikha43 have documented anti-inflammatory,
analgesic and ulcerogenic activity of some newly synthesized oxadiazoles. A. Ali et
al.44 have investigated some oxadiazole derivatives possessing antimicrobial and
anti-HIV-1 activity. A. Sherif et al.45 have reported oxadiazoles as potential
antitumor and anti-HIV agents. A. Zarghi et al.46 have synthesized R-substituted-5-
(2-benzyloxyphenyl)-1,3,4-oxadiazoles (16) possessing anticonvulsant activity. M.
Tareq et al.47 have synthesized 2,5-disubstituted-1,3,4-oxadiazoles (17) useful as
tyrosinase inhibitors.
N
O
NNH2
O
F(16)
N
O
NBr
N(17)
Work done from our laboratory
K. M. Thaker48 have synthesized 2-(3',5'-dichlorobenzo[b]thiophen-2'-yl)-5-
aryl-1,3,4-oxadiazoles in the presence of aromatic acid. S. L. Vasoya49 reported facile
synthesis of some new acetyl oxadiazoles bearing benzo[b]thiophene nucleus as a
potent biological active agent. Preparation and antimicrobial activity of 2-aryl-5-(5',7'-
diiodo-8'-quinolinoxy)-1,3,4-oxadiazoles have been reported by H. S. Joshi.50 Thus
with an effort to capitalize the biological potential of the heterocyclic system and to
provide more interesting compounds for biological screening, we have under taken the
synthesis of several oxadiazoles which has been described as under.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(5-ARYL-
1,3,4-OXADIAZOL-2-YL)-1-PROPYL-1H-INDOLES.
Studies on chemical…
Oxadiazole derivatives… 70
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(5-ARYL-1,3,4-
OXADIAZOL-2-YL)-1-PROPYL-1H-INDOLES.
Synthesis of 1,3,4-oxadiazole derivatives has attracted considerable attention
in view of therapeutic applications. Looking to this, the synthesis of 1,3,4-
oxadiazoles was undertaken by the condensation of different aromatic acid with 1-
propyl-1H-indole-2-carbohydrazide in presence of phosphorous oxychloride, as
show in reaction scheme.
REACTION SCHEME
N
CH3
O
OH N
O
O CH3
CH3
N
O
NH NH2
CH3
MeOHHydrazine Hydrate
MeOH
Con. H2SO4
R-COOHPOCl3
N
CH3
N
O
N
R
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Oxadiazole derivatives… 71
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Synthesis of 1-Propyl-1H-indole-2-carbohydrazide.
Methyl 1-propyl-1H-indole-2-carboxylate (2.17 g, 0.01 mol) in absolute ethanol
(25 ml) was refluxed with hydrazine hydrate (1.0 ml) for 2 hour. After the completion of
the reaction checked by TLC, the reaction mixture was cooled to room temperature. The
separated solid was filtered, washed with cold ethanol and crystallized from ethanol.
[B] General procedure for the preparation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-
propyl-1H-indole.
A mixture of 1-propyl-1H-indole-2-carbohydrazide (2.17 g, 0.01 mol) and
different aryl acids (0.01 mol) in phosphorous oxychloride (10 ml), was refluxed with
continuous stirring. After completion the reaction (8-10 hour monitoring by TLC), the
content was cooled to room temperature then add ice cooled water and neutralized with
sodium bicarbonate solution. Then extracted into ethyl acetate. The organic extracts was
washed with water (2 x 10 ml), dried with Na2SO4, solvent was removed in vacuo and the
resulting crude product was purified by colum chromatography to give the analytical pure
compound. The physical constants of the product are recorded in Table-3a.
[C] Biological evaluation of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indole.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-3b.
Studies on chemical…
Oxadiazole derivatives… 72
Table-3a: Physical constant of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-indoles.
N
CH3
N
O
N
R
Sr. No Substitution R M. F. M. W. Yield (%) Rf value
3a
Cl
C19H16ClN3O
337.80 83 0.42
3b N
+O
-
O C19H16N4O3
348.35 79 0.39
3c OCH3
C20H19N3O2
333.38 85 0.51
3d NH2
C19H18N4O
318.37 91 0.47
3e
Cl
C19H16ClN3O
337.80 86 0.52
3f N
+O
-
O
C19H16N4O3
348.35
76
0.56
3g F
C19H16FN3O
321.34 77 0.49
3h
Cl
N+
O-
O
C19H15ClN4O3
382.80 71 0.36
3i N
C18H16N4O
304.34 81 0.63
3j
OH
C19H17N3O2
319.35 78 0.61
TLC solvent system:- E.A. : Hexane = 2 : 8
Studies on chemical…
Oxadiazole derivatives… 73
ANALYTICAL DATA
2-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3a). mp 133-135 °C;
Purity by HPLC: 87 %; IR (KBr): 3001 (Ar, C-H str), 2933 (C-H str), 2908 (C-H str),
1626 (oxadiazole, C=N str ), 1585 (Ar, C=C str), 1533 (Ar, C=C str), 1465 (C-O-C str),
1172 (N-N str), 748 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.96-1.00
(t, J=7.44 Hz, 3H, CH3), 1.87-1.96 (m, 2H, CH2), 4.70-4.74 (t, J=7.48 Hz, 2H, CH2),
7.16-7.20 (m, 1H, ArH), 7.33-7.37 (m, 2H, ArH), 7.44-7.55 (m, 3H, ArH), 7.70-7.72 (d,
J=8.0 Hz, 1H, ArH), 8.03-8.05 (m, 1H, ArH), 8.11-8.12 (m, 1H, ArH). 13C NMR (100
MHz, CDCl3): δ ppm 11.28, 23.57, 46.75, 107.13, 110.53, 120.75, 122.09, 122.33,
124.67, 125.07, 125.33, 126.93, 126.94, 130.52, 131.84, 135.27, 139.10, 159.87, 162.44;
MS: m/z = 340 [M+2]+; Anal. Calcd for C19H16ClN3O: C, 67.56; H, 4.77; N, 12.44.
Found: C, 66.89; H, 4.68; N, 12.36%.
2-[5-(3-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3b). mp 148-149 °C;
Purity by HPLC: 86 %; IR (KBr): 3064, 2972, 2859, 1700, 1643, 1576, 1435, 1141, 720
cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.97-1.00 (t, J=7.28 Hz, 3H, CH3), 1.89-1.99
(m, 2H, CH2), 4.91-4.95 (t, J=7.48 Hz, 2H, CH2), 7.33-7.37 (m, 1H, ArH), 7.50-7.54 (m,
3H, ArH), 7.62-7.63 (d, J=7.08 Hz, 1H, ArH), 7.87-7.89 (d, J=7.4 Hz, 1H, ArH), 8.20-
8.23 (m, 2H, ArH), 8.28-8.30 (m, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 11.10,
22.17, 47.10, 109.00, 112.00, 121.15, 121.50, 121.99, 126.01, 126.50, 126.94, 128.30,
128.55, 131.01, 132.31, 136.70, 140.57, 160.13, 164.17; MS: m/z = 348 [M]+; Anal.
Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C, 65.18; H, 4.57; N, 15.93%.
2-[5-(4-Methoxyphenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3c). mp 123-125
°C; IR (KBr): 3030, 2964, 2853, 1642, 1612, 1581, 1471, 1156, 819 cm-1; MS: m/z =
334 [M+1]+; Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.35;
H, 5.64; N, 12.55%.
4-[5-(1-Propyl-1H-indol-2-yl)-1,3,4-oxadiazol-2-yl]aniline (3d). mp 117-119 °C; IR
(KBr): 3074, 2987, 2851, 1645, 1612, 1585, 1468, 1184, 820 cm-1; MS: m/z = 318 [M]+;
Anal. Calcd for C19H18N4O: C, 71.68; H, 5.70; N, 17.60. Found: C, 71.28; H, 5.63; N,
17.54%.
2-[5-(2-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3e). mp 109-111 °C;
IR (KBr): 3081, 2975, 2844, 1641, 1579, 1556, 1464, 1202, 750 cm-1; MS: m/z = 338
Studies on chemical…
Oxadiazole derivatives… 74
[M+1]+; Anal. Calcd for C19H16ClN3O: C, 67.56; H, 4.77; N, 12.44. Found: C, 67.20; H,
4.61; N, 12.33%.
2-[5-(4-Nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3f). mp 178-179 °C;
IR (KBr): 3080, 2983, 2867, 1629, 1572, 1525, 1462, 1245, 1196, 830 cm-1; MS: m/z =
348 [M]+; Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C, 65.03; H,
4.48; N, 15.83%.
2-[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3g). mp 165-167 °C;
IR (KBr): 3077, 2978, 2863, 1625, 1609, 1563, 1464, 1238, 1142, 870 cm-1; MS: m/z =
323 [M+2]+; Anal. Calcd for C19H16FN3O: C, 71.01; H, 5.02; N, 13.08. Found: C, 70.65;
H, 5.00; N, 12.91%.
2-[5-(2-Chloro-5-nitrophenyl)-1,3,4-oxadiazol-2-yl]-1-propyl-1H-indole (3h). mp 139-
141 °C; IR (KBr): 2962, 2854, 1603, 1545, 1542, 1452, 1260, 1146 cm-1; MS: m/z = 383
[M+1]+; Anal. Calcd for C19H15ClN4O3: C, 59.61; H, 3.95; N, 14.64. Found: C, 59.35; H,
3.87; N, 14.54%.
1-Propyl-2-[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]-1H-indole (3i). mp 141-143 °C; IR
(KBr): 3075, 2964, 2853, 1721, 1601, 1581, 1423, 1149, 720 cm-1; MS: m/z = 304 [M]+;
Anal. Calcd for C18H16N4O: C, 71.04; H, 5.30; N, 18.41. Found: C, 70.65; H, 5.07; N,
18.37%.
2-[5-(1-Propyl-1H-indol-2-yl)-1,3,4-oxadiazol-2-yl]phenol (3j). mp 184-186 °C; IR
(KBr): 3061, 2951, 2872, 1689, 1589, 1579, 1462, 1099, 755 cm-1; MS: m/z = 319 [M]+;
Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C, 71.08; H, 5.21; N,
13.01%.
Studies on chemical…
Oxadiazole derivatives… 75
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 3a
Column : Phenomenex Luna C8 (2) (250mm x 4.6mm i.d., 5 μm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 3a
Minutes0 2 4 6 8 10 12 14
mA
U
0
200
400
0.30
9 0
.01
344
2.06
9 0
.25
102
792.
325
0.4
1 1
6795
2.82
7 1
0.66
433
927
3.50
9 0
.23
941
3
4.00
0 0
.27
109
84
4.70
4 0
.11
436
7
5.48
3 0
.08
332
8
6.04
8 0
.13
515
5
6.78
4 8
7.31
355
5119
7.78
7 0
.32
129
83
8.78
9 0
.09
368
1
11.6
59 0
.01
348
5007501000125015001750200025003000350040001/cm
30
45
60
75
90
105
%T
3001
.34
2933
.83
2908
.75
2850
.88 16
87.7
716
26.0
515
85.5
415
33.4
614
65.9
5
1344
.43
1292
.35
1197
.83
1172
.76
1122
.61 10
93.6
710
49.3
110
10.7
398
7.59
902.
7282
9.42
748.
41 709.
8365
1.96
569.
0250
5.37
464.
86
JP- 504
N
CH3
N
O
N
Cl
Studies on chemical…
Oxadiazole derivatives… 76
Mass spectrum of compound 3a
Mass spectrum of compound 3c
N
CH3
N
O
N
Cl
M. Wt. = 337.80
N
CH3
N
O
N
OCH3
M. Wt. = 333.38
Studies on chemical…
Oxadiazole derivatives… 77
1H NMR spectrum of compound 3a
Expanded spectrum of compound 3a
N
CH3
N
O
N
Cl
Studies on chemical…
Oxadiazole derivatives… 78
1H NMR spectrum of compound 3b
Expanded spectrum of compound 3b
N
CH3
N
O
N
N+
O-
O
Studies on chemical…
Oxadiazole derivatives… 79
13C NMR spectrum of compound 3a
13C NMR spectrum of compound 3b
N
CH3
N
O
N
Cl
N
CH3
N
O
N
N+
O-
O
Studies on chemical…
Oxadiazole derivatives… 80
Table-3b: Antimicrobial activity of 2-(5-Aryl-1,3,4-oxadiazol-2-yl)-1-propyl-1H-
indoles.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
3a 500 500 200 250 1000 250 500 3b 100 200 250 62.5 500 500 1000 3c 250 250 100 200 1000 500 500 3d 50 100 500 250 200 250 200 3e 250 200 500 100 250 1000 500 3f 500 250 250 200 >1000 500 200 3g 250 100 100 500 500 250 500 3h 250 500 500 200 250 500 1000 3i 200 500 200 150 250 500 500 3j 62.5 100 100 100 200 200 250
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Oxadiazole derivatives… 81
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Part – B
Introduction
Studies on Imidazo[1,2-a]pyridine Derivatives
Studies on chemical…
Imidazo[1,2-a]pyridine… 84
INTRODUCTION
Bridge nitrogen containing fused heterocycles represents important building
blocks in both natural and synthetic bioactive compounds which have been shown to
possess diverse therapeutic activities.1 Hence they are interesting target to be prepared to
our research on medicinally interesting heterocyclic entities. Aza-indolizine are of two
types, imidazo[1,2-a]pyridine (1) and imidazo[1,5-a]pyridine (2).
N
N
NN
(1) (2)
The aza-indolizine contains a phenyl ring fused to a imidazole ring is indicated in
the structure, hence it is also known as imidazo[1,2-a]pyridine.2 Several procedure for
their synthesis have been extensively studied. Such studies have been stimulated by
various promising applications, especially in the case of bridgehead nitrogen containing
fused heterocyclic entities.
The constitution of imidazo[1,2-a]pyridine was reviewed by W. L. Mosby3 in
1961. Imidazo[1,2-a]pyridine derivatives not only known for their pharmacological
applications, they are also used in disperse dyes.4
SYNTHETIC ASPECT
Classical methods have been reported in the literature for the synthesis of
imidazo[1,2-a]pyridines. The procedure for synthesizing imidazo[1,2-a]pyridines have
been described as under.
1. The synthesis of imidazo[1,2-a]pyridine from 2-aminopyridine with ω-
bromoacetophenone was reported by M. Aginagalde.5
2. 2-Acetylimidazo[1,2-a]pyridine6 can be constructed by the cyclocondensation of
2-aminopyridine with bromo butanedione.
N NH2Ph C
OCH2Br
N
NPh+
Studies on chemical…
Imidazo[1,2-a]pyridine… 85
N
N
CH3
O
3. Reaction of 2-chloropyridine with 1,2,3-triazoles and subsequent elimination of
nitrogen’s give the imidazo[1,2-a]pyridine.7
NHN
NN
N
N Cl+
4. Shankarappa A Biradar8 have synthesized 6-bromo-2-(3,4-dichlorophenyl)
imidazo[1,2-a]pyridine using microwave irradiation from 5-bromo-2-
aminopyridine and 2-bromo-1-(3,4-dichlorophenyl)ethanone.
N
Br
NH2
Cl
Cl
O
Br
Microwave DMF N
N
Br
Cl
Cl+
5. Jumat Salimon et al.9 synthesized imidazo[1,2-a]pyridine-3(2H)-one and 3-
Substituted-4-yl imidazo[1,2-a] pyridine from 2-aminopyridine.
N NH2
N N
(a)
N NN N
O(c)
(b)
(i) (ii) (iii)
(i) 4-phenyl phenacyl bromide(ii) phenacyl chloride(iii) chloro aceticacid
6. Synthesis of imidazo[1,2-a]pyridines using catalytic zinc chloride microwave
irradiation from 2-aminopyridine and aryl aldehyde, aryl nitrile reported by
Amanda L. Rousseau.10
Studies on chemical…
Imidazo[1,2-a]pyridine… 86
N NH2
R-CHO
R2NC
catalystN
NR
NHR2
7. Synthesis of Cu(OTf)2-catalyzed imidazo[1,2-a]pyridines from a-diazoketones
and 2-aminopyridines reported by J. S. Yadav.11
N NH2
Cu(OTf)2+O
N2Cl
CF3DCE,80'C
Cl
F3CN
N
8. Guchhait and coworkers12 reported towards molecular diversity: dealkylation of
tert-butyl amine in Ugi-type multicomponent reaction product establishes tert-
butyl isocyanide as a useful convertible isonitrile.
N
NCl
NH2
N NH2
CHO
Cl
N+
CHt-Bu+ +
9. Zhu Dongjian et al.13 have synthesized imidazo[1,2-a]pyridines from 2-
aminopyridine and phenasyl bromide at room temperature.
NNH2
PhC(=O)CH2Br 10 min, rt N
NPh+
REACTION MECHANISM
N
NH2
R4R3
R2R1
X
R5 R6
O
N+
NH2
R4R3
R2R1 R5
R6
O
X-
N
N
R4R3
R2R1
R5
R6
(3) (4) (5) (6)
+
Studies on chemical…
Imidazo[1,2-a]pyridine… 87
The majority of imidazo[1,2-a]pyridine have been synthesized by the reaction of
2-aminopyridine with a a-halocarbonyl compound which form oniumhalide which is
further cyclize at room temperature to gives imidazo[1,2-a]pyridine.
THERAPEUTIC IMPORTANCE
Imidazo[1,2-a]pyridines are potential bioactive agents due to their wide spectrum
of therapeutic importance. A large number of substituted imidazo[1,2-a]pyridine
derivatives are prepared and tested for varieties of biological activities such as,
1. Antiinflammatory14
2. Anti cancer15
3. Antiviral16,17
4. Antianxiety18
5. Antiulcer19,20
6. Antifungal agents21
7. Antibacterials22,23
8. Hypnotic24
9. Gastric antisecretory25
10. Antimalarial26
11. Anticancer27
12. Anticytomegalo-zoster and antivaricellazoster virus28
Alexander C. Humphries and coworkers29
have synthesized 8-fluoro imidazo[1,2-
a]pyridine derivatives (7) and evaluated as a bioisosteric replacement for imidazo[1,2-
a]pyridine in an allosteric modulator ligand of the GABA-A receptor. Carlos Jaramillo,
and coworkers30 reported stereo dynamics of Ar–CO rotation and conformational
preferences of 2-amino-3-(2,4-difluorobenzoyl)-imidazo[1,2-a]pyridine. I. Aramori et
al.31 have been synthesized imidazo[1,2-a]pyridine derivatives which are highly potent
and selective non-peptide bradykinin receptor antagonist (8).
