Ugwoke Oluchi C.
(HETEROARYL
Digitally Signed by: Content manager’s
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Ugwoke Oluchi C.
FACULTY OF PHSCIAL SCIENCES
DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY
SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF
(HETEROARYL- SUBSTITUTED)–P-TOLUENESULPHONAMIDES.
OZOH CHINWE FRANCISCA
PG/M.Sc/11/59538
1
: Content manager’s Name
bmaster’s name
a, Nsukka
DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY
YNTHESIS AND ANTIMICROBIAL ACTIVITIES OF N-
TOLUENESULPHONAMIDES.
2
TITLE PAGE
UNIVERSITY OF NIGERIA, NSUKKA
FACULTY OF PHSCIAL SCIENCES
DEPARTMENT OF PURE AND INDUSTRIAL CHEMISTRY
CHM 592, RESEARCH (PROJECT).
SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OFN-(HETEROARYL-
SUBSTITUTED)–P-TOLUENESULPHONAMIDES.
A RESEARCH PROJECT SUBMITTED IN PARTIAL FULFILMENT OF THE
REQIREMENT FOR THE AWARD OF MASTER OF SCIENCE (M.Sc) DEGREE.
INORGANIC CHEMISTRY
BY
OZOH CHINWE FRANCISCA
PG/M.Sc/11/59538
PROJECT SUPERVISOR: PROF. U. C. OKORO.
3
APPROVAL PAGE
This work has been approved by the Department of Pure and Industrial Chemistry, University of
Nigeria, Nsukka.
__________________ ___________________
PROF. U. C. OKOROPROF. P. O. UKOHA
Project Supervisor Head of Department
Date____________ Date______________
4
CERTIFICATION
This is to certify that the research work tittled “Synthesis and Antimicrobial activities of N-
(heteroaryl-substituted)-p–toluenesulphonamides” was carried out by OZOH CHINWE
F.(PG/M.Sc/11/59538) and has been approved by the under signed as having met the standard of
the Department of Pure and Industrial Chemistry, University of Nigeria Nsukka, submitted in
partial fulfillment of the requirements for the award of M.Sc degree in Organic Chemistry.
_______________________ _________________________
PROF. U. C. OKOROPROF. P. O. UKOHA
Prof. Supervisor Head of Department
Date______________ Date___________
5
DEDICATION
I dedicate this work to God the Father, Son and the Holy Spirit, my source of life and strength.
6
ACKNOWLEDGEMENT
My sincere gratitude goes to all the faculty members of Pure and Industrial Chemistry
Department, University of Nigeria, Nsukka. I am grateful to Professor P.O. Ukoha, Head of
Department, for providing me the facilities to carry out this work.
I am exceedingly delighted in expressing my most sincere gratitude to my respected
supervisor, teacher and guide, Professor U. C. Okoro. Throughout my research period, I received
from him constant guidance, valuable suggestions, tremendous skills and creative ideas
whenever needed. Without his loving care and priceless supervision, it could have been very
difficult for me to complete this work. For this, I will ever remain thankful to him. I am also
thankful to Professor C. O. Okafor for his advice whenever needed.
My profound gratitude goes to my parents, Mr. and Mrs. Pius ObiorahOzoh, my siblings,
Amaka, Ijeoma, Edozie and Chizoba for their great encouragement and support. I want to thank
specially my friend, Ernest for his love and care. I will never forget to appreciate my
coursemates, Thompson, Ogechi, Chinelo, David and Nonye for being there for me. May God
see us through in our project work. I also want to thank my roommates and friends, Martina,
Chizzy, Adaora, Ben and Oge for their great encouragement. I will never forget to appreciate
Catholic Association of Post-graduate Student family for their prayers and supports. May God
almighty rewards you all.
7
ABSTRACT
Sulphonamides are known to represent a class of medicinally important compounds which are
extensively used as antimicrobial agents. Hence in this present study, a series of new N-
(heteroaryl-substituted)–p-toluenesulphonamides146(a-g) were synthesized by direct
condensation of p-toluenesulphonyl chloride 144 with various readily available amino pyridines
145(a-g). The chemical structures of the products were confirmed using spectroscopic methods
which include Fourier Transform–Infrared (FT-IR) spectroscopy, proton and carbon-13 Nuclear
Magnetic Resonance (1H and
13C- NMR) spectroscopy. The antimicrobial properties of the
synthesized sulphonamides were determined on Bacillus subtilis, Bacillus cereus,
Staphylococcus aureus, Peudomonasaeruginosa, Escherichia coli, Klebsiellapneumoniae,
Candida albicans and Asperigellusniger using agar-diffusion method. Results indicated
improved biological activities over reference drugs such as Tetracycline and Fluconazole.
8
TABLE OF CONTENT
TITLE PAGE-----------------------------------------------------------------------------------------------i
APPROVAL PAGE---------------------------------------------------------------------------------------ii
CERTIFICATION-----------------------------------------------------------------------------------------iii
DEDICATION---------------------------------------------------------------------------------------------iv
ACKNOWLEDGEMENT---------------------------------------------------------------------------------v
ABSTRACT------------------------------------------------------------------------------------------------vi
TABLE OF CONTENT-------------------------------------------------------------------------------vii-ix
LIST OF ABBREVIATIONS--------------------------------------------------------------------------x-xi
LIST OF TABLES-----------------------------------------------------------------------------------------xii
LIST OF FIGURES---------------------------------------------------------------------------------------xiii
CHAPTER ONE--------------------------------------------------------------------------------------------1
1.0Introduction------------------------------------------------------------------------------------1-2
1.1 Background of the Study--------------------------------------------------------------------2-7
1.2 Statement of the Problem---------------------------------------------------------------------7
1.3 Objective of the Study-------------------------------------------------------------------------7
1.4 Justification of Study---------------------------------------------------------------------------8
CHAPTER TWO--------------------------------------------------------------------------------------------9
2.0Literature Review--------------------------------------------------------------------------------9
2.1 Synthesis of Sulphonamides as Antibacterial and Antifungal Agents----------------9-13
9
2.1.2 Synthesis of Sulphonamides as Antimalarial Agents-------------------------------14-15
2.1.3 Synthesis of Sulphonamides as an Antioxidant Agent------------------------------15-16
2.1.4 Synthesis of Sulphonamides as Anticancer and Antitumor Agents--------------16-17
2.1.5 Synthesis of sulphonamides as Anti-inflammatory Agent-------------------------17-18
2.1.6 Synthesis of Sulphonamides as Antiviral and Anti- HIV Agent-----------------18-19
2.1.7 Synthesis of Sulphonamides as Diuretic Agent------------------------------------19-20
2.1.8 Synthesis of Sulphonamides as Analgesic Agent--------------------------------------20
2.1.9 Synthesis of Sulphonamides as Anticonvulsant Agent--------------------------------21
2.1.10 Synthesis of Sulphonamides as Inhibitors of Butyryl Cholinesterase----------21-22
2.2 Applications of Sulphonamides in Synthetic Organic Chemistry-------------------22-23
2.2.1 Miscellaneous Applications of Sulphonamides-------------------------------------24-25
CHAPTER THREE---------------------------------------------------------------------------------------26
3.0 Experimental Section-------------------------------------------------------------------------26
3.1 General------------------------------------------------------------------------------------------26
3.2 General Procedure for Derivatives------------------------------------------------------26-27
3.2.1. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-------------------------------------27
3.2.2. 4-Methyl-N-(4-methyl pyridin-2-yl) benzenesulphonamide-------------------------27
3.2.3. 4-Methyl-N-(5-nitro pyridin-2-yl) benzenesulphonamide----------------------------27
3.2.4. 4-Methyl-N-(3-nitro pyridin-2-yl) benzenesulphonamide------------------------27-28
3.2.5. N-(3-Hydroxy pyridin-2-yl)-4–methyl benzenesulphonamide-----------------------28
3.2.6. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide-------------------------28
10
3.2.7. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-------------------------------------28
3.3 Antimicrobial Activity--------------------------------------------------------------------28-29
3.3.1 Sensitivity Testing of Compounds-------------------------------------------------------29
3.3.2Minimium Inhibitory Concentration (MIC) Testing of Compounds----------------29
CHAPTER FOUR----------------------------------------------------------------------------------------30
4.0 Results and Discussion-----------------------------------------------------------------------30
4.1 4-Methyl –N-(pyridin-2-yl) benzenesulphonamide146a------------------------------30
4.1.1 4-Methyl–N-(4-methyl pyridin-2-yl) benzenesulphonamide146b--------------30-31
4.1.2 4-Methyl-N-(5–nitro pyridin-2-yl) benzenesulphonamide146c---------------------31
4.1.3 4-Methyl-N-(3–nitro pyridin-2-yl) benzenesulphonamide146d---------------------32
4.1.4 N-(3-Hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide146e--------------32-33
4.1.5 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide146f -------------------33
4.1.6 4-Methyl–N-( pyridin-4-yl) benzenesulphonamide 146g--------------------------33-34
4.2. Antimicrobial Activity Evaluation------------------------------------------------------34-35
4.2.1. Results of Sensitivity Testing of Compounds-------------------------------------------35