Studies on chemical…
Imidazo[1,2-a]pyridine… 88
N
N
F
F
NC
OH N
N
O
NNH
O
O
N
OBr
(7) (8)
Several imidazo[1,2-a]pyridine nucleus already in market which include
alpidem32 [a ligand of both the central benzodiazepine receptors and the peripheral type
(Mitochondrial) benzodiazepine receptor] has sedative and anxiolytic properties and
zolpidem32 [a selective ligand for the central benzodiazepine receptor] is a hypnotic drug.
Both alpidem and zolpidem have higher affinity for benzodiazepine-1 than for
benzodiazepine-2 receptors33 and their interaction with various receptors has been
reported.34
N
N
ON
ClCl
CH2-CH2-CH3H3C-H2C-H2C
Alpidem
N
N
ON
CH3CH3
CH3CH3
Zolpidem
James J. Kaminski and coworkers35 have investigated imidazo[1,2-a]pyridine
derivative 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (9) for
an antiulcer activity. On the basis of the reported metabolism of zolimidine, they reported
that the 3-cyanomethyl and 8-phenylmethoxy group have been established as metabolic
sites.
ON
N
NCH2C(9)
N
NPhSO2CH3-P
Zolmidine
Brian A. Johns et al.36 and Chaouni-Bendallah A. et al.37 synthesized a novel
imidazo[1,2-a]pyridines (10) with potent activity against Herpes Simplex viruses. J. T.
Studies on chemical…
Imidazo[1,2-a]pyridine… 89
Starr et al.38 have synthesized 5-(2-pyrimidinyl)-imidazo[1,2-a]pyridines (11) from 2-
amino-4-bromo-6-ethoxycarbonylpyridine and evaluated as a antibacterial agent.
(10)
N
N
NN
NNH
NHEtO
(11)
N
N
N
NNH
NH
F
Sebastien Follot et al.39 have synthesized 2-(4-fluorophenyl)-6-iodo-3-pyridin-4-
limidazo[1,2-a]pyridine (12) from 6-iodo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine and
evaluated as anti-apoptosis agents. Imidazo[1,2-a]pyridine units appear as important
building blocks in both natural and synthetic bioactive compounds40-42 and recognition on
DNA binding and to yield different pharmacokinetic profile.
N
N
N
IF
(12)
Mohamed A. Ismail and coworkers43 have synthesized some newer diamine
imidazo[1,2-a]pyridine (13), 5,6,7,8-tetrahydo imidazo[1,2-a]pyridines and their
corresponding N-hydroxy and N-methoxy analogues and evaluated against Trypanosoma
b. rhodesiense (T. B. rhodesiense) and Plasmodium falciparum (P. falciparum). Luke R.
Odell and coworkers44 have synthesized 6-substituted 3-amino-imidazo[1,2-a]pyridines
(14) which has active against Mycobacterium tuberculosis glutamine synthetase
inhibitors. R. B. Lacerda and coworkers45 have find out a novel analgesic and anti-
inflammatory 3-arylamine- imidazo [1,2-a] pyridine.
Studies on chemical…
Imidazo[1,2-a]pyridine… 90
N
N
NH
NH2
O
NH2
NH
(13)
N
N
NHR
1
OH
O
(14) Work done from our laboratory
M. J. Ladani et al.46 reported oxopyrimidines and thiopyrimidines of 2-(2,4-
dichlorophenyl)imidazo[1,2-a]pyridin-3-carbaldehyde and their biological study.
Thus the important role displayed by imidazo[1,2-a]pyridine and its derivatives
for various therapeutic and biological activities prompted us to synthesize some
Glyoxylamide, Mannich base and Bis-Imidazo[1,2-a]Pyridin derivatives bearing
Imidazo[1,2-a]pyridine moiety in order to achieve compounds having better therapeutic
activities described as in the following parts.
STUDIES ON IMIDAZO[1,2-a]PYRIDINE DERIVATIVES
PART-I: STUDIES ON IMIDAZO[1,2-a]PYRIDINE-3-YL-GLYOXYLAMIDE
DERIVATIVES
PART-II: STUDIES ON MANNICH BASE DERIVATIVES
PART-III: STUDIES ON BIS-IMIDAZO[1,2-a]PYRIDIN DERIVATIVES
Studies on chemical…
Imidazo[1,2-a]pyridine… 91
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Part – B
(Part – I)
Studies on Imidazo[1,2-a]pyridine-3-yl-glyoxylamide Derivatives
Studies on chemical…
Glyoxylamide derivatives… 94
INTRODUCTION
Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives having nitrogen-bridgehead
fused heterocycles containing an imidazole ring. It is a common structural motif in
pharmacologically important molecules, with activities spanning a diverse range of
targets.1,2 The diversity, efficiency and rapid access to small and highly functionalized
organic molecules makes this approach of central current interest in the construction of
compounds library and optimization in drug discovery process.3,4
N
N
O
NO
R1
R2
In recent year glyoxylamide derivatives have gained lot of interest because of their
prominent pharmaceutical properties.
SYNTHETIC ASPECT
Various methods for the preparation of imidazo[1,2-a]pyridine-3-yl-glyoxylamide
derivatives have been cited in literature, some of the methods are as under.
1. R. Max and coworkers5 have synthesized imidazopyridinylacetamide derivatives
from imidazopyridine using oxalyl halide and amine.
N
NCH3
CH3
O
Cl O
Cl NHCH3CH3 N
NCH3
CH3
O N
O
+ +
2. T. Eszter et al.6 have synthesized primary amide and keto amide via palladium-
catalyzed carbonylation-deprotection reaction sequence.
IC CH3
NH2
CH3
CH3 CH O+
O
O
NH2+ +
3. B. Roman et al.7 reported mild and efficient conversion of nitriles to amides with
basic urea-hydrogen peroxide adduct.
Studies on chemical…
Glyoxylamide derivatives… 95
CN
O O
O
NH2
4. L. K. Tin et al.8 reported catalytic hydration of nitriles to amides with manganese
dioxide on silica gel.
CNO
O
NH2
THERAPEUTIC IMPORTANCE
See Part-A, Part-I, Section-I, Therapeutic importance
Looking to the diversified biological activities we have synthesized some
glyoxylamide derivatives in order to achieving better therapeutic agents. These studies are
described in following section.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-[2-(4-
FLUOROPHENYL)-6-METHYLIMIDAZO[1,2-a]PYRIDIN-3-YL]-
2-(N,N-DIALKYLAMINE-4-YL)ETHANE-1,2-DIONES.
Studies on chemical…
Glyoxylamide derivatives… 96
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 1-[2-(4-FLUOROPHENYL)-
6-METHYLIMIDAZO[1,2-a]PYRIDIN-3-YL]-2-(N,N-DIALKYLAMINE-4-YL)
ETHANE-1,2-DIONES.
The discovery of Imidazo[1,2-a]pyridine-3-yl-glyoxylamide derivatives as potent
biologically active agent has led to the exploration of large number of structural variants,
containing imidazo[1,2-a]pyridine-3-yl-glyoxylamide moiety as an invariable ingredient.
In view of these reports, we have synthesize imidazo[1,2-a]pyridine-3-yl-glyoxylamide
derivatives by the condensation of 2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridine
with oxalyl chloride and different secondary amine in the presence of DCM.
REACTION SCHEME
N NH2
CH3
OCl
FN
NF
CH3
N
NF
CH3OO
R
MeOHTEA
(ii) Sec. amine
(i) (COCl)2
+
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Glyoxylamide derivatives… 97
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Synthesis of 2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine.
A solution of 5-methylpyridin-2-amine (1.08 g, 0.01 mol) in methanol (10 ml)
was added to 2-chloro-1-(4-fluorophenyl)ethanone (1.72 g, 0.01 mol) and the reaction
mixture was refluxed with stirring for 6 hour in the presence of catalytic amount of TEA.
After the completion of reaction (monitoring by TLC), cool the content, the solid
separated was filtered and dried in vacuo. Yield 68%, m.p 192 °C, Anal. Calcd. for
C14H11FN2: Require: C, 74.32, H, 4.90, N, 12.38 %; Found: C, 74.30, H, 4.89, N, 12.35
%. MS: m/z = 226.
[B] General procedure for the preparation of 1-[2-(4-Fluorophenyl)-6-
methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-
diones.
To a stirred solution of oxalyl chloride (1.01 ml, 0.012 mol) in dry DCM (10 ml),
2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (2.26 g, 0.01 mol) was added
portion wise in solution. The obtained solution was stirred at room temperature for 10-15
minute and then added TEA (1.22 ml, 0.012 mol) dropwise. The resulting mixture was
stirred 25-30 oC for 2 hour dark yellow colored was formed. The solvent was removed in
vacuo, the residue was dissolved in dry DCM (12 ml) and different secondary amine
(0.015 mol) was added dropwise. The reaction mixture was stirred at 0 oC for 30.0 minute
and then 25-30 oC for another 30.0 minute (monitored by TLC). The solvent was removed
in vacuo. The product was extracted with ethyl acetate and the organic layers washed
with water, dried over anhydrous Na2SO4. The solvent was removed in vacuo and the
solid was triturated with hexane and resulting precipitate was filtered, washed with
Studies on chemical…
Glyoxylamide derivatives… 98
hexane and dried to give analytical pure product. The physical constants of the product
are recorded in Table-4a.
[C] Biological evaluation of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]
pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-4b.
Studies on chemical…
Glyoxylamide derivatives… 99
Table-4a: Physical constant of 1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]
pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.
N
NF
CH3OO
R
Sr. No Substitution R M.F. M.W. Yield (%) Rf value
4a N O
C20H18FN3O3
367.37 86 0.49
4b NCH3
CH3
C20H20FN3O2
353.59 81 0.36
4c N N C26H23FN4O2 442.48 76 0.57
4d N
C21H20FN3O2
356.40 90 0.61
4e N N CH3
C21H21FN4O2
380.41 85 0.38
4f N NCH3
C22H23FN4O2
394.44 89 0.43
4g NCH3
CH3
CH3
CH3
C22H24FN3O2
381.44 83 0.39
4h N
C20H18FN3O2
351.37 78 0.56
4i N
CH3
C22H22FN3O2
379.42 82 0.45
4j N CH3
C22H22FN3O2
379.42 77 0.46
TLC solvent system:- E.A. : Hexane = 5 : 5
Studies on chemical…
Glyoxylamide derivatives… 100
ANALYTICAL DATA
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(morpholin-4-yl)
ethane-1,2-dione (4a). mp 196-198 °C; Purity by HPLC: 97 %; IR (KBr): 3116 (Ar, C-H
str), 2979 (C-H str), 2942 (C-H str), 1729 (ketone, C=O str), 1708 (amide, C=O str), 1627
(C=N str), 1528 (Ar, C=C str), 1442 (Ar, C=C str), 1254 (C-N str), 1090 (C-F) cm-1; 1H
NMR (400 MHz, CDCl3): δ ppm 2.48 (s, 3H, CH3), 3.14-3.19 (m, 4H, CH2), 3.43-3.49
(m, 4H, CH2), 7.15-7.20 (m, 2H, ArH), 7.50-7.52 (m, 1H, ArH), 7.60-7.65 (m, 2H, ArH),
7.71-7.73 (d, J=9.08 Hz, 1H, ArH), 9.57 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ
ppm 18.51, 40.84, 45.90, 65.97, 114.98, 115.20, 116.79, 118.52, 126.31, 127.41, 129.06,
129.09, 132.01, 132.09, 134.07, 147.13, 156.41, 162.41, 164.46, 164.90, 180.61; MS: m/z
= 368 [M+1]+; Anal. Calcd for C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C,
64.87; H, 4.87; N, 11.32%.
N,N-Diethyl-2-[2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-
oxoacetamide (4b). mp 279-281 °C; Purity by HPLC: 99 %; IR (KBr): 3061, 2985, 2857,
1711, 1687, 1596, 1573, 1456, 1122, 1082 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm
1.30-1.34 (t, J=7.48 Hz, 6H, CH3), 2.45 (s, 3H, CH3), 3.50-3.55 (q, J=7.12 Hz, 4H, CH2),
7.07-7.10 (m, 2H, ArH), 7.47-7.50 (m, 1H, ArH), 7.59-7.62 (m, 2H, ArH), 7.69-7.71 (d,
J=9.88 Hz, 1H, ArH), 9.42 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 12.61,
14.41, 20.15, 39.38, 41.44, 114.30, 115.60, 116.85, 118.11, 126.30, 127.41, 129.10,
129.15, 132.22, 132.30, 134.27, 147.13, 157.42, 162.81, 164.46, 164.90, 182.11; MS: m/z
= 354 [M+1]+; Anal. Calcd for C20H20FN3O2: C, 67.97; H, 5.70; N, 11.89. Found: C,
67.37; H, 5.63; N, 11.81%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-phenylpiperazin-4-
yl)ethane-1,2-dione (4c). mp 223-225 °C; IR (KBr): 3088, 2976, 2864, 1702, 1683,
1601, 1589, 1471, 1134, 1084 cm-1; MS: m/z = 443 [M+1]+; Anal. Calcd for
C26H23FN4O2: C, 70.57; H, 5.24; N, 12.66. Found: C, 70.06; H, 5.14; N, 12.57%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(piperidin-1-yl)ethane-
1,2-dione (4d). mp 193-195 °C; IR (KBr): 3070, 2968, 2842, 1718, 1699, 1581, 1578,
1459, 1113, 1079 cm-1; MS: m/z = 356 [M]+; Anal. Calcd for C21H20FN3O2: C, 69.03; H,
5.52; N, 11.50. Found: C, 68.84; H, 5.43; N, 11.41%.
Studies on chemical…
Glyoxylamide derivatives… 101
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-methylpiperazin-1-
yl)ethane-1,2-dione (4e). mp 275-277 °C; IR (KBr): 3084, 2951, 2823, 1710, 1681,
1600, 1589, 1423, 1196, 1089 cm-1; MS: m/z = 380 [M]+; Anal. Calcd for C21H21FN4O2:
C, 66.30; H, 5.56; N, 14.73. Found: C, 65.78; H, 5.40; N, 14.58%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-ethylpiperazin-1-yl)
ethane-1,2-dione (4f). mp 212-214 °C; IR (KBr): 3075, 2956, 2846, 1699, 1680, 1586,
1579, 1485, 1096, 1086 cm-1; MS: m/z = 394 [M]+; Anal. Calcd for C22H23FN4O2: C,
66.99; H, 5.88; N, 14.20. Found: C, 66.26; H, 5.73; N, 14.01%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(N,N-diisopropyl-1-yl)
ethane-1,2-dione (4g). mp 187-189 °C; IR (KBr): 3082, 2958, 2875, 1701, 1689, 1596,
1567, 1489, 1118, 1076 cm-1; MS: m/z = 381 [M]+; Anal. Calcd for C22H24FN3O2: C,
69.27; H, 6.34; N, 11.02. Found: C, 68.53; H, 6.13; N, 10.88%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(pyrrolidin-1-yl)
ethane-1,2-dione (4h). mp 238-239 °C; IR (KBr): 3089, 2971, 2853, 1709, 1700, 1588,
1564, 1443, 1191, 1087 cm-1; MS: m/z = 352 [M+1]+; Anal. Calcd for C20H18FN3O2: C,
68.36; H, 5.16; N, 11.96. Found: C, 67.57; H, 5.05; N, 11.79%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(2-methylpiperidin-1-
yl)ethane-1,2-dione (4i). mp 166-168 °C; IR (KBr): 3070, 2954, 2856, 1706, 1602, 1582,
1556, 1457, 1166, 1081 cm-1; MS: m/z = 379 [M]+; Anal. Calcd for C22H22FN3O2: C,
69.64; H, 5.84; N, 11.07. Found: C, 69.06; H, 5.71; N, 10.86%.
1-[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]-2-(4-methylpiperidin-1-
yl)ethane-1,2-dione (4j). mp 144-145 °C; IR (KBr): 3071, 2952, 2864, 1708, 1694, 1584,
1571, 1458, 1184, 1089 cm-1; MS: m/z = 379 [M]+; Anal. Calcd for C22H22FN3O2: C,
69.64; H, 5.84; N, 11.07. Found: C, 68.87; H, 5.73; N, 10.88%.
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Glyoxylamide derivatives… 102
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 4a
Column : Phenomenex Luna C8 (2) (250mm x 4.6mm i.d., 5 μm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (40: 60, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 4a
Minutes0 2 4 6 8 10 12 14 16 18 20
mAU
0
1000
2000
1.83
5 5
4328
0.1
02.
101
655
074
1.2
42.
496
593
64 0
.11
2.85
9 3
4625
0.0
7
3.60
5 2
4977
0.0
5
4.51
2 2
4576
5 0
.47
5.16
3 2
5403
7 0
.48
6.62
4 5
1400
831
97.
40
5007501000125015001750200025003000350040001/cm
0
15
30
45
60
75
90
%T 3116
.11
2979
.16
2942
.51
2856
.67
1729
.24
1708
.02
1627
.97
1528
.64
1442
.80
1365
.65
1299
.10
1254
.74
1238
.34
1207
.48
1154
.43
1090
.78
985.
6695
2.87
908.
5085
3.53
818.
8177
4.45
673.
1863
8.46
569.