4.2.2. Results of Inhibition Zone Diameter (IZD)----------------------------------------------36
4.2.3. Results of MIC Testing of Compounds----------------------------------------------36-37
CHAPTER FIVE-------------------------------------------------------------------------------------------38
5.0 Conclusion--------------------------------------------------------------------------------------38
REFERENCES-----------------------------------------------------------------------------------------39-45
11
LIST OF ABBREVIATIONS
AIDS – Acquired Immune Deficiency Syndrome
Ar – Aromatic
Asp.niger – Asperigellusniger
B.cereus – Bacillus cereus
B. subtilis – Bacillus subtilis
C. albicans – Candida albicans
Cat. - Catalysis
13C-NMR – Proton Nuclear Magnetic Resonance
DARA- Dual Action Receptor Antagonist
DMF – N,N- Dimethyl Formamide
DMSO – Dimethyl Sulphoxide
E. coli – Echerichia coli
FT-IR- Fourier Transform-InfraRay
HCV – Hepatitis C Virus
HIV – Human Immunodeficiency Virus
1H-NMR – Proton Nuclear Magnetic Resonance
J – Coupling constant symbol
K. pneumonia – Klebsiella pneumonia
12
MIC – Minimium Inhibitory Concentration
MOTA- MesoionicOxatriazoles
NO- Nitric Oxide
P. aeruginosa – Pseudomonas aeruginosa
p-TsCl – p-toluenesulphonyl chloride
RT – Room Temperature
S. aureus – Staphylococcus aureus
TEA- Triethyl amine
THF – Tetrahydro furan
Chemical Symbols
cm - centimeter
oC - degree celsius
g -gramme
mg/ml -milligramme per millilitre
mL - milliliter
mmol -millimole
13
LIST OF TABLES
TABLE 1: Results of General Sensitivity Test--------------------------------------------35
TABLE 2: Results of Inhibition Zone Diameter------------------------------------------36
TABLE 3: Results of MIC Test-------------------------------------------------------------36
14
LIST OF FIGURES
Fig 1: IR- Spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide-----------------46
Fig 2: IR- Spectral of chart of 4-Methyl-N-( 4-methyl-2-pyridinyl) benzenesulphonamide-----47
Fig 3: IR- Spectral of chart of 4-Methyl-N-(5-nitro-2-pyridinyl) benzenesulphonamide---------48
Fig 4: IR- Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl) benzenesulphonamide---------49
Fig 5: IR- Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl benzenesulphonamide----50
Fig 6: IR- Spectral of chart of 4-Methyl-N- (6-methyl-2-pyridinyl) benzenesulphonamide-----51
Fig 7: IR- Spectral of chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide-----------------52
Fig 8: 1H-NMR- Spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide---------53
Fig 9:13
C-NMR- spectral of chart of 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide---------54
Fig 10: 1H-NMR -Spectral of chart of 4-Methyl-N-(4-methyl-2-pyridinyl)
benzenesulphonamide---------------------------------------------------------------------------------------55
Fig 11: 1H-NMR - Spectral of chart of 4-Methyl-N-(5-nitro-2-pyridinyl)
benzenesulphonamide---------------------------------------------------------------------------------------56
Fig 12: 1H-NMR - Spectral of chart of 4-Methyl-N-(3-nitro-2-pyridinyl)
benzenesulphonamide---------------------------------------------------------------------------------------57
Fig 13: 1H-NMR - Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl
benzenesulphonamide---------------------------------------------------------------------------------------58
Fig 14:13
C-NMR – Spectral of chart of N-(3-Hydroxy-2-pyridinyl)-4-methyl
benzenesulphonamide---------------------------------------------------------------------------------------59
Fig 15: 1H-NMR - Spectral of chart of 4-Methyl-N-(6-methyl-2-pyridinyl)
benzenesulphonamide---------------------------------------------------------------------------------------60
Fig 16: 1H-NMR - Spectral of chart of 4-Methyl-N-(pyridin-4-yl) benzenesulphonamide-------6
15
CHAPTER ONE
1.0 INTRODUCTION
In the olden days, people were suffering from unknown ailments until Louis
Pasteur1discovered that the cause of such illnesses was micro-organisms. Before the discovery of
antibiotics in 1940, sulphonamides were the main compounds used to treat these microbial
infections.
Sulphonamides are the amides of sulphonic acid with the general structure, 1.2
Sulphonamides belong to distinctive class of compounds that constitute at least five different
classes of pharmacologically active agents.2The basic sulphonamide group –SO2NH- occurs in
various biologically active compounds including antimicrobial agents, antimalarial agents,
antithyroid agents, antitumor and inhibitors of carbonic anhydrase.3 They were introduced into
medical practice before the discovery of penicillins. It was discovered that such compounds
could be used for the treatment of infectious diseases. As a result, many workers from various
countries started producing several derivatives of sulphonamide by modifying the substituent on
the benzene ring and also by replacement of the benzene ring with heterocyclic rings.
Furthermore, several derivatives of these compounds were synthesized, characterized and tested
by biologists and found to be useful as antimicrobial agents. They inhibit multiplication of
bacteria. They have been used against most gram-positive and many gram-negative organisms,
fungi and certain protozoa.4Sulphonamides such as mixtures