02
reaction-91-R
N
NF
CH3OO
N
O
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Glyoxylamide derivatives… 103
Mass spectrum of compound 4a
Mass spectrum of compound 4c
N
NF
CH3OO
N
OM.Wt. = 367.37
N
NF
CH3OO
N
N
M.Wt. = 442.48
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Glyoxylamide derivatives… 104
1H NMR spectrum of compound 4a
Expanded spectrum of compound 4a
N
NF
CH3OO
N
O
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Glyoxylamide derivatives… 105
1H NMR spectrum of compound 4b
Expanded spectrum of compound 4b
N
NF
CH3OO
NCH3CH3
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Glyoxylamide derivatives… 106
13C NMR spectrum of compound 4a
13C NMR spectrum of compound 4b
N
NF
CH3OO
N
O
N
NF
CH3OO
NCH3CH3
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Glyoxylamide derivatives… 107
Table-4b: Antimicrobial activity of 1-[2-(4-Fluorophenyl)-6-methylimidazo [1,2-a]
pyridin-3-yl]-2-(N,N-dialkylamine-4-yl)ethane-1,2-diones.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
4a 100 200 250 250 1000 >1000 >1000 4b 200 200 200 100 250 500 250 4c 100 100 100 200 500 500 200 4d 200 250 100 100 250 1000 1000 4e 250 200 50 200 >1000 1000 500 4f 500 100 250 100 1000 250 200 4g 250 200 500 500 500 500 250 4h 250 500 500 250 250 200 1000 4i 200 200 100 100 500 200 500 4j 500 200 250 200 200 250 200
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Glyoxylamide derivatives… 108
REFERENCES
1. S. Howard, In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,
Scriven, E. V. F., Eds.; Pergamon: London, Vol. 8, Chapter 10, pp 262-274 (1996).
2. D. R. Sliskovic, In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,
Scriven, E. V. F., Eds.; Pergamon: London, Vol. 8, Chapter 12, pp 345-365 (1996).
3. I. Bennacef, C. N. Haile, A. Schmidt, A. O. Koren, J. P. Seibyl, J. K. Staley, F. Bois, R. M.
Baldwin, G. Tamagnan, Bioorg. Med. Chem., 14(22), 7582-7591 (2006).
4. F. Stefania, D. G. Sara, D. L. Laura, B. M. Letizia, D. Zeger, C. Alba, Heterocycles, 78(4),
947-959 (2009).
5. R. Max, R. Armin, D. Giusep, P. Kyoung, PCT Int. WO 2002014306A1 20020221, (2002).
6. T. Eszter, V. Csilla, S. Rita, K. Laszlo, Tet. Lett., 48(14), 2453-2456 (2007).
7. B. Roman, K. Lukasz, Syn. Comm., 23(22), 3149-3155 (1993).
8. L. K. Tin, S. M. Hsiu, H. H. Wen, H. C. Jeui, Synthesis, (9), 715-717 (1988).
Part – B
(Part – II)
Studies on Mannich base Derivatives
Studies on chemical…
Mannich base derivatives… 109
INTRODUCTION
Mannich bases containing bridged N-atom exhibit pronounced biological
activities. The study of mannich reaction attracted a great deal of attention to the chemists
because it plays a vital role due to their wide range of biological and industrial
applications. Mannich bases are also employed as intermediate in chemical synthesis.1-3
Much interest has been focused on the synthesis of mannich bases due to its wide
a variety of pharmacological activities. Mostly, they are found to be antineoplastic,
analgesic and antibiotic drugs. Several therapeutic important molecules prepared through
mannich reaction have received more attention in recent years.4-6 Mannich bases have
gained important because of their technological application in polymer chemistry,7
especially as paints and surface active agent and it also exhibits complexation
characteristic with many transition metal ions.
SYNTHETIC ASPECT
Different methods have been cited to synthesize some new mannich bases by
several coworkers using various interesting substrates.
1. Gabriela Laura Almajan et al.8 have synthesized mannich bases (1) from some
triazole moiety.
X SO
O
N NH
N SN
Ar
X SO
O
N N
N SN
Ar
NO
morpholine, CH2O
X=H,Cl
37 % reflux
(1)
2. Y. Sumalatha et al.9 have synthesized mannich base (2) of imidazo[1,2-a]pyridine
moiety.
N
N
CH3
CH3 N
NCH3
NCH3
CH3
CH3COOH
formaline, RT
(2)
3. A. Katsifis et al.10 have prepared mannich bases (3) of imidazo[1,2-a]pyridine.
Studies on chemical…
Mannich base derivatives… 110
N
N
AR3
B HCHON
N
AR3
Me2N
B
(3) 4. Several new aminobenzylated mannich bases (4) have been prepared by
condensing reaction between heterocyclic secondary amines, aldehydes and
acetamide, urea and thiourea.11
X NH
HO
R C
O
NH2 CH3
X NH
OH X NH
NH NHH
N XO
R R(4)
R=ArylX=O/CH2
+
Over the years there has been much controversy about the mechanism of the
mannich reaction. Studies of the reaction kinetics have led to the following mechanistic
proposals.
REACTION MECHANISM
The mechanism of the Mannich reaction starts with the formation of an iminium
ion from the amine and the formaldehyde.
O
H
HH
+
O+
H
HH
N R2
R1
HO
H
HH
N+
R1
R2
H -H+
O
H
HH
N
R1
R2
H+
N+
R1
R2
H
H
-H2OO
+
H
HH
H
N
R1
R2
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Mannich base derivatives… 111
Because the reaction takes place under acidic conditions, the compound with the
carbonyl functional group (in this case a ketone) can tautomerize to the enol form, after
which it can attack the iminium ion.
R3
OR
4
HH
H+
R3
O+
R4
HH
H
-H+ OH
R3
H
R4
OH
R3
H
R4
+ N+
R1
R2
H
H R3
O+
HN
R1
R2
H
HH
R4
-H+
R3
O
N
R1
R2
H
HH
R4
THERAPEUTIC IMPORTANCE
A wide variety of pharmacological properties and industrial applications have
been encountered with several mannich bases such as,
1. Antibacterial12
2. Antitumor13
3. Antiinflammatory14
4. Cytotoxic Activity15
5. AntiHIV16
6. Antimalarial17
7. Antiproliferation18
8. Antiparasitic19
9. Antitubercular20
10. Antifungal21
11. Anticancer22
Several therapeutic important molecules containing heterocyclic secondary
amines are well known. For example, Manafflazineis a famous antiarthritic agent and
Minorine is used as antidepressant.
S. K. Sridhar23 have synthesized some new mannich bases and screened for anti-
inflammatory activity. A. R. Bhat et al.24 have reported mannich bases of quinoxaline and
evaluated for their antibacterial, antifungal and antitubercular activities.
Studies on chemical…
Mannich base derivatives… 112
P. Y. Shirodkar and M. M. Vartak25 have studied the antitubercular activity of
mannich bases of 6-nitro-3-N-arylaminomethyl-1,2,3,4-tetrahydro-4-oxo-2-thioqui-
noxalines (5).
N
NH
O2N
O
NH
R
(5)
Craig J. Roxburgh et al.26 have reported mannich bases and tested them for local
anesthetic activity (6).
H
S
O
O
N
(6)
Christina Reichwald et al.27 have synthesized mannich bases of 9-tert-butyl-2-
phenylethinylpaullone (7) from 1,3-diarylpropenones using aromatic aldehydes and
acetophenone derivatives as starting materials and studied their antileishmanial activity.
NH O
C(CH3)3
(7)
Yan Huang, et al.28 have synthesized some mannich bases and reported as
anticancer agent. Ya. L. Garazd et al.29 have prepared mannich bases of hydroxyl-
coumarines (8) which posses various biological activities.
Studies on chemical…
Mannich base derivatives… 113
O
N
X
O
OH
(8)
X = NCH3
Work done from our laboratory
K. S. Nimavat30 have synthesized some new aminobenzylated mannich bases
and reported as an antimicrobial agent. Study of mannich bases of 4-amino-3-
mercapto-5-pyridin-3'-yl-[1,2,4]-triazole reported by T. K. Dave.31 Green chemistry
approach to potentially bioactive aminobenzylated mannich bases through active
hydrogen compounds reported by S. L. Vasoya.32
Thus with an effort to capitalize the biological potential of the heterocyclic
system and to provide more interesting compounds for biological screening, we have
under taken the synthesis of several mannich bases which has been described as under.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-
FLUOROPHENYL)-6-METHYL-3-(N,N-DIALKYLAMINE-4-YL
METHYL) IMIDAZO[1,2-a]PYRIDINES.
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Mannich base derivatives… 114
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-
FLUOROPHENYL)-6-METHYL-3-(N,N-DIALKYLAMINE-4-YLMETHYL)
IMIDAZO[1,2-a]PYRIDINES.
Encouraged by earlier positive result in respect of mannich bases compounds have
gained lot of interest in last several year due to their biological, physiological and
industrial importance, based on extensive studies of pharmacological properties, it was
thought of interest to synthesize some new mannich bases by condensation of 2-(4-
fluorophenyl)-6-methylimidazo[1,2-a]pyridine with different secondary amines and
formaldehydes in the presence of acid catalyst.
REACTION SCHEME
N
NF
CH3N
NF
CH3
R
MeOH
HCHOSec. amine
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
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Mannich base derivatives… 115
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Synthesis of 2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine.
See Part-B, Part-I, Section-I, Experimental section [A].
[B] General procedure for the preparation of 2-(4-Fluorophenyl)-6-methyl-3-
(N,N-dialkylamine-4-ylmethyl)imidazo[1,2-a]pyridines.
To a solution of 2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (2.26 g,
0.01 mol), formaldehyde (0.3 g, 0.01 mol) and different secondary amine (0.01 mol) in
methanol (20 ml) was added and the reaction mixture was refluxed with stirring in the
presence of 1-2 drop concentrated HCl. After completion of reaction (monitoring by
TLC) cool the reaction mass and add ice cold water and extracted with ethyl acetate. The
organic layer was washed with water (2 x 10 ml) and dried with Na2SO4, solvent was
removed in vacuo and the resulting crude product was pure by colum chromatography to
give the analytical pure compound. The physical constants of the product are recorded in
Table-5a.
[C] Biological evaluation of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-
ylmethyl)imidazo[1,2-a]pyridines.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-5b.
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Mannich base derivatives… 116
Table-5a: Physical constant of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkylamine-4-
ylmethyl)imidazo[1,2-a]pyridines.
N
NF
CH3
R
Sr. No Substitution R M. F. M. W. Yield (%) Rf value
5a N O
C19H20FN3O
325.28 75 0.56
5b NCH3
CH3
C19H22FN3
311.39 78 0.39
5c N N
C25H25FN4
400.49 81 0.46
5d N
C20H22FN3
323.40 69 0.62
5e NCH3
CH3
CH3
CH3
C21H26FN3
339.44 73 0.48
5f N NCH3
C21H25FN4
352.44 86 0.36
5g
N N CH3
C20H23FN4
338.42 80 0.53
5h
N
C19H20FN3
309.38 79 0.57
5i N
CH3
C21H24FN3
337.43 70 0.61
5j N CH3
C21H24FN3
337.43 73 0.44
TLC solvent system:- E.A. : Hexane = 6 : 4
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Mannich base derivatives… 117
ANALYTICAL DATA
2-(4-Fluorophenyl)-6-methyl-3-(morpholin-4-ylmethyl)imidazo[1,2-a]pyridine (5a).
mp 183-185 °C; Purity by HPLC: 98 %; IR (KBr): 3114 (Ar, C-H str), 3009 (C-H str),
2956 (C-H str), 1657 (C=N str), 1576 (Ar, C=C str), 1460 (Ar, C=C str), 1345 (C-H str),
1214 (C-N str), 1158 (C-F), 841 (C-H, o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ
ppm 2.29 (s, 3H, CH3), 2.38-2.40 (t, J=4.44 Hz, 4H, 2CH2), 3.58-3.61 (t, J=4.52 Hz, 4H,
2CH2), 3.81 (s, 2H, CH2), 6.98-7.01 (m, 1H, ArH), 7.03-7.08 (m, 2H, ArH), 7.45-7.47 (d,
J=9.12 Hz, 1H, ArH), 7.68-7.72 (m, 2H, ArH), 8.06 (s, 1H, ArH). 13C NMR (100 MHz,
CDCl3): δ ppm 18.55, 51.94, 53.18, 66.97, 115.29, 115.50, 116.55, 121.68, 122.66,
127.93, 130.43, 130.51, 130.66, 130.69, 144.08, 144.18, 161.29, 163.74; MS: m/z = 326
[M+1]+; Anal. Calcd for C19H20FN3O: C, 70.13; H, 6.20; N, 12.91. Found: C, 69.83; H,
6.13; N, 12.76%.
N-Ethyl-N-{[2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}
ethanamine (5b). mp 147-148 °C; Purity by HPLC: 99 %; IR (KBr): 3072, 2980, 2862,
1603, 1554, 1434, 1456, 1119, 1035, 820 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 0.99-
1.03 (t, J=7.08 Hz, 6H, CH3), 2.29 (s, 3H, CH3), 2.46-2.52 (q, J=7.2 Hz, 4H, CH2), 3.98
(s, 2H, CH2), 6.99-7.02 (m, 1H, ArH), 7.06-7.09 (m, 2H, ArH), 7.52-7.54 (d, J=10.56 Hz,
1H, ArH), 7.74-7.78 (m, 2H, ArH), 8.10 (s, 1H, ArH). 13C NMR (100 MHz, CDCl3): δ
ppm 13.11, 21.68, 50.93, 52.18, 115.50, 115.80, 116.75, 122.20, 123.30, 128.50, 130.80,
130.99, 131.06, 131.10, 144.48, 144.60, 161.80, 164.12; MS: m/z = 311 [M]+; Anal.
Calcd for C19H22FN3: C, 73.28; H, 7.12; N, 13.49. Found: C, 72.53; H, 7.03; N, 13.33%.
2-(4-Fluorophenyl)-6-methyl-3-[(4-phenylpiperazin-1-yl)methyl]imidazo[1,2-a]
pyridine (5c). mp 192-194 °C; IR (KBr): 3080, 2968, 2835, 1599, 1574, 1481, 1463,
1138, 1043, 850 cm-1; MS: m/z = 400 [M]+; Anal. Calcd for C25H25FN4: C, 74.97; H,
6.29; N, 13.99. Found: C, 74.21; H, 6.07; N, 13.75%.
2-(4-Fluorophenyl)-6-methyl-3-(piperidin-1-ylmethyl)imidazo[1,2-a]pyridine (5d).
mp 198-199 °C; IR (KBr): 3076, 2961, 2863, 1645, 1542, 1453, 1378, 1143, 1037, 832
cm-1; MS: m/z = 325 [M+2]+; Anal. Calcd for C20H22FN3: C, 74.28; H, 6.86; N, 12.99.
Found: C, 74.05; H, 6.77; N, 12.71%.
N-{[2-(4-Fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl]methyl}-N-isopropyl
propan-2-amine (5e). mp 124-126 °C; IR (KBr): 3084, 2967, 2857, 1605, 1559, 1462,
Studies on chemical…
Mannich base derivatives… 118
1376, 1134, 1054, 845 cm-1; MS: m/z = 339 [M]+; Anal. Calcd for C21H26FN3: C, 74.30;
H, 7.72; N, 12.38. Found: C, 73.17; H, 7.59; N, 12.26%.
2-(4-Fluorophenyl)-6-methyl-3-[(4-ethylpiperazin-1-yl)methyl]imidazo[1,2-a]
pyridine (5f). mp 223-224 °C; IR (KBr): 3078, 2959, 2886, 1612, 1551, 1487, 1389,
1144, 1046, 848 cm-1; MS: m/z = 353 [M+1]+; Anal. Calcd for C21H25FN4: C, 71.56; H,
7.15; N, 15.90. Found: C, 71.34; H, 7.01; N, 15.72%.
2-(4-Fluorophenyl)-6-methyl-3-[(4-methylpiperazin-1-yl)methyl]imidazo[1,2-a]
pyridine (5g). mp 173-175 °C; IR (KBr): 3097, 2956, 2872, 1611, 1534, 1456, 1451,
1129, 1034, 865 cm-1; MS: m/z = 339 [M+1]+; Anal. Calcd for C20H23FN4: C, 70.98; H,
6.85; N, 16.56. Found: C, 70.83; H, 6.74; N, 16.47%.
2-(4-Fluorophenyl)-6-methyl-3-(pyrrolidin-1-ylmethyl)imidazo[1,2-a]pyridine (5h).
mp 144-145 °C; IR (KBr): 3082, 2954, 2868, 1614, 1559, 1446, 1471, 1139, 1043, 870
cm-1; MS: m/z = 309 [M]+; Anal. Calcd for C19H20FN3: C, 73.76; H, 6.52; N, 13.58.
Found: C, 72.32; H, 6.29; N, 13.45%.
2-(4-Fluorophenyl)-6-methyl-3-[(2-methylpiperidin-1-yl)methyl]imidazo[1,2-a]
pyridine (5i). mp 153-155 °C; IR (KBr): 3046, 2964, 2834, 1621, 1558, 1448, 1356,
1126, 1048, 837 cm-1; MS: m/z = 337 [M]+; Anal. Calcd for C21H24FN3: C, 74.75; H,
7.17; N, 12.45. Found: C, 74.37; H, 7.05; N, 12.36%.
2-(4-Fluorophenyl)-6-methyl-3-[(4-methylpiperidin-1-yl)methyl]imidazo[1,2-a]
pyridine (5j). mp 134-136 °C; IR (KBr): 3089, 2956, 2885, 1625, 1545, 1446, 1426,
1146, 1023, 842 cm-1; MS: m/z = 337 [M]+; Anal. Calcd for C21H24FN3: C, 74.75; H,
7.17; N, 12.45. Found: C, 74.36; H, 7.09; N, 12.31%.
Studies on chemical…
Mannich base derivatives… 119
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 5a
Column : Phenomenex Luna C8 (2) (250mm x 4.6mm i.d., 5 μm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 5a
Minutes0 1 2 3 4 5 6 7 8 9 10
mA
U
0
500
1000
1.82
4 1
2825
1 0
.87
2.41
1 1
4475
616
98.
18
3.46
7 3
0266
0.2
1
7.92
5 3
5674
0.2
4
8.36
3 2
4485
0.1
7
9.29
1 4
9833
0.3
4
5007501000125015001750200025003000350040001/cm
30
45
60
75
90
105
%T
3114
.18
3009
.05
2956
.01 29
02.9
6
1657
.87
1576
.86 15
18.0
3 1502
.60
1460
.16
1419
.66
1345
.39
1324
.18
1305
.85
1257
.63
1214
.23
1158
.29
1114
.89
1029
.06
986.
6284
1.96 82
0.74
731.
0570
8.86
508.
26
4-NO2-chal
N
NF
CH3
N
O
Studies on chemical…
Mannich base derivatives… 120
Mass spectrum of compound 5a
Mass spectrum of compound 5c
N
NF
CH3
N
O
M. Wt. = 325.38
N
NF
CH3
N
N
M. Wt. = 400.49
Studies on chemical…
Mannich base derivatives… 121
1H NMR spectrum of compound 5a
Expanded spectrum of compound 5a
N
NF
CH3
N
O
Studies on chemical…
Mannich base derivatives… 122
1H NMR spectrum of compound 5b
Expanded spectrum of compound 5b
N
NF
CH3
N
CH3
CH3
Studies on chemical…
Mannich base derivatives… 123
13C NMR spectrum of compound 5a
13C NMR spectrum of compound 5b
N
NF
CH3
N
O
N
NF
CH3
NCH3
CH3
Studies on chemical…
Mannich base derivatives… 124
Table-5b: Antimicrobial activity of 2-(4-Fluorophenyl)-6-methyl-3-(N,N-dialkyl-
amine-4-ylmethyl)imidazo[1,2-a]pyridines.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
5a 100 100 250 250 200 1000 1000 5b 100 200 100 500 250 500 250 5c 250 250 250 125 500 1000 1000 5d 200 250 125 500 1000 250 500 5e 250 200 500 500 500 1000 1000 5f 100 62.5 100 200 500 200 500 5g 200 500 62.5 250 250 500 250 5h 500 250 500 200 200 200 500 5i 200 500 200 100 500 200 250 5j 500 200 250 250 500 250 200
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Mannich base derivatives… 125
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Part – B
(Part – III)
Studies on Bis-imidazo[1,2-a]pyridin Derivatives
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 127
INTRODUCTION
Bis imidazo[1,2-a]pyridine (1) is an aromatic heterocyclic organic compound
having one carbon atom is common with attached two imidazo[1,2-a]pyridine ring
system. Hence they are interesting target to be prepared to our research on medicinally
interesting heterocyclic entities.
N
N
N
N(1)
As evident from the literature in recent years a significant portion of research
work in heterocyclic chemistry has been devoted to bis imidazo[1,2-a]pyridine containing
different aryl, alkyl and heteroaryl groups as substituent.
SYNTHETIC ASPECT
Various methods for the preparation of dimer have been cited in literature, some
of the methods are as under.
1. R. Zhang et al.1 synthesized bis-imidazo[1,2-a]pyridinylmethanes from imidazole
with different aryl aldehydes.
N
NR
1
HO
RN
NR
1
N
N
R1 R+
2. Y. Sumalatha and coworkers2 have been reported bis-imidazo[1,2-a]pyridine
substances as hypnotic agent.
N
NCH3
CH3
OH
N
NCH3
CH3 N
N
N
N
CH3
CH3
CH3
CH3
+
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 128
3. J. C. Teulade and coworkers3 have been reported some bis imidazo[1,2-a]azines
from acetaldehyde.
N
NN
NN
N
CH3
CH3 CH ON
N
OHCH3
4. K. Asakawa et al.4 have synthesized bis benzimidazoles and reported alternative
preparation shown in-situ reaction.
N
NH
O
O
CH3NH
N
N
NH
COH
+
5. M. Fabio da Silva and coworkers5 have reported new method for the preparation
of bis(1H-benzimidazol-2-yl)methanone.
NH2
NH2
O
OEt
O
OEtNH
N
NH
N
+
6. W. Oi and coworkers6 synthesized phenyl bis indole and reported selective
receptor for chloride anion.
NH
CH3O
NH
CH3
NH
CH3
+
7. G. V. Ramin, et al.7 synthesized bis(indolyl)methanes in water and also
synthesized di-, tri-, and tetra(bis-indolyl)methanes under thermal conditions
catalyzed by oxalic acid dehydrate.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 129
O
OCH3 N
H
(CH2)3 COOH
NH
NH (CH2)3
(CH2)3HOOC
COOH
OCH3
+
8. G. K. P. Surya and coworkers8 reported microwave assisted synthesis of
triarylmethanes by using Nafion-H catalyst.
O
+
THERAPEUTIC IMPORTANCE
A wide variety of pharmacological properties and industrial applications have
been encountered with several dimer such as,
1. Antimicrobial9
2. Antiinflammatory10
3. Anti cancer11
4. Analgesic12
5. Antifungal13
6. Anti-HIV14
7. Anti protozoal15
8. Anti malarial16
9. Cytotoxic Activity17
10. Anti tumor18
N. P. Kozyreva and coworkers19 synthesized co-bis benzo[g]quinol (2) derivatives
and tested their antimalarial activity. A. O. Abdelhamid et al.20 have reported
antimicrobial evaluation of synthesized compound. L. S. Fernandez et al.21 have reported
synthesis of bis-indole alkaloids from flindersia species and their antimalarial activity.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 130
NN (CH2)n N N
NN (2)
R. Rohini et al.22 have synthesized bis-indolo[1,2-c]quinazolines (3) and evaluated
them for antimicrobial studies. L. Dassonneville et al.23 reported plant alkaloid
usambarensine intercalates into DNA and induces apoptosis in human HL60 leukemia
cells.
NN
X
NN
(3)
K. Oh et al.24 have reported synthesis and antimicrobial activities of halogenated
bis(hydroxyphenyl)methanes (4). C. S. Reddy and coworkers25 have synthesized and
evaluated novel bis[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles as potent antimicrobial agents.
S. M. Sondhi and coworkers26 reported biological activity of novel bis Schiff bases, bis
hydrazone and bis guanidine derivatives.
OH OH
Cl
Cl Cl
Cl
(4)
K. V. Sashidhara et al.27 have synthesized and reported antihyperlipidemic activity
of novel coumarin bisindole (5) derivatives. X. H. Gu et al.28 synthesized and reported
biological activities of bis(3-indolyl)thiazoles, analogs of marine bis(indole)alkaloid
nortopsentins. G. A. Youngdale et al. synthesized 5-substituted 2,3-bis(p-methoxyphenyl)
indoles and reported their antiinflammatory activity. C. Praveen and coworkers29 have
documented bis(indolyl)methanes and evaluated of their antimicrobial and antioxidant
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 131
activity. S. Ahn and coworkers30 reported a novel bis-indole destabilize microtubules and
displayed potent in vitro and in vivo antitumor activity in prostate cancer.
NH
OO
CO2Et
NH
(5)
M. A. Ismail and coworkers31 have reported synthesis and antiprotozoal activity of
novel bis-benzamidino imidazo[1,2-a]pyridines and 5,6,7,8-tetrahydro-imidazo[1,2-
a]pyridines. M. R. Jacobs et al.32 have prepared some novel bis-indole agents active
against multidrug resistant acinetobacter baumannii. B. B. Dey et al.33 reported a
coumarin dimer directly linked without any bridge. R. Rohini and coworkers34 presented
bis-6-arylbenzimidazo[1,2-c]quinazolines, a new class of antimicrobial agents.
Thus with an effort to capitalize the biological potential of the heterocyclic
system and to provide more interesting compounds for biological screening, we have
under taken the synthesis of several dimer which has been described as under.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-
FLUROPHENYL)-3-((2-(4-FLUROPHENYL)-6-METHYLH-
IMIDAZO[1,2-a]PYRIDINE-3-YL)(ARYL)METHYL)-6-METHYL
H-IMIDAZO[1,2-a]PYRIDINES.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 132
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-(4-FLUROPHENYL)-3-
((2-(4-FLUROPHENYL)-6-METHYLH-IMIDAZO[1,2-a]PYRIDINE-3-YL)
(ARYL)METHYL)-6-METHYL H-IMIDAZO[1,2-a]PYRIDINES.
Bis imidazo[1,2-a]pyridine derivatives are important intermediates in organic
synthesis, especially in the synthesis of biologically active and medicinally useful agents.
For instance, they are widely used in the synthesis of cyclin-dependent kinases (CDK)
inhibitors, sleep inducers, anticonvulsant agents, etc. The synthesis of some new
potentially bioactive bis imidazo[1,2-a]pyridine derivatives have been show in reaction
scheme.
REACTION SCHEME
N
NF
CH3 N
NF
CH3
N
NF
CH3R
acetic acid
R-CHO
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 133
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Synthesis of 2-(4-Fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine.
See Part-B, Part-I, Section-I, Experimental section [A].
[B] General procedure for the preparation of 2-(4-Fluorophenyl)-3-((2-(4-
fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(aryl)methyl)-6-methyl
H-imidazo[1,2-a]pyridines.
To a mixture of 2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (4.52 g,
0.02 mol) and aromatic aldehydes (0.01 mol) in acetic acid (4 ml), sodium acetate 1.0 g
was added and refluxed for 24 hour (monitoring by TLC). After cooling to room
temperature, the reaction mixture was diluted with water and made basic with saturated
sodium carbonate solution. The solution was extracted with dichloromethane and the
organic layer was dried over anhydrous Na2SO4. After the solvent was evaporated, the
residue was chromatographed on silica gel (eluent 6 : 4 = E.A. : Hexane) to give
analytical pure products. The physical constants of the product are recorded in Table-6a.
[C] Biological evaluation of 2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH
-imidazo[1,2-a]pyridin-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]
pyridines.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-6b.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 134
Table-6a: Physical constant of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-methylH-
imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo[1,2-a]
pyridines.
N
NF
CH3
N
NF
CH3 R
Sr. No Substitution R M. F. M. W. Yield (%) Rf value
6a CH3
C36H28F2N4
554.63 73 0.52
6b S
C33H24F2N4S
546.63 67 0.54
6c
C35H26F2N4
540.60 72 0.48
6d N+
O-
O
C35H25F2N5O2
585.60 65 0.38
6e Cl
C35H25ClF2N4
575.04 71 0.42
6f NH2
C35H27F2N5
555.61 78 0.58
6g F
C35H25F3N4
558.59 63 0.61
6h Br
C35H25BrF2N4
619.50 72 0.45
6i OCH3
C36H28F2N4O
570.63 78 0.57
6j OH
C35H26F2N4O
556.60 81 0.35
TLC solvent system:- E.A. : Hexane = 6 : 4
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 135
ANALYTICAL DATA
2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(p-
tolyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6a). mp 161-163 °C; Purity by
HPLC: 87 %; IR (KBr): 3069 (Ar, C-H str), 2920 (C-H str), 2862 (C-H str), 1616 (C=N
str), 1534 (Ar, C=C str), 1464 (Ar, C=C str), 1340 (C-H ban), 1179 (C-N str), 1089 (C-F),
845 (C-H o.p. ban) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 2.34 (s, 3H, CH3), 2.44 (s,
6H, CH3), 5.34 (s, 1H, CH), 7.03-7.05 (m, 2H, ArH), 7.08-7.16 (m, 4H, ArH), 7.20-7.24
(m, 2H, ArH), 7.51-7.52 (d, J=7.16 Hz, 2H, ArH), 7.53-7.55 (d, J=9.2 Hz, 2H, ArH),
7.72-7.80 (m, 4H, ArH), 7.88-7.92 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm
18.15, 21.74, 40.49, 107.54, 115.57, 115.78, 116.63, 122.41, 123.36, 127.59, 127.67,
128.31, 129.76, 144.30, 144.55, 163.91; MS: m/z = 554 [M]+; Anal. Calcd for
C36H28F2N4: C, 77.96; H, 5.09; N, 10.10. Found: C, 76.31; H, 4.87; N, 10.03%.
2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)
(thiophen-2-yl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6b). mp 192-193 °C;
Purity by HPLC: 84 %; IR (KBr): 3068, 2977, 2823, 1600, 1576, 1435, 1377, 1150, 1067,
840 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 2.52 (s, 6H, CH3), 5.41 (s, 1H, CH), 6.54-
6.56 (m, 1H, ArH), 6.81-6.87 (m, 1H, ArH), 6.99-7.07 (m, 1H, ArH), 7.11-7.18 (m, 4H,
ArH), 7.19-7.23 (m, 2H, ArH), 7.31-7.58 (m, 2H, ArH), 7.74-7.79 (m, 4H, ArH), 7.95-
7.99 (m, 2H, ArH). 13C NMR (100 MHz, CDCl3): δ ppm 19.17, 41.12, 104.24, 111.40,
111.78, 112.90, 126.67, 126.80, 127.44, 129.04, 139.64, 140.46, 146.93, 147.14, 164.33;
MS: m/z = 546 [M]+; Anal. Calcd for C33H24F2N4S: C, 72.51; H, 4.43; N, 10.25. Found:
C, 71.78; H, 4.38; N, 10.07%.
2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)
(phenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6c). mp 175-177 °C; IR (KBr):
3099, 2975, 2849, 1599, 1557, 1439, 1366, 1134, 1054, 842 cm-1; MS: m/z = 541 [M+1]+;
Anal. Calcd for C35H26F2N4: C, 77.76; H, 4.85; N, 10.36. Found: C, 77.17; H, 4.71; N,
10.23%.
2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(4-
nitrophenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6d). mp 209-211 °C; IR
(KBr): 3081, 2966, 2843, 1634, 1584, 1446, 1366, 1240, 1138, 1031 cm-1; MS: m/z = 585
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 136
[M]+; Anal. Calcd for C35H25F2N5O2: C, 71.79; H, 4.30; N, 11.96. Found: C, 70.70; H,
4.17; N, 11.79%.
3-((4-Chlorophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)
methyl)-2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (6e). mp 203-204 °C;
IR (KBr): 3087, 2988, 2867, 1616, 1558, 1467, 1346, 1135, 1021, 720 cm-1; MS: m/z =
577 [M+2]+; Anal. Calcd for C35H25ClF2N4: C, 73.10; H, 4.38; N, 9.74. Found: C, 72.18;
H, 4.26; N, 9.66%.
4-(Bis(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)methyl)
benzenamine (6f). mp 185-187 °C; IR (KBr): 3490, 3073, 2973, 2864, 1611, 1567, 1454,
1386, 1138, 1036 cm-1; MS: m/z = 556 [M+1]+; Anal. Calcd for C35H27F2N5: C, 75.66; H,
4.90; N, 12.60. Found: C, 75.18; H, 4.77; N, 12.43%.
2-(4-Fluorophenyl)-3-((4-fluorophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-
a]pyridin-3-yl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6g). mp 232-234 °C; IR
(KBr): 3090, 2961, 2853, 1614, 1546, 1467, 1369, 1129, 1043 cm-1; MS: m/z = 558 [M]+;
Anal. Calcd for C35H25F3N4: C, 75.26; H, 4.51; N, 10.03. Found: C, 74.83; H, 4.25; N,
9.83%.
3-((4-Bromophenyl)(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)
methyl)-2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridine (6h). mp 226-228 °C;
IR (KBr): 3088, 2976, 2858, 1606, 1568, 1434, 1374, 1144, 1046, 840 cm-1; MS: m/z =
619 [M]+; Anal. Calcd for C35H25BrF2N4: C, 67.86; H, 4.07; N, 9.04. Found: C, 67.33; H,
3.83; N, 9.00%.
2-(4-Fluorophenyl)-3-((2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)(4-
methoxyphenyl)methyl)-6-methylH-imidazo[1,2-a]pyridine (6i). mp 157-159 °C; IR
(KBr): 3087, 2973, 2851, 1600, 1587, 1446, 1379, 1099, 1063 cm-1; MS: m/z = 570 [M]+;
Anal. Calcd for C36H28F2N4O: C, 75.77; H, 4.95; N, 9.82. Found: C, 75.15; H, 4.58; N,
9.53%.
4-(Bis(2-(4-fluorophenyl)-6-methylH-imidazo[1,2-a]pyridin-3-yl)methyl)phenol (6j).
mp 177-178 °C; IR (KBr): 3440, 3082, 2946, 2864, 1609, 1579, 1446, 1378, 1149, 1081
cm-1; MS: m/z = 557 [M+1]+; Anal. Calcd for C35H26F2N4O: C, 75.52; H, 4.71; N, 10.07.
Found: C, 74.67; H, 4.47; N, 9.84%.
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 137
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 6a
Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 6a
Minutes0 1 2 3 4 5 6 7 8 9 10 11 12
0
50
100
1.24
8 2
2122
1.7
4
1.70
7 5
887
0.4
61.
813
315
0 0
.25
2.06
9 4
6010
3.6
2
2.60
3 1
1146
34 8
7.75
3.48
8 4
9490
3.9
0
4.37
3 2
1377
1.6
8
6.41
1 2
019
0.1
6
7.28
5 3
502
0.2
8
7.89
3 2
011
0.1
6
5007501000125015001750200025003000350040001/cm
30
45
60
75
90
105
%T
3069
.81
3003
.27
2920
.32
2868
.24
1616
.40
1588
.43
1534
.42
1464
.02
1424
.48
1340
.57
1301
.03
1179
.51
1148
.65
1123
.57
1089
.82
1050
.28
1007
.84
988.
5596
3.48
845.
8180
7.24
751.
3067
8.97
581.
5653
4.30
475.
4742
725
JP-104
N
N
N
N
CH3
F
F
CH3CH3
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 138
Mass spectrum of compound 6b
Mass spectrum of compound 6c
N
N
N
N F
F
CH3CH3
M. Wt. = 540.60
N
N
N
N F
F
CH3CH3 S
M. Wt. = 546.63
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 139
1H NMR spectrum of compound 6a
Expanded spectrum of compound 6a
N
N
N
N
CH3
F
F
CH3CH3
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 140
1H NMR spectrum of compound 6b
Expanded spectrum of compound 6b
N
N
N
N F
F
CH3CH3 S
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 141
13C NMR spectrum of compound 6a
13C NMR spectrum of compound 6b
N
N
N
N
CH3
F
F
CH3CH3
N
N
N
N F
F
CH3CH3 S
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 142
Table-6b: Antimicrobial activity of 2-(4-Flurophenyl)-3-((2-(4-flurophenyl)-6-
methylH-imidazo[1,2-a]pyridine-3-yl)(aryl)methyl)-6-methylH-imidazo
[1,2-a]pyridines.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
6a 250 500 100 500 250 500 1000 6b 200 100 250 100 200 1000 500 6c 50 100 250 100 1000 500 250 6d 250 250 500 500 500 250 500 6e 200 250 100 250 250 500 250 6f 500 250 200 100 200 250 250 6g 100 500 125 500 500 1000 500 6h 250 100 500 200 1000 500 250 6i 250 200 200 200 500 200 500 6j 125 100 250 100 250 250 250
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Bis imidazo[1,2-a]pyridine derivatives… 143
REFERENCES
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Part – C
Introduction
Studies on Thiophene Derivatives
Studies on chemical…
Thiophene derivatives… 145
INTRODUCTION
Thiophene-2-carbaldehyde (1) is an aromatic heterocyclic compound consisting of
four carbon atoms and one sulfur atom in a five-membered ring. Thiophene was
discovered by Viktor Meyer in 1883 as a contaminant in benzene.1 Related to thiophene
are benzothiophene and dibenzothiophene, containing the thiophene ring fused with one
and two benzene rings.
It was observed that isatin forms a blue dye if it is mixed with sulfuric acid and
crude benzene. Victor Meyer was able to isolate the substance responsible for this
reaction from benzene. This new heterocyclic compound was thiophene.2
SO
(1)
Thiophenes are important class of heterocyclic compounds and are recurring
building blocks in organic chemistry with applications in pharmaceuticals. The benzene
ring of a biologically active compound may often be replaced by a thiophene without loss
of activity.3 Thiophene and its derivatives occur in petroleum, sometimes in
concentrations up to 1-3%. The thiophenic content of liquids from oil and coal is removed
via the hydrodesulfurization (HDS) process.
SYNTHETIC ASPECT
Various methods for the preparation of thiophene derivatives have been cited in
literature, some of the methods are as under.
1. Y. Kopylov and coworkers4 synthesized thiophene via butane, (methyldi-
sulfanyl)ethane, (ethyldisulfanyl)ethane and aluminum oxide as a catalyst.
CH3
CH3
CH3S S
CH3
Et SS Et
SAl2O3, 450 °C75 min+ +
2. Liang, Xinmiao and coworkers5 have synthesized thiophene using ferrous nitrate
and cynomethane.
S
OHSFe(NO3)3,CH3CN
12 hrs , RT
Studies on chemical…
Thiophene derivatives… 146
3. Moon, Jeongju and coworkers6 synthesized thiophenes and 2,2'-bithiophene using
sodium butoxide and cyclohexenone, palladium as catalyst.
S Br NaoBu, Cyclohexanol
Ph2,Pentadienone Pd
S S S+
4. N. T. Berberova et al.7 have synthesized thiophenes and thiophene-2-thiol via
dichloro methane and hydrogen sulphide at 20-25 °C.
O S SH SH2S, CH2Cl2
+
5. A. R. Katritzky et al.8 have synthesized thiophenes from 2,5-dimethylthiophene
using hydrophosphoric acid.
S CH3CH3
SH3PO4
6. E. N. Deryagina and coworkers9 synthesized thiophenes from 2-chlorothiophene
and ethyne.
S Cl S
CH CH
THERAPEUTIC IMPORTANCE
Over recent years there has been an increasing interest in the chemistry of
thiophene because of their biological significance.
1. Analgesic10
2. Antimicrobial11,12
3. Anticonvulsant13,14
4. Antifungal15
5. Antihistaminic16
6. Antiinflammatory17,18
7. Antitumor19,20
8. Antiviral21,22
Studies on chemical…
Thiophene derivatives… 147
9. Diuretic23
10. Insecticidal24
11. Antipsychotic25
12. Anticancer26,27
S. F. Mohmad28 have prepared {[4-(thiophen-2-yl)-3,4,5,6-tetrahydrobenzo
[H]quinazolin-2-yl]sulfanyl} acid (2) as a antiviral and anticancer agent.
NH
N
S
S
OOH
(2)
Gautam Panda29 have prepared 2-{phenyl[4-(2-phenylethoxy)phenyl] methyl}
thiophene (3) and tested for its antitubercular activity.
S
OR
(3)
M. S. Malamas and coworkers30 have synthesized novel thiophene derivatives
inhibitors of protein tyrosine phosphatase 1B with antihyperglycemic properties. S. S.
Perez et al.31 developed 5-substituted thiophene derivatives with dual action at 5-HT1A
serotonin receptors and serotonin transporter as a new class of antidepressants. Synthesis
and serotonergic activity of thiophene-4-piperazine derivatives as novel antagonists for
the vascular 5-HT1B receptor has been achieved by G. P. Moloney and group.32
Derivatives of benzo[b]thiophene are also available as drug, some of them are
shown as under:
Studies on chemical…
Thiophene derivatives… 148
S
NOH NH2
O
Zileuton (ZYFLOTM)Antiashthamatic
S
OH
OH
O
ON
RaloxifeneAnticancer/Osteroporosis
S
Cl
O
NN Cl
Cl
SertaconazoleAntifungal
Work done from our laboratory
V. V. Kachhadia et al.33 have synthesized 6-carbethoxy-5-aryl-3-[p-(3'-chloro-2'-
benzo[b]thiophenoylamino)phenyl]-2-cyclohexenones derivatives bearing benzo[b]
thiophene nucleus and reported their antitubercular and antimicrobial activity.34
S. L. Vasoya et al.35 reported facile synthesis of some new azetidinones and acetyl
oxadiazoles as a potent biological active agent, he also synthesized thiosemicarbazides
and 1,3,4-thiadiazoles as potent antitubercular and antimicrobial agents,36 moreover he
has reported thiosemicarbazide and 1,2,4-triazoles heterocycles as a potent antitubercular
and antimicrobial agents37 bearing benzo[b]thiophene nucleus.
Prior art search reveals that thiophene derivatives are proved to be potent
biodynamic agents, for their various methods of synthesis and different biological
activities, synthesis of thiophene derivatives have been undertaken in order to achieving
superior therapeutic agents. This can be summarized in the following sections as under.
STUDIES ON THIOPHENE DERIVATIVES
PART-I: STUDIES ON PYRAZOLINE DERIVATIVES
PART-II: STUDIES ON PYRIMIDINE DERIVATIVES
Studies on chemical…
Thiophene derivatives… 149
REFERENCES
1. V. Meyer, Berichte der Deutschen chemischen Gesellschaft, 16, 1465-1478 (1883).
2. W. C. Sumpter, Chemical Reviews, 34(3), 393-434 (1944).
3. D. Lednicer, Wiley Interscience, 14, 187 (1999).
4. A. Y. Kopylov, R. R. Sadykov, K. G. Sadikov, A. M. Mazgarov, A. V. Vildanov, Z. R.
Ismagilov, S. R. Khairulin, S. A. Yashnik, Uglevodorodnogo Syrya Neftekhimiya, 48(2),
112-117 (2008).
5. L. Xinmiao, W. Xinliang, L. Renhua, X. Qing, X. Xingya, Z. Feifang, Faming Zhuanli
Shenqing Gongkai Shuomingshu, CN 101544548, pp 13 (2009).
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(2009).
14. K. P. Kumar, J. V. Rao, K. Mukkanti, M. B. Raju, K. A. Khan, Journal of Pharmacy
Research, 3(5), 1021-1024 (2010).
15. S. Bondock, W. Fadaly, M. A. Metwally, Eur. J. Med. Chem., 45(9), 3692-3701 (2010).
16. W. J. Moree, F. Jovic, T. Coon, J. Yu, B. Li, F. C. Tucci, D. Marinkovic, R. S. Gross, S.
Malany, M. J. Bradbury, Bioorg. Med. Chem. Lett., 20(7), 2316-2320 (2010).
17. R. P. Alexander, B. Stuart, D. C. Brookings, J. A. Brown, C. Sacha, F. C. Pollard, PCT
Int. Appl. WO 2010001126, pp 46 (2010).
18. B. Ramesh, B. Someswara Rao, E-Journal of Chemistry, 7(2), 433-436 (2010).
19. M. A. El-Sherbeny, A. A. Abdel-Aziz, M. A. Ahmed, Eur. J. Med. Chem., 45(2), 689-
697 (2010).
20. K. Wilson, D. A. Gabriela, H. Andrew, K. Kaleen, M. Michelle, Z. Anna, PCT Int. Appl.
WO 2010005841, pp 74 (2010).
21. M. R. Leivers, R. Lauchli, PCT Int. Appl. WO 2010006096, pp 236 (2010).
Studies on chemical…
Thiophene derivatives… 150
22. A. E. Rashad, A. H. Shamroukh, R. E. Abdel-Megeid, A. Mostafa, R. El-Shesheny, A.
Kandeil, M. A. Ali, K. Banert, Eur. J. Med. Chem., 45(11), 5251-5257 (2010).
23. S. M. Abdel Wahab, N. M El-Fiki, M. A. Amin, S. F. Mostafa, Bulletin of the Faculty of
Pharmacy (Cairo University), 45(1), 93-104 (2007).
24. J. W. Hull, D. R. Romer, T. J. Adaway, D. E. Podhorez, Organic Process Research &
Development, 13(6), 1125-1129 (2009).
25. O. Tadaaki, I. Nobuaki, Y. Hiroshi, M. Shin, M. Motoyuki, M. Jun, PCT Int. Appl. WO
2009128537, pp 46. (2009).
26. S. Fletcher, E. P. Keaney, C. G. Cummings, M. A. Blaskovich, M. A. Hast, M. P. Glenn,
S. Y. Chang, C. J. Bucher, R. J. Floyd, W. P. Katt, J. Med. Chem., 53(19), 6867-6888
(2010).
27. M. A. Shaaban, M. M. Ghorab, H. I. Heiba, M. M. Kamel, N. H. Zaher, M. I. Mostafa,
Arch. Pharm., 343(7), 404-410 (2010).
28. S. F. Mohmad, H. K. Thabet, E. E. Mustafa, M. M Abdalla, S. H. Shafik, World J.
Chemistry, 4(2), 100-108, (2009).
29. G. Panda, M. K. Parai, A. K. Shrivastava, V. Chaturvedi, Y. K. Manju, S. Sinha, Indian J.
Chem.: B, 48(B), 1121-1127, (2009).
30. M. S. Malamas, J. Sredy, C. Moxham, A. Katz, F. O. Adebayo, D. R. Sawicki, J. R.
Taylor, J. Med. Chem., 43(7), 1293-1310 (2000).
31. S. S. Perez, E. J. Martinez, B. Lasheras, R. J. Del, A.Monge, Pharmazie, 59(7), 499-501
(2004).
32. G. P. Moloney, A. Garavelas, G. R. Martin, M. Maxwell, R. C. Glen, Eur. J. Med. Chem.,
39(4), 305-321 (2004).
33. V. V. Kachhadia, K. H. Popat, K. S. Nimavat, H. S. Joshi, J. Indian Chem. Soc., 81(8),
694-695 (2004).
34. V. V. Kachhadia, M. R. Patel, H. S. Joshi, J. Serb. Chem. Soc., 70(2), 153-161 (2005).
35. S. L. Vasoya, M. R. Patel, S. V. Dobaria, H. S. Joshi, Indian J. Chem.: B, 44(2), 405-409
(2005).
36. S. L. Vasoya, D. J. Paghdar, P. T. Chovatia, H. S. Joshi, J. Sci., I. R. Iran, 16(1), 33-36,
(2005).
37. S. L. Vasoya, P. T. Chovatia, D. J. Paghdar, H. S. Joshi, J. Indian Chem. Soc., 84(7), 709-
710, 2007.
Part – C
(Part – I)
Studies on Pyrazoline Derivatives
Studies on chemical…
Pyrazole derivatives… 151
INTRODUCTION
The chemistry of pyrazoles has been reviewed by Jarobe in 1967. Pyrazoles have
attracted attention of medicinal chemists for both with regard to heterocyclic chemistry
and the pharmacological activities associated with them. Pyrazole have been studied
extensively because of ready accessibility, diverse chemical reactivity, broad spectrum of
biological activity1 and varieties of industrial applications.2
Pyrazole has three possible tautomeric structures. But 2-pyrazole (1) consist a
unique class of nitrogen containing five member heterocycles.
NNH(1)
As evident from the literature in recent years a significant portion of research
work in heterocyclic chemistry has been devoted to pyrazoles containing different alkyl,
aryl and heteroaryl groups as substituents.
SYNTHETIC ASPECT
Different methods are available from the literature for the preparation of 2-
pyrazole derivatives. The most common procedure for the synthesis of 2-pyrazoles is the
reaction of an aliphatic or aromatic hydrazine with α,β-unsaturated carbonyl compounds.
R1
O
R2 NH2 NH
RN
NR
R2
R1
+
ALTERNATIVE SYNTHETIC ROUTES FOR IMPROVED YIELD, SHORTER
REACTION TIME AND MILDER CONDITIONS TO SYNTHESIZE NEW ANALOGS
Solid-Phase Synthesis
L. L. De3 reported cellulose beads as a new versatile solid support for microwave-
assisted synthesis of pyrazole and isoxazole libraries.
Studies on chemical…
Pyrazole derivatives… 152
R
O
YOR
1
CSA (cat.)
MW
Cellulose
R
O
Y
OR
1
NHNH2XH
MW
XN R
YO R
1
N
N
CH(OCH3)2
Cellulose NH2
Cellulose NH2
Wang resin supported solid-phase synthesis of pyrazoledicarboxylic acid
derivatives by functionalization of cyanoformate was reported by C. F. Morelli et al.4
OH OCN
O
O
O N NR
3
R1
OO
R2
Similarly many other solid phase synthesis of pyrazole motif were reported using
different solid support such as (4-formyl-3-methyoxyphenoxy)methylpolystyrene (FMP)
resin,5 polymer-supported vinylsulfone,6 Kenner ‘safety catch’ resin,7 KOH powder.8
Liquid-Phase Synthesis
X. L. Ren and coworkers9 have synthesized pyrazole derivatives using liquid
phase synthesis strategy.
R
1
R2 R
NNHR
1
NH2R
NH2NH2 . HCl
V. N. Pathak and coworkers10,11 reported 3,5-diarylpyrazole synthesis using phase
transfer catalyst. Heterocyclic pyrazole was synthesized by the W. C. Shen and
coworkers.12
Microwave Assisted Synthesis
Microwave irradiation and solvent-free conditions was reported for the rapid and
efficient synthesis of pyrazole was reported by M. A. H. Zahran.13
R CHONH2
XH
MWNR
HOH
N
XR+
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Pyrazole derivatives… 153
New "Green" approaches to the synthesis of pyrazole derivatives were reported by
A. Corradi et al.14
H
R H
OR
1
NH2NHTs, K2CO3
MW, 130 °C
H
R H
NR
1
NHTsNN
R
R1
H
Similarly in literature there are number of the reports for the use of microwave
irradiation for the rapid synthesis, high yield or towards the green approach of the
reaction under solvent free conditions. Some of them are reported as below.
S. S. Chauhan15 derived pyrazoles from diaryl 1,3-diketones, I. Rinski and
coworkers16 prepared 1,3-dipolar cycloaddition of diazo compounds to acetylene
derivatives, M. A. P. Martins et al.17 reported regiospecific synthesis of 5-trifluoromethyl-
4,5-dihydropyrazoles, H. S. P. Rao18 derived microwave mediated combinatorial
synthesis, S. A. Swelam19 derived pyrazole under dry media, M. A. P. Martins and
coworkers20 reported regiospecific synthesis of pyrazole, B. R. Rao and
coworkers21synthesis pyrazole by use of p-toluenesulphonic acid and S. Katade et al.22
reported microwave synthesis of pyrazole.
P. Kumar et al.23 have synthesized of pyrazole chalcones under solvent free
condition at room temperature. X. H. Liu et al.24 reported novel dihydropyrazole
derivatives linked with 4H-chromene.
Catalysts
Many of the organic chemists prefered to use catalyst to get the desire product
with high yield and within sort reaction time and to convert the reaction condition from
drastic to easily operational with some specific catalyst.
R. Ali reported stereoselective synthesis of N-vinyl pyrazoles in solvent-free
conditions using dipotassium hydrogen phosphate powder.25 Zinc-catalyzed syntheses of
pyrazolines and pyrazoles via hydrohydrazination were reported by K. Alex.26
NHNH2
OH 5 mol % Zn(OTf)2 NN CH3COOH, air N
N
RR R
+
Studies on chemical…
Pyrazole derivatives… 154
In literature there are number of the catalysts are used for the synthesis of pyrazole
system like Conjugate base,27 Iodine(III),28 Hafnium chloride,29 Tungstophosphoric
acid,30 p-Toluenesulphonic acid,31 Sulfamic acid,32 Ytterbium(III)perfluorooctanoate,33
Silver(I),34 Organocatalysts.35
REACTION MECHANISM
The following mechanism seems to be operable for pyrazoline by the
condensation of chalcones with hydrazine hydrate.36
R
O
R1
R CH-
O
R1
NH2+NHR
2
NH2NH - R2. .
H+ transferR
C+
CH-
OH
R1
NHNHR
2
R
O
R1
NHNHR
2
N NH
R1
OHR
R2N N
H
R1
R2
R - H2O
( I ) ( II )
( III ) ( IV )( V )
Nucleophillic attack by hydrazine at the β-carbon of the α,β-unsaturated carbonyl
system (I) forms species (II), in which the negative charge is mainly accommodated by
the electronegative oxygen atom.
Proton transfer from the nitrogen to oxygen produces an intermediate and which
simultaneously ketonises to ketoamine (III). Another intramolecular nucleophillic attack
by the primary amino group of ketoamine on its carbonyl carbon followed by proton
transfer from nitrogen to oxygen leads ultimately to hydroxyl amine (IV). The later with a
hydroxy group and amine group on the same carbon loses water easily to yield the
pyrazolines (V).
THERAPEUTIC IMPORTANCE
From the literature survey, it was revealed that 2-pyrazolines are better therapeutic
agents. They possess valuable bioactivities like
Studies on chemical…
Pyrazole derivatives… 155
1. Antiinflammatory37,38
2. Analgesic39,40
3. Bactericidal41
4. Fungicidal42,43
5. Anticonvulsant44
6. Pesticidal45,46
7. Antidepressant47
8. Antiamoebic48
9. Insecticidal49
10. Antineoplastic50,51
11. Herbicidal52
M. K. Shivnanda and coworkers53 have prepared pyrazolines and reported their
antibacterial activity. Antimicrobial activity of pyrazoline derivatives (2) have been
reported by K. N. Sharma et al.54 J. Almstead et al.55 have prepared pyrazolines as
vascularization agent. T. Z. Gulhan and coworkers56 have prepared pyrazolines as a
hypotensive agent.
NH
O
N NR2
R1
(2)
M. Q. Fan et al.57 have synthesized pyrazolines and tested their antidepressant
activity. Antiamoebic activity of pyrazoline derivatives have been reported by Asha
Budakoti and coworkers.58 J. H. Ahn et al.59 have reported cyanopyrazoline (3)
derivatives as potent antidiabetic agents. T. S. Jeong et al.60 have synthesized some novel
3,5-diaryl pyrazolines (4) as human acyl-Co A: cholesterol acyltransferase inhibitors. G.
Ucar et al.61 reported pyrazolines as cholinstearase andselective monoamine oxidase-B
inhibitiors for the treatment of parkinson and alzheimer’s diseases. M. N. Nasr et al.62
have reported the synthesis of newer arylthiazolylpyrazoline derivatives as
antiinflammatory agents. M. A. Berghot et al.63 have prepared for convergent synthesis
and antibacterial activity of pyrazole and pyrazoline derivatives of diazepam.
Studies on chemical…
Pyrazole derivatives… 156
N NH
OH OH
R
R2R
1
t - Bu
NN
CNONH
R
(3) (4)
N. Gokhan et al.64 have synthesized the pyrazoline derivatives of 1-N-substituted
thiocarbamoyl-3-phenyl-5-thienyl-2-pyrazolines (5) as MAO inhibitors. Mohammad
Abid and Amir Azam65 have synthesized 1-N-substituted cyclized pyrazoline of
thiosemicarbazones (6) and reported as antiamoebic agents. V. Malhotra et al.66 have
documented new pyrazolines as a cardiovascular agents. Antidepressant activity of
pyrazoline derivatives have been reported by M. Q. Fan and coworkers.67
NN R
CH3
ClNN
S
S
NHR
1
R
(5) (6)
Abd El-Galil E. Amr et al.68 have synthesized some new 3-substituted
androstano[17,16-c]-5,2-aryl-pyrazolines and reported their antiandrogenic activity. B.
Bizzarri et al.69 have reported in vitro selective anti-helicobacter pylori activity (7) of
pyrazoline derivatives. Bhat and coworkers70 reported cytotoxic properties of pyrazoline
derivatives. Antibacterial activity of pyrazoline derivatives have been reported by A. M.
Gandhi and coworkers.71 S. Bondock et al.72 have synthesized pyrazolines as
antimicrobial agents. S. P. Hiremath et al.73 have synthesized pyrazolines as analgesic,
antiinflammatory and antimicrobial agents. Rajendra Prasad et al.74 have synthesized
some 1,3,5-triphenyl-2-pyrazolines (8) and 3-(2"-hydroxynaphthalen-1"-yl)-1,5-diphenyl-
2-pyrazolines and reported as antidepressant agents. J. H. M. Lange et al.75 synthesized
and reported 3,4-diaryl pyrazoline analogues as potent and selective CB1 cannabinoid
receptor antagonists. N. T. Ha Duong et al.76 have been synthesized some pyrazole
derivatives as inhibitors for the active sites of human liver cytochromes P450 of the 2C
subfamily.
Studies on chemical…
Pyrazole derivatives… 157
NN
R
R1
NNR
2
R1R
(7) (8)
X. Zhang and coworkers77 have been prepared pyrazoline derivatives (9) as potent
selective androgen receptor modulators. R. M. Mohareb and coworkers78 have been
reported pyrazole derivatives (10) as a antitumor agent.
NH
N
O
NH
R6R
5
R3R
2
R1 R
4
(9)
NN
COCH2CN
NH2
X
(10)
F. Chimenti and coworkers79 have been demonstrated a novel series of 1-acetyl-3-
(4-hydroxy and 2,4-dihydroxyphenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole derivatives
(11) and investigated for the ability to selectively inhibit the activity of monoamine
oxidase (MAO). Y. R. Huang et al.80 have been prepared a series of 4-alkyl-1,3,5-
triarylpyrazoles (12) as ligands for the estrogen receptor. C. D. Cox et al.81 and J. R.
Goodell et al.82 have been reported separately some pyrazoline derivatives as anti-obesity
agents by antagonizing CB1 receptors and therapeutic candidates for parkinson’s disease.
A series of 3-(4-fluorophenyl)-4,5-dihydro-N-[4-(trifluoromethyl)-phenyl]-4-[5-
(trifluoromethyl)-2-pyridyl]-1H-pyrazole-1-carboxamide has been synthesized and
studied for their potent foliar activity against both lepidoptera and orthoptera insects by P.
K. Leonard et al.83 Bruce G. Szczepankiewicz et al.84 have been prepared some pyrazole
derivatives as ant mitotic agents with activity in multi-drug resistant cell lines.
N N
R1
R2NN
O
R1
R
(11) (12)
Studies on chemical…
Pyrazole derivatives… 158
Guniz Kuchkguzel et al.85 have synthesized pyrazolines as a antimicrobial and
anticonvulsant agents. P. Singh and coworkers86 have prepared pyrazolines as a antitumor
agent.
Work done from our laboratory
K. S. Nimavat87 have synthesized 1-substituted 3-aryl-5-(3’-bromophenyl)-
pyrazolines which shows anticancer, antitubercular and antimicrobial activity. D. H.
Vyas88 reported synthesis and biological activity of some pyrazoline derivatives bearing
3,5-dibromo-4-methoxybenzaldehyde nucleus.
P. T. Chovatia89 have been reported 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-
pyrazole derivatives as a antitubercular and antimicrobial agent. T. K. Dave90 reported
synthesis, antitubercular and antimicrobial evaluation of pyrazole derivatives bearing
nicotinic acid nucleus. Synthesis of some pyrazolo[3,4-d]pyrimidines and thiazolo[4,5-
d]pyrimidines and evaluation of their antimicrobial activities with derivatives of urea and
thiourea was reported by J. D. Akbari et al.91,92
Literature survey reveals that the compounds bearing pyrazole moiety possess
potential drug activity. Looking to the diversified biological activities we have
synthesized some pyrazole derivatives in order to achieving better therapeutic agents.
These studies are described in following section.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 1H-INDOL-2-
YL[3-ARYL/THIOPHENE-5-(THIOPHEN/ARYL-2-YL)-4,5-
DIHYDRO-1H-PYRAZOL-1-YL]METHANONES.
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Pyrazole derivatives… 159
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 1H-INDOL-2-YL[3-
ARYL/THIOPHENE-5-(THIOPHEN/ARYL-2-YL)-4,5-DIHYDRO-1H-PYRAZOL-
1-YL]METHANONES.
Pyrazole derivatives represent one of the most active class of compound having a
wide spectrum of biological activities. Looking to the interesting properties of pyrazoles
it was considered worthwhile to synthesize a series of pyrazoles for obtaining biologically
potent agent which were prepared by reacting chalcones with 1H-indole-2-
carbohydrazide in glacial acetic acid.
REACTION SCHEME
NH
NH
O
NH2
SO
R
SO
R
NH
NN
S
O
R
NH
NN
O
S
R
gla. acetic acid
gla. acetic acid
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Pyrazole derivatives… 160
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in CDCl3 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Preparation of 1H-Indole-2-carbohydrazide.
See Part-A, Part-II, Section-I, Experimental section [A].
[B] Preparation of 1-Phenyl-3-(thiophen-2-yl)prop-2-en-1-ones.
These were prepared by condensation of thiophen-2-carbaldehyde and substituted
acetophenones in the presence of sodium hydroxide as described by N. M. Rateb93 and
Dalla Via,94 M. M. Hania.95
[C] Preparation of 3-Phenyl-1-(thiophen-2-yl)prop-2-en-1-one.
These were prepared by condensation of 2-acetylthiophen and substituted aryl
aldehyde in the presence of sodium hydroxide as described by B. Ramesh et al.96
[D] General procedure for the preparation of 1H-Indol-2-yl[3-aryl/thiophene-5-
(thiophen/aryl-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.
1H-Indole-2-carbohydrazide (1.75 g, 0.01 mol) was charged into 250 ml round
bottom flask. 10 ml of glacial acetic acid was added to dissolve it. Then add substituted
chalcones (0.01 mol). The reaction mixture was refluxed on an oil bath for 12 hour. The
progress and the completion of the reaction were monitoring by TLC. After the
completion of reaction the mixture was poured onto crushed ice to give solid product.
Finally, it was purified by colum chromatography. (eluent 3 : 7 = E.A. : Hexane)
Similarly other compounds were prepared. The physical constants of the product are
recorded in Table-7a.
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Pyrazole derivatives… 161
[E] Biological evaluation of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-
yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-7b.
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Pyrazole derivatives… 162
Table-7a: Physical constant of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-2-
yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.
NH
NN
R
R1
O
Sr. No Substitution R Substitution R1 M. F. M. W. Yield
(%) Rf
value
7a S
Cl
C22H16ClN3OS
405.89 68 0.41
7b ″ CH3
C23H19N3OS
385.48 73 0.53
7c ″
C22H17N3OS
371.45 71 0.67
7d ″ F
C22H16FN3OS
389.44 69 0.49
7e ″ Cl
Cl
C22H15Cl2N3OS
440.34 82 0.59
7f ″
NH2 C22H18N4OS
386.46 75 0.54
7g ″ NH2
C22H18N4OS
386.46 63 0.66
7h ″ N
+O
-
O C22H16N4O3S
416.45 77 0.43
7i ″ Br
C22H16BrN3OS
450.35 75 0.51
7j ″ OH
C22H17N3O2S
387.45 68 0.55
7k F
S C22H16FN3OS
389.44 81 0.47
7l
Cl
″
C22H16ClN3OS
405.89 76 0.46
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Pyrazole derivatives… 163
7m CH3
″
C23H19N3OS
385.48 73 0.53
7n
″
C22H17N3OS
371.45 66 0.64
7o Cl
″
C22H16ClN3OS
405.89 62 0.68
7p N
+
O-
O
″
C22H16N4O3S
416.45 68 0.50
7q N+
O-
O
″
C22H16N4O3S
416.45 74 0.38
7r NH2
″
C22H18N4OS
386.46 62 0.48
7s Br
″
C22H16BrN3OS
450.35 80 0.39
7t
OCH3
″
C23H19N3O2S
401.48 79 0.59
TLC solvent system:- E.A. : Hexane = 3 : 7
ANALYTICAL DATA
[5-(4-Chlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7a). mp 145-147 °C; Purity by HPLC: 94 %; IR (KBr): 3365 (N-H str), 3090
(Ar, C-H str), 2955 (C-H str), 2908 (C-H str), 1637 (amide, C=O str), 1610 (C=N str),
1556 (Ar, C=C str), 1475 (Ar, C=C str), 1184 (N-N str), 1014 (C-N str), 796 (C-Cl) cm-1; 1H NMR (400 MHz, CDCl3): δ ppm 3.20-3.26 (dd, J=3.92&17.60 Hz, 1H, CH), 3.70-
3.76 (dd, J=8.64&16.60 Hz, 1H, CH), 5.82-5.86 (dd, J=3.80&11.40 Hz, 1H, CH), 6.87-
6.98 (m, 2H, ArH), 7.02-7.16 (m, 2H, ArH), 7.19-7.25 (m, 1H, ArH), 7.27-7.44 (m, 4H,
ArH), 7.45-7.57 (m, 2H, ArH), 7.59-7.68 (m, 1H, ArH), 9.61 (s, 1H, NH). 13C NMR (100
MHz, CDCl3): δ ppm 41.97, 55.43, 115.84, 124.70, 124.83, 125.08, 126.87, 127.86,
127.95, 128.15, 128.40, 129.07, 129.31, 129.74, 130.37, 130.45, 131.10, 137.01, 159.23,
164.58; MS: m/z = 405 [M]+; Anal. Calcd for C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35.
Found: C, 65.03; H, 3.85; N, 10.21%.
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Pyrazole derivatives… 164
1H-Indol-2-yl[5-(4-methylphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]
methanone (7b). mp 231-232 °C; Purity by HPLC: 97 %; IR (KBr): 3580, 3072, 2956,
2842, 1682, 1600, 1582, 1438, 1146, 1021, 840 cm-1; 1H NMR (400 MHz, CDCl3): δ ppm
2.44 (s, 3H, CH3), 3.36-3.42 (dd, J=4&17.6 Hz, 1H, CH), 3.73-3.80 (dd, J=11.36&17.6
Hz, 1H, CH), 6.12-6.16 (dd, J=3.96&11.32 Hz, 1H, CH), 7.08-7.19 (m, 4H, ArH), 7.27-
7.33 (m, 4H, ArH), 7.39-7.46 (m, 1H, ArH), 7.63-7.68 (m, 1H, ArH), 7.74-7.76 (d,
J=8.16 Hz, 2H, ArH), 9.79 (s, 1H, NH). 13C NMR (100 MHz, CDCl3): δ ppm 21.64,
21.72, 41.13, 56.65, 110.44, 111.85, 120.39, 120.82, 122.63, 124.84, 124.94, 126.87,
126.91, 128.26, 128.35, 128.58, 128.65, 129.36, 129.47, 129.72, 131.97, 136.87, 141.54,
143.95, 156.00, 158.42; MS: m/z = 387 [M+2]+; Anal. Calcd for C23H19N3OS: C, 71.66;
H, 4.97; N, 10.90. Found: C, 71.49; H, 4.82; N, 10.86%.
1H-Indol-2-yl[5-phenyl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanone
(7c). mp 169-171 °C; IR (KBr): 3561, 3071, 2941, 2862, 1683, 1621, 1558, 1423, 1175,
1012 cm-1; MS: m/z = 371 [M]+; Anal. Calcd for C22H17N3OS: C, 71.14; H, 4.61; N,
11.31. Found: C, 71.02; H, 4.55; N, 11.27%.
[5-(4-Fluorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7d). mp 133-135 °C; IR (KBr): 3568, 3086, 2955, 2872, 1681, 1593, 1588,
1568, 1422, 1156, 1113, 820 cm-1; MS: m/z = 390 [M+1]+; Anal. Calcd for C22H16FN3OS:
C, 67.85; H, 4.14; N, 10.79. Found: C, 67.76; H, 4.10; N, 10.69%.
[5-(2,4-Dichlorophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-
yl)methanone (7e). mp 128-130 °C; IR (KBr): 3572, 3071, 2936, 2858, 1686, 1598,
1570, 1554, 1429, 1188, 1050, 720 cm-1; MS: m/z = 441 [M+1]+; Anal. Calcd for
C22H15Cl2N3OS: C, 60.01; H, 3.43; N, 9.54. Found: C, 59.87; H, 3.31; N, 9.42%.
[5-(3-Aminophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7f). mp 205-207 °C; IR (KBr): 3564, 3068, 2976, 2828, 1684, 1613, 1579,
1546, 1438, 1164, 1049, 780 cm-1; MS: m/z = 386 [M]+; Anal. Calcd for C22H18N4OS: C,
68.37; H, 4.69; N, 14.50. Found: C, 67.35; H, 4.47; N, 14.37%.
[5-(4-Aminophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7g). mp 117-119 °C; IR (KBr): 3579, 3079, 2982, 2837, 1690, 1609, 1559,
Studies on chemical…
Pyrazole derivatives… 165
1558, 1429, 1186, 1020, 740 cm-1; MS: m/z = 386 [M]+; Anal. Calcd for C22H18N4OS: C,
68.37; H, 4.69; N, 14.50. Found: C, 67.89; H, 4.52; N, 14.35%.
1H-Indol-2-yl[5-(3-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]
methanone (7h). mp 123-124 °C; IR (KBr): 3548, 3062, 2979, 2842, 1689, 1606, 1576,
1568, 1434, 1164, 1024, 780 cm-1; MS: m/z = 417 [M+1]+; Anal. Calcd for C22H16N4O3S:
C, 63.45; H, 3.87; N, 13.45. Found: C, 62.35; H, 3.75; N, 13.38%.
[5-(4-Bromophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7i). mp 165-167 °C; IR (KBr): 3589, 3079, 2961, 2853, 1682, 1600, 1575,
1562, 1451, 1174, 1029, 855 cm-1; MS: m/z = 450 [M]+; Anal. Calcd for C22H16BrN3OS:
C, 58.67; H, 3.58; N, 9.33. Found: C, 57.82; H, 3.22; N, 9.27%.
[5-(4-Hydroxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7j). mp 159-161 °C; IR (KBr): 3588, 3086, 2946, 2866, 1686, 1611, 1588,
1573, 1466, 1166, 1010, 842 cm-1; MS: m/z = 388 [M]+; Anal. Calcd for C22H17N3O2S: C,
68.20; H, 4.42; N, 10.85. Found: C, 67.88; H, 4.29; N, 10.68%.
[3-(4-Fluorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7k). mp 135-136 °C; IR (KBr): 3481, 3108, 2923, 2871, 1697, 1590, 1578,
1554, 1492, 1135, 1028, 830 cm-1; MS: m/z = 391 [M+1]+; Anal. Calcd for C22H16FN3OS:
C, 67.85; H, 4.14; N, 10.79. Found: C, 66.88; H, 4.07; N, 10.57%.
[3-(3-Chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7l). mp 212-214 °C; IR (KBr): 3395, 3051, 2987, 2856, 1704, 1617, 1608,
1585, 1578, 1089, 1042, 740 cm-1; MS: m/z = 406 [M+1]+; Anal. Calcd for
C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35. Found: C, 64.87; H, 3.71; N, 10.23%.
1H-Indol-2-yl[3-(4-methylphenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]
methanone (7m). mp 187-189 °C; IR (KBr): 3371, 3108, 3005, 2915, 1689, 1584, 1578,
1566, 1463, 1183, 1018, 870 cm-1; MS: m/z = 385 [M]+; Anal. Calcd for C23H19N3OS: C,
71.66; H, 4.97; N, 10.90. Found: C, 70.49; H, 4.73; N, 10.56%.
1H-Indol-2-yl[3-phenyl-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanone
(7n). mp 232-234 °C; IR (KBr): 3386, 3067, 2984, 2859, 1694, 1605, 1591, 1595, 1483,
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1204, 1023, 845 cm-1; MS: m/z = 371 [M]+; Anal. Calcd for C22H17N3OS: C, 71.14; H,
4.61; N, 11.31. Found: C, 70.66; H, 4.28; N, 11.07%.
[3-(4-Chlorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7o). mp 221-223 °C; IR (KBr): 3365, 3048, 2988, 2851, 1682, 1571, 1580,
1536, 1456, 1134, 1093, 856 cm-1; MS: m/z = 406 [M+1]+; Anal. Calcd for
C22H16ClN3OS: C, 65.10; H, 3.97; N, 10.35. Found: C, 64.59; H, 3.61; N, 10.09%.
1H-Indol-2-yl[3-(2-nitrophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]
methanone (7p). mp 213-214 °C; IR (KBr): 3486, 3152, 3046, 2846, 1676, 1651, 1612,
1551, 1491, 1008, 1281, 750 cm-1; MS: m/z = 416 [M]+; Anal. Calcd for C22H16N4O3S: C,
63.45; H, 3.87; N, 13.45. Found: C, 62.38; H, 3.53; N, 13.39%.
1H-Indol-2-yl[3-(4-nitrophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-
yl]methanone (7q). mp 188-189 °C; IR (KBr): 3386, 3089, 3018, 2914, 1689, 1586,
1579, 1523, 1469, 1087, 1028, 825 cm-1; MS: m/z = 416 [M]+; Anal. Calcd for
C22H16N4O3S: C, 63.45; H, 3.87; N, 13.45. Found: C, 62.87; H, 3.59; N, 13.19%.
[3-(4-Aminophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7r). mp 195-197 °C; IR (KBr): 3519, 3076, 2964, 2852, 1704, 1609, 1581,
1568, 1542, 1159, 1065, 810 cm-1; MS: m/z = 386 [M]+; Anal. Calcd for C22H18N4OS: C,
68.37; H, 4.69; N, 14.50. Found: C, 67.78; H, 4.53; N, 14.28%.
[3-(4-Bromophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl](1H-indol-2-yl)
methanone (7s). mp 173-175 °C; IR (KBr): 3312, 3128, 3064, 2883, 1683, 1615, 1586,
1542 1453, 1286, 1003, 737 cm-1; MS: m/z = 451 [M+1]+; Anal. Calcd for
C22H16BrN3OS: C, 58.67; H, 3.58; N, 9.33. Found: C, 57.63; H, 3.27; N, 9.05%.
1H-Indol-2-yl[3-(4-methoxyphenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl]
methanone (7t). mp 104-106 °C; IR (KBr): 3428, 3162, 3029, 2918, 1711, 1610, 1591,
1542, 1508, 1162, 1063, 760 cm-1; MS: m/z = 401 [M]+; Anal. Calcd for C23H19N3O2S: C,
68.81; H, 4.77; N, 10.47. Found: C, 68.23; H, 4.23; N, 10.05%.
Studies on chemical…
Pyrazole derivatives… 167
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 7a
Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 7a
Minutes0 1 2 3 4 5 6 7 8 9 10 11 12
0
200
400
600
2.17
6 1
1677
0.1
22.
421
267
14 0
.28
2.98
7 2
5028
5 2
.62
3.63
7 3
2176
0.3
4
4.41
6 9
0745
36 9
4.98
5.50
4 1
5401
9 1
.61
7.75
5 3
073
0.0
3
10.1
01 1
862
0.0
2
5007501000125015001750200025003000350040001/cm
20
40
60
80
100
%T
3365
.90
3155
.65
3090
.07
2955
.04
2908
.75
2866
.32
1637
.62
1610
.61
1581
.68
1556
.61
1475
.59
1410
.01
1344
.43
1313
.57
1274
.99
1184
.33
1138
.04
1105
.25
1072
.46
1014
.59
993.
3794
7.08
900.
7986
8.00
835.
2179
6.63
765.
7770
7.90
669.
3260
760
KAJ-PHV-1
NH
NN
O
S
Cl
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Mass spectrum of compound 7a
Mass spectrum of compound 7b
NH
NN
O
S
ClM. Wt. = 405.89
NH
NN
O
S
CH3
M. Wt. = 385.48
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Pyrazole derivatives… 169
1H NMR spectrum of compound 7a
Expanded spectrum of compound 7a
NH
NN
O
S
Cl
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Pyrazole derivatives… 170
1H NMR spectrum of compound 7b
Expanded spectrum of compound 7b
NH
NN
O
S
CH3
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Pyrazole derivatives… 171
13C NMR spectrum of compound 7a
13C NMR spectrum of compound 7b
NH
NN
O
S
Cl
NH
NN
O
S
CH3
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Table-7b: Antimicrobial activity of 1H-Indol-2-yl[3-aryl/thiophene-5-(thiophen/aryl-
2-yl)-4,5-dihydro-1H-pyrazol-1-yl]methanones.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
7a 250 200 100 62.5 200 200 200 7b 500 100 100 200 250 500 250 7c 200 500 200 250 500 250 500 7d 100 200 100 200 1000 1000 1000 7e 200 250 62.5 100 200 >1000 250 7f 200 125 250 500 1000 500 500 7g 500 100 250 200 500 1000 200 7h 125 250 500 250 200 200 250 7i 100 200 200 100 250 200 250 7j 50 100 125 200 500 500 500 7k 250 200 100 250 1000 250 250 7l 100 250 250 500 500 1000 500
7m 250 200 500 200 250 500 250 7n 250 500 250 100 1000 500 >1000 7o 500 100 200 125 250 200 200 7p 250 500 100 200 200 250 500 7q 100 100 500 250 250 500 1000 7r 250 500 500 200 500 200 500 7s 100 250 200 500 >1000 200 200 7t 500 200 100 250 200 1000 500
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
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Part – C
(Part – II)
Studies on Pyrimidine Derivatives
Studies on chemical…
Pyrimidine derivatives… 178
INTRODUCTION
Pyrimidine is the most important member of all the diazines as this ring system
occurs widely in living organisms. Purines, uric acid, barbituric acid, anti-malarial and
anti-bacterial agents also contain the pyrimidine ring. The chemistry of pyrimidine has
been widely studied. Pyrimidine was first isolated by Gabriel and Colman in 1899. Since
pyrimidine is symmetrical about the line passing C-2 and C-5, the positions C-4 and C-6
are equivalent and so N-1 and N-3 are equivalent. Depicts the five possible isomeric
structures of dihydropyrimidines, exhibiting different dispositions of the double bonds.
N
NH
NH
NH
N
NH
N
N
N
N
1,2- 1,4- 1,6- 2,5- 4,5-
A B C D E
SYNTHETIC ASPECT
Different methods have been cited to synthesize some new pyrimidines by several
coworkers using various interesting substrates.
1. N. A. Hassan et al.1 have synthesized various differently substituted
furopyrimidine moieties via different sets of reactants and varying reaction
parameters.
O
CN
NH2
R
R1
PhNCO
O
R
R1
NH
N
O
PhNH
2. Ladda and Bhatnagar2 have described an efficient nimentowski synthesis of novel
pyrimido pyrimidinones via the intermediate preparation of pyrimidin-4-one.
X
CN
NH2
R
R1
X
R
R1
N
NH
O
HCOOH
X = O/S
Studies on chemical…
Pyrimidine derivatives… 179
3. X. S. Wang3 have synthesized 5,7-diarylpyrido[2,3-d]pyrimidine derivatives using
KF-alumina catalyst.
Ar CH CH CO
Ar'N
N
OH
NH2NH2
KF/Al2O3
N
Ar
Ar'
NH
N
O
NH2
+
4. Sachin S. Laddha et al.4 have synthesized 8H-pyrido[2',3':4,5]pyrimido.
N NH2
CNR1
R2
HCOOHReflux
N
R1
R2
NH
N
O
There are several strategies to prepare fused pyrimidine ring systems. The
construction of a pyrimidine ring system from 2-amino five / six membered heterocyclic
derivatives follows the typical reaction sequence. One of the most popular approaches to
construct the pyrimidine ring is via the synthesis of substituted ureas and thio ureas. In a
first step, the amino group of the any heterocycle moiety is converted into a urea by
treatment with an isocyanate5, potassium cyanate hydrochloride6, or chlorosulfonyl
isocyanate7 and into a thiourea by reaction with an isothiocyanate8, or thiophosgene and
an amine9. The resulting ureas and thioureas readily undergo an intramolecular
cyclization upon treatment with bases or acids to afford the fused pyrimidine ring
systems.
X
H2NA
X
NH
AY
NHR
NH
AY
NR
Z
A : Hetrocycle ringX = CO2Et or CN
Y = O or S X = CN, Z = NHX = CO2Et, Z = O
The synthesis of substituted pyrimidin-4-ones is well studied and can be
categorized into four groups according to the functional groups on the fused heterocyclic
moiety and the structures of the intermediates.
(1) Substituted pyrimidinones can be prepared via cyclization of diamides
intermediates, which are generated from aminocarbamoylbenzopyrans by reaction
Studies on chemical…
Pyrimidine derivatives… 180
with acylating agents such as orthoesters,10 acid anhydrides and acid chlorides,11
formic acid12 and diethyl oxalate.13
(2) Alternatively, the synthesis of substituted pyrimidinones can be achieved from
aminoalkoxycarbonylbenzopyrans. Amidine intermediates, formed by the reaction
of the fused heterocyclic compound with amides,14 nitrites under acidic
conditions,15 orthoesters and amines,16 undergo an intramolecular cyclization to
afford chromeno pyrimidinones.
(3) A third procedure is based on the recyclization of substituted oxazinones, which
are generated by reaction of aminocarboxylic acids or esters with acid chlorides or
orthoesters.17 The recyclization proceeds through the diamide intermediate which
is generated upon treatment with amines.18
(4) Aminocyanoheterocyclic compounds also serve as valuable starting materials for
the synthesis of substituted pyrimidinones. Initially, the oxazinimine intermediates
are generated by the acylation of the amino group and then recyclization in the
presence of an acid occurs to afford substituted pyrimidinones.19
NH2
O
NH2
A1)RCOX NH2
O
NHA
R O
OR'''
O
NH2
A RCONH2 or RCN, H+ OR''
O
NA
R NH2
2)or RC(OEt)3, amine
NX
NA
O
R
A : Hitrocyclic ringX = H or R'
OR'''
O
NH2
A3) RCOCl or RC(OEt)3 O
NA
O
R
NH2
O
NH2
A4) RCOCl or (RCO)2OH+
O
NA
NH
R
NX
NA
O
R
A : Hetrocyclic ringX = H or R'
R''' = H or alkyl
R'NH2
Studies on chemical…
Pyrimidine derivatives… 181
THERAPEUTIC IMPORTANCE
A wide variety of pharmacological properties and industrial applications have
been encountered with several pyrimidines such as,
1. Antibacterial20
2. Antitumor21
3. Antiinflammatory22
4. Cytotoxic activity23
5. Antimalarial24
6. Antiproliferation25
7. Antiparasitic26
8. Antifungal27
9. Anticancer28
10. Antineoplastics29
Alloxan (1) is known for its diabetogenic action in a number of animals30 Uracil
(2), thymine (3) and cytisine (4) are the three important constituents of nucleic acids.
NH
NH
O O
OO
NH
NH
O
O
NH
NH
O
O
N
NH
O
NH2
(1) Alloxan (2) Uracili (3) Thymine (4) Cytisine
Calcium ion plays a vital role in a large number of cellular processes, including
excitation-contraction and stimulus-secretion.31,32 The regulation of the intracellular
concentration of this ion makes possible the control of such Ca2+ dependent processes.
One means of accomplishing this is by the use of agents known as calcium channel
antagonists, which inhibit the movement of calcium through certain membrane channel.33-
35 K. S. Atwal36 prepared the 2-heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-
pyrimidinecarboxylic acid esters (5), which lack the potential C3 symmetry of
dihydropyridine calcium channel blockers. The solid-state structure of dihydropyrimidine
analogue (6) shows that these compounds can adopt a molecular conformation which is
similar to the reported conformation of dihydropyridine calcium channel blockers.
Studies on chemical…
Pyrimidine derivatives… 182
NH
NCOOR
3
R2X
R1
NH
NCOOEt
S
NO2
(5) (6)
S. Sarac and coworkers37,38 have synthesized 4-arlyl-3,4-dihydropyrimidin-2(1H)-
one/thione derivatives. The calcium channel blocker activities of all compounds
performed on isolated rat ileum. Product (7), 2-nitrophenyl derivative and (8), 2-
bromophenyl derivative have potent antispasmodic activity on BaCl2 stimulated rat ileum.
NH
NH
SH5C2
NO2H3COOC
(7)
NH
NH
OCH3
BrO
CH3
(8)
N. Dhanapalan and coworkers39 have synthesized dihydropyrimidinones and
describe compound (9) have a high binding affinity (Ki = 0.2nM) for a1a receptor and
greater than 1500 fold selectivity over a1b and a1d adrenoceptors.
N
NH
CH3
O
CH3
FF
O
NH
O
N
COOMePh
(9)
2-Thiouracil (10c) and its alkyl analogue, thiobarbital (10e) are effective drugs
against hyperthyroidism. Propylthiouracil (10d) is used as a drug for hyperthyroidism
with minimum side effects.40
Studies on chemical…
Pyrimidine derivatives… 183
NH
NH
O
X
RR1
R2
(9c-e)(10c) = R = R1 = R2 = H, X = S, 2-Thiouracil
(10d) = R = R1 = H, R2 = C3H7, X = S, Propylthiouracil
(10e) = R = R1 = C2H5, R2 = O, X = S, Thiobarbital
These drugs have the ability of ridding the body of parasitic worms. Pyrantel
pamoate (11) is a depolarizing neuromuscular blocking agent that causes spastic paralysis
in helminthes and is employed in the treatment of infestations caused by pinworms and
roundworms.41
(11) Pyrantel pamoate
N
NSCH3
Work done from our laboratory
P. D. Zalavadiya42 have synthesized some new dihydropyrimidines by iodine
catalyst at ambient temperature and reported as antitubercular agent. Pyrazolo[3,4-d]
pyrimidines and thiazolo[4,5-d]pyrimidines reported by J. D. Akbari et al.43 Green
chemistry approach to synthesis of some new trifluoromethyl containing
tetrahydropyrimidines was reported by H. S. Joshi et al.44
Thus with an effort to capitalize the biological potential of the heterocyclic
system and to provide more interesting compounds for biological screening, we have
under taken the synthesis of several pyrido[2,3-d]pyrimidin which has been described
as under.
SECTION-I: SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-METHYL
-5-ARYL/THIOPHEN-7-(THIOPHEN/ARYL-2-YL)PYRIDO[2,3-
d]PYRIMIDIN-4(3H)-ONES.
Studies on chemical…
Pyrimidine derivatives… 184
SECTION-I
SYNTHESIS AND BIOLOGICAL EVALUATION OF 2-METHYL-5-
ARYL/THIOPHEN-7-(THIOPHEN/ARYL-2-YL) PYRIDO[2,3-d]PYRIMIDIN -
4(3H)-ONES.
Much interest has been focused around pyrido[2,3-d]pyrimidines derivatives
because of their wide variety of pharmacological properties and industrial application. In
view of these finding and achieve to better drug potency, we have synthesized 2-Methyl-
5-aryl/thiophen-7-(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones by the
cyclocondensation of 2-amino-6-aryl/thiophene-4-(thiophene/aryl-2-yl)pyridine-3-
carbonitrile with glacial acetic acid.
REACTION SCHEME
SO
R
SO
R
N S
N
NH2
R
N
SN
NH2 R
N
NH
N S
O
CH3
R
N
S
NH
N
O
CH3 R
MeOH
MeOH
Malanonitrile
Malanonitrile
gla. acetic acid
gla. acetic acid
Reflux
Reflux
The constitution of all the synthesized compounds have been characterized by
using elemental analysis, FT-IR, 1H NMR, 13C NMR spectroscopy and further supported
by mass spectroscopy. Purity of all the compounds has been checked on thin layer
chromatographic plate and HPLC technique.
All the synthesized compounds were tested for their antibacterial and antifungal
activity (MIC) in vitro by broth dilution method with two Gram-positive bacteria, two
Gram-negative bacteria and three fungal strains. The biological activities of the
synthesized compounds have been compared with standard drugs.
Studies on chemical…
Pyrimidine derivatives… 185
EXPERIMENTAL SECTION
Melting points were determined in open capillary tubes and are uncorrected.
Formation of the compounds was checked by TLC on silica gel-G plates of 0.5 mm
thickness and spots were located by iodine and UV light. IR spectra were recorded on
Shimadzu FT-IR-8400 instrument using KBr pellet method. Mass spectra were recorded
on Shimadzu GC-MS-QP-2010 model using direct inlet probe technique. 1H NMR and 13C NMR was determined in DMSO-d6 solution on a Bruker Ac 400 MHz spectrometer.
Purity of the synthesized compounds was checked by HPLC Shimadzu-10AT. Elemental
analysis of the all the synthesized compounds was carried out on Euro EA 3000 elemental
analyzer and the results are in agreements with the structures assigned.
[A] Preparation of 1-Aryl/thiophen-3-(thiophen/aryl-2-yl)prop-2-en-1-one.
See Part-C, Part-I, Section-I, Experimental section [B] and [C].
[B] Preparation of 2-Methyl-4-aryl/thiophen-6-(thiophen/aryl-2-yl)pyridine-3-
carbonitrile.45
A mixture of chalcone (0.01 mol), malononitrile (0.66 g, 0.01 mol) and
ammonium acetate (6.16 g, 0.08 mol) in a methanol (20 ml) was refluxed for 4-6 hour.
After the completion of reaction (monitoring by TLC), cool the content, the solid
separated was filtered and wash with methanol and dried to give analytical pure product.
[C] General procedure for the preparation of 2-Methyl-5-aryl/thiophen-7-
(thiophen/aryl-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-ones.
A mixture of an appropriate 2-methyl-4-aryl/thiophen-6-(thiophen/aryl-2-yl)
pyridine-3-carbonitrile (0.01 mol) and acetic acid (20 ml) was stirred under reflux for 12-
14 hour in the presence of catalytic amount of concentrated H2SO4. The reaction mixture
was allowed to cool to room temperature and was poured into ice cold water. The solid
thus formed was collected by filtration, washed with chloroform (20 ml) and the resulting
crude product was crystallized from methanol to give the analytical pure compound. The
physical constants of the product are recorded in Table-8a.
[D] Biological evaluation of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)
pyrido[2,3-d]pyrimidin-4(3H)-ones.
Antimicrobial testing was carried out as described in Part-A, Part-1, Section-I,
antimicrobial activity. The MIC values of the test compounds are recorded in Table-8b.
Studies on chemical…
Pyrimidine derivatives… 186
Table-8a: Physical constant of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)
pyrido[2,3-d]pyrimidin-4(3H)-ones.
N
R
NH
N R1
O
CH3
Sr. No Substitution R Substitution R1 M. F. M. W. Yield
(%) Rf
value
8a S
Cl C18H12ClN3OS 353.82 75 0.36
8b ″ CH3 C19H15N3OS 333.40 82 0.48
8c ″ C18H13N3OS 319.38 69 0.41
8d ″ F C18H12FN3OS 337.37 73 0.37
8e ″ Cl
Cl
C18H11Cl2N3OS
388.27
71 0.51
8f ″
NH2 C18H14N4OS
334.39
63 0.46
8g ″ NH2
C18H14N4OS
334.39
65 0.52
8h ″ N
+O
-
O C18H12N4O3S
364.37
78 0.59
8i ″ Br
C18H12BrN3OS
398.27
77 0.63
8j ″ OH
C18H13N3O2S
335.37
81 0.33
8k F
S C18H12FN3OS
337.37
83 0.57
8l
Cl
″ C18H12ClN3OS 353.82 78 0.50
8m CH3
″
C19H15N3OS
333.40
76 0.47
Studies on chemical…
Pyrimidine derivatives… 187
8n
″
C18H13N3OS
319.38
70 0.60
8o Cl
″
C18H12ClN3OS
353.82
69 0.63
8p N
+
O-
O
″
C18H12N4O3S
364.37
72 0.62
8q N+
O-
O
″
C18H12N4O3S
364.37
74 0.58
8r NH2
″
C18H14N4OS
334.39
65 0.40
8s Br
″
C18H12BrN3OS
398.27
68 0.53
8t
OCH3
″
C19H15N3O2S
349.40
71 0.42
TLC solvent system:- MeOH : CHCl3 = 1 : 9
ANALYTICAL DATA
7-(4-Chlorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8a). mp 179-181 °C; Purity by HPLC: 95 %; IR (KBr): 3390 (N-H str), 3028 (Ar, C-H
str), 2935 (C-H str), 2853 (C-H str), 1687 (amide, C=O str), 1611 (C=N str), 1532 (Ar,
C=C str), 1446 (Ar, C=C str), 1015 (C-N str), 820 (C-H, o.p. ban) cm-1; 1H NMR (400
MHz, DMSO-d6): δ ppm 2.51 (s, 3H, CH3), 7.29-7.31 (m, 1H, ArH), 7.46-7.49 (m, 1H,
ArH), 7.59-7.60 (d, J=4.4 Hz, 1H, ArH), 7.69-7.70 (d, J=5.20 Hz, 2H, ArH), 7.83-7.84
(d, J=4.40 Hz, 2H, ArH), 7.98 (s, 1H, NH), 8.18-8.20 (d, J=9.08 Hz, 1H, ArH). 13C NMR
(100 MHz, DMSO-d6): δ ppm 21.08, 111.23, 112.70, 114.62, 117.92, 123.23, 124.00,
128.80, 130.20, 132.10, 135.45, 139.12, 141.14, 154.16, 159.78, 165.18; MS: m/z = 355
[M+1]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H, 3.42; N, 11.88. Found: C, 60.31; H,
3.27; N, 11.65%.
2-Methyl-7-(4-methylphenyl)-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8b). mp 186-188 °C; Purity by HPLC: 96 %; IR (KBr): 3365, 3068, 2979, 2851, 1694,
1611, 1571, 1567, 1456, 1078, 840 cm-1; 1H NMR (400 MHz, DMSO-d6): δ ppm 2.44 (s,
Studies on chemical…
Pyrimidine derivatives… 188
3H, CH3), 2.79 (s, 3H, CH3), 7.16-7.18 (m, 1H, ArH), 7.33-7.37 (m, 1H, ArH), 7.46-7.47
(d, J=2.92 Hz, 1H, ArH), 7.59-7.62 (d, J=4.64 Hz, 2H, ArH), 7.74-7.75 (d, J=3.88 Hz,
1H, ArH), 7.88 (s, 1H, NH), 8.05-8.07 (d, J=8.20 Hz, 2H, ArH). 13C NMR (100 MHz,
DMSO-d6): δ ppm 19.96, 21.03, 110.20, 117.72, 121.10, 123.45, 127.02, 127.41, 129.40,
130.28, 131.78, 135.20, 138.64, 141.76, 153.20, 158.21, 163.28; MS: m/z = 334 [M+1]+;
Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N, 12.60. Found: C, 68.07; H, 4.41; N,
12.29%.
2-Methyl-7-phenyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8c). mp 141-
142 °C; IR (KBr): 3433, 3078, 2976, 2858, 1692, 1612, 1569, 1567, 1443, 1013 cm-1;
MS: m/z = 319 [M]+; Anal. Calcd for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16. Found: C,
66.38; H, 4.04; N, 13.00%.
7-(4-Fluorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8d). mp 159-161 °C; IR (KBr): 3459, 3086, 2966, 2846, 1693, 1611, 1572, 1564, 1450,
1061, 825 cm-1; MS: m/z = 339 [M+2]+; Anal. Calcd for C18H12FN3OS: C, 64.08; H, 3.59;
N, 12.46. Found: C, 63.66; H, 3.49; N, 12.34%.
7-(2,4-Dichlorophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8e). mp 239-241 °C; IR (KBr): 3464, 3068, 2969, 2884, 1693, 1613, 1586, 1570, 1454,
1029, 747 cm-1; MS: m/z = 389 [M+1]+; Anal. Calcd for C18H11Cl2N3OS: C, 55.68; H,
2.86; N, 10.82. Found: C, 55.13; H, 2.48; N, 10.72%.
7-(3-Aminophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8f). mp 167-169 °C; IR (KBr): 3497, 3068, 2946, 2860, 1697, 1609, 1576, 1568, 1446,
1007, 759 cm-1; MS: m/z = 334 [M]+; Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N,
16.75. Found: C, 64.31; H, 4.10; N, 16.35%.
7-(4-Aminophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8g). mp 118-120 °C; IR (KBr): 3455, 3055, 2968, 2835, 1691, 1618, 1561, 1569, 1453,
1081, 867 cm-1; MS: m/z = 334 [M]+; Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N,
16.75. Found: C, 64.18; H, 4.08; N, 16.43%.
2-Methyl-7-(3-nitrophenyl)-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8h).
mp 243-245 °C; IR (KBr): 3500, 3097, 2976, 2849, 1695, 1600, 1565, 1562, 1435, 1071,
Studies on chemical…
Pyrimidine derivatives… 189
738 cm-1; MS: m/z = 365 [M+1]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,
15.38. Found: C, 58.91; H, 3.13; N, 15.06%.
7-(4-Bromophenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8i). mp 144-146 °C; IR (KBr): 3468, 3079, 2991, 2864, 1690, 1605, 1573, 1565, 1459,
1034, 690 cm-1; MS: m/z = 399 [M]+; Anal. Calcd for C18H12BrN3OS: C, 54.28; H, 3.04;
N, 10.55. Found: C, 53.65; H, 2.84; N, 10.36%.
7-(4-Hydroxyphenyl)-2-methyl-5-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8j). mp 188-189 °C; IR (KBr): 3488, 3086, 2946, 2868, 1697, 1612, 1581, 1580, 1456,
1022, 857 cm-1; MS: m/z = 335 [M]+; Anal. Calcd for C18H13N3O2S: C, 64.46; H, 3.91; N,
12.53. Found: C, 63.54; H, 3.77; N, 12.31%.
5-(4-Fluorophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8k). mp 201-203 °C; IR (KBr): 3364, 3060, 3045, 2891, 1693, 1585, 1558, 1545, 1463,
1075, 851 cm-1; MS: m/z = 338 [M+1]+; Anal. Calcd for C18H12FN3OS: C, 64.08; H, 3.59;
N, 12.46. Found: C, 63.18; H, 3.41; N, 12.26%.
5-(3-Chlorophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8l). mp 256-258 °C; IR (KBr): 3468, 3051, 3008, 2960, 1698, 1618, 1604, 1578, 1471,
1078, 770 cm-1; MS: m/z = 355 [M]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H, 3.42;
N, 11.88. Found: C, 60.58; H, 3.17; N, 11.53%.
2-Methyl-5-(4-methylphenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8m). mp 294-296 °C; IR (KBr): 3504, 3145, 2978, 2861, 1712, 1645, 1618, 1563, 1545,
1063, 841 cm-1; MS: m/z = 333 [M]+; Anal. Calcd for C19H15N3OS: C, 68.45; H, 4.53; N,
12.60. Found: C, 67.57; H, 4.30; N, 12.49%.
2-Methyl-5-phenyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8n). mp 216-
217 °C; IR (KBr): 3341, 3029, 2983, 2866, 1709, 1595, 1583, 1568, 1478, 1018 cm-1;
MS: m/z = 319 [M]+; Anal. Calcd for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16. Found: C,
67.09; H, 3.97; N, 13.05%.
5-(4-Chlorophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8o). mp 176-177 °C; IR (KBr): 3309, 3151, 2998, 2905, 1691, 1683, 1578, 1543, 1518,
Studies on chemical…
Pyrimidine derivatives… 190
1023, 854 cm-1; MS: m/z = 354 [M+1]+; Anal. Calcd for C18H12ClN3OS: C, 61.10; H,
3.42; N, 11.88. Found: C, 60.48; H, 3.21; N, 11.49%.
2-Methyl-5-(2-nitrophenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8p).
mp 181-183 °C; IR (KBr): 3290, 3043, 3023, 2818, 1890, 1609, 1590, 1579, 1449, 1065,
720 cm-1; MS: m/z = 364 [M]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,
15.38. Found: C, 58.86; H, 3.18; N, 15.09%.
2-Methyl-5-(4-nitrophenyl)-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (8q).
mp 166-167 °C; IR (KBr): 3351, 3031, 3015, 2957, 1876, 1602, 1589, 1578, 1479, 1043,
710 cm-1; MS: m/z = 364 [M]+; Anal. Calcd for C18H12N4O3S: C, 59.33; H, 3.32; N,
15.38. Found: C, 56.87; H, 3.15; N, 15.27%.
5-(4-Aminophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8r). mp 210-211 °C; IR (KBr): 3481, 3147, 2969, 2884, 1707, 1578, 1563, 1533, 1469,
1021, 844 cm-1; MS: m/z = 334 [M]+; Anal. Calcd for C18H14N4OS: C, 64.65; H, 4.22; N,
16.75. Found: C, 64.01; H, 4.16; N, 16.58%.
5-(4-Bromophenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8s). mp 248-250 °C; IR (KBr): 3501, 3170, 3046, 2930, 1681, 1619, 1615, 1578, 1503,
1056, 866 cm-1; MS: m/z = 399 [M+1]+; Anal. Calcd for C18H12BrN3OS: C, 54.28; H,
3.04; N, 10.55. Found: C, 53.81; H, 2.91; N, 10.41%.
5-(3-Methoxyphenyl)-2-methyl-7-(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one
(8t). mp 229-230 °C; IR (KBr): 3349, 3093, 29636, 2847, 1680, 1620, 1595, 1583, 1493,
1037, 767 cm-1; MS: m/z = 349 [M]+; Anal. Calcd for C19H15N3O2S: C, 65.31; H, 4.33; N,
12.03. Found: C, 64.72; H, 4.23; N, 11.87%.
Studies on chemical…
Pyrimidine derivatives… 191
SPECTRAL STUDY OF SYNTHESIZED COMPOUNDS
HPLC of compound 8a
Column : YMC C-8 (4.6 x 150 mm, 5 µm particle size)
Mobile phase : Acetonitrile – 0.02M phosphate buffer pH 3.5 (60: 40, v/v).
Flow rate : 1.0 ml/min
IR spectra of compound 8a
Minutes0 1 2 3 4 5 6 7 8 9 10
mA
U
0
250
500
750
0.17
1 2
87 0
.00
0.64
0 1
963
0.0
2
1.90
9 9
0223
71 9
5.60
3.27
5 3
9743
5 4
.21
3.62
7 1
3653
0.1
4
4.05
3 1
747
0.0
2
4.39
5 4
39 0
.00
5007501000125015001750200025003000350040001/cm
0
20
40
60
80
100
%T
3390
.97
3243
.41
3028
.34
2935
.76 28
53.7
8
1687
.77
1611
.58
1532
.50 14
46.6
613
64.6
813
30.9
312
75.9
5
1166
.97 11
10.0
710
15.5
698
7.59 86
3.17 70
6.93
644.
25
556.
48
JP-302
N
NH
N
O
CH3
S
Cl
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Pyrimidine derivatives… 192
Mass spectrum of compound 8a
Mass spectrum of compound 8b
N
NH
N
O
CH3
S
CH3M. Wt. = 333.40
N
NH
N
O
CH3
S
ClM. Wt. = 353.82
Studies on chemical…
Pyrimidine derivatives… 193
1H NMR spectrum of compound 8a
Expanded spectrum of compound 8a
N
NH
N
O
CH3
S
Cl
Studies on chemical…
Pyrimidine derivatives… 194
1H NMR spectrum of compound 8b
Expanded spectrum of compound 8b
N
NH
N
O
CH3
S
CH3
Studies on chemical…
Pyrimidine derivatives… 195
13C NMR spectrum of compound 8a
13C NMR spectrum of compound 8b
N
NH
N
O
CH3
S
Cl
N
NH
N
O
CH3
S
CH3
Studies on chemical…
Pyrimidine derivatives… 196
Table-8b: Antimicrobial activity of 2-Methyl-5-aryl/thiophen-7-(thiophen/aryl-2-yl)
pyrido[2,3-d]pyrimidin-4(3H)-ones.
Sr. No.
Antibacterial Activity Antifungal activity
Minimal bactericidal concentration μg/ml Minimal fungicidal concentration μg/ml Gram +ve Bacteria Gram –ve Bacteria
S.aureus S.pyogenus E.coli P.aeruginosa C.albicans A.niger A.clavatus
8a 50 500 250 100 500 250 250 8b 100 250 100 250 1000 200 500 8c 125 62.5 100 200 250 500 >1000 8d 250 200 500 200 200 1000 500 8e 500 100 200 250 1000 500 1000 8f 200 100 500 200 500 >1000 500 8g 200 100 250 100 200 250 250 8h 100 200 200 250 500 200 500 8i 250 200 250 200 500 500 200 8j 500 250 500 500 >1000 500 500 8k 200 500 62.5 100 500 200 250 8l 250 100 100 500 1000 200 500
8m 100 200 500 250 500 250 500 8n 500 125 500 200 250 500 1000 8o 250 100 100 200 200 500 500 8p 200 250 200 250 >1000 >1000 500 8q 500 250 250 200 500 200 250 8r 500 200 100 250 200 250 500 8s 200 250 250 200 250 500 200 8t 200 100 500 100 250 500 200
MINIMAL INHIBITION CONCENTRATION
Standard Drugs S.aureus S.pyogenus E.coli P.aeruginosa
(microgramme/ml) Gentamycin 0.25 0.5 0.05 1 Ampicillin 250 100 100 100
Chloramphenicol 50 50 50 50 Ciprofloxacin 50 50 25 25 Norfloxacin 10 10 10 10
MINIMAL FUNGICIDAL CONCENTRATION
Standard Drugs C.Albicans A.Niger A.Clavatus
(microgramme/ml) Nystatin 100 100 100
Greseofulvin 500 100 100
Studies on chemical…
Pyrimidine derivatives… 197
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Publication
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Publication… 199
LIST OF PUBLICATION
D. H. Purohit, B. L. Dodiya, R. M. Ghetiya, P. B. Vekariya and H. S. Joshi*
Synthesis and antimicrobial activity of some new 1,3,4-thiadiazoles and 1,3,4-
thiadiazines containing 1,2,4 triazolo nucleus, Acta chemica slovenica, 58, 53-59,
2011.
K. M. Thaker, B. L. Dodiya, K. A. Joshi, R. M. Ghetiya, P. B. Vekariya & H. S.
Joshi*, Synthesis and antimicrobial activity of some new aryl amide and
dihydroquinoline derivatives containing benzo[b]thiophene nucleus, Indian journal
of heterocyclic chemistry, 20, 21-24, 2010.
S. M. Dave, V. R. Ram, G. J. Kher, B. L. Dodiya, H. S. Joshi* Synthesis and
Spectrophotometric studies of Ni (II)-HMCPP complex and their use as an analytical
reagent, Analytical chemistry: An Indian Journal, 8(4), 430-435, 2009.
K. M. Thaker, R. M. Ghetiya, S. D. Tala, B. L. Dodiya, K. A. Joshi, K. L. Dubal &
H. S. Joshi*, Synthesis of oxadiazoles and pyrazolones nucleus as antimycobacterial
and antimicrobial agents, Indian Journal of Chemistry, Section B: Organic
Chemistry Including Medicinal Chemistry, Accepted article [MS No. SCCB-1351
Dt. 03/07/09].
P. D. Zalavadiya, R. M. Ghetiya, B. L. Dodiya, P. B. Vekariya and H. S. Joshi*
Synthesis of some new dihydropyrimidines by iodine as a catalyst at ambient
temperature and evaluation of their biological activity, journal of heterocyclic
chemistry, Accepted article [MS No. JHET-10-0340].
M. J. Joshi, P. B. Vekariya, B. L. Dodiya, R. M. Ghetiya and H. S. Joshi*
Synthesis and biological study of some new chalcones and oxopyrimidines
containing imidazo[1,2-a]pyridine nucleus, journal of heterocyclic chemistry,
Accepted article [MS No. JHET-10-0513].
M. R. Patel, B. L. Dodiya, R. M. Ghetiya, K. A. Joshi, P. B. Vekariya, A. H.
Bapodara and H. S. Joshi* Synthesis, Antitubercular and Antimicrobial Biological
Evaluation of Pyrazoline derivatives, International journal of chemtech research,
(Accepted article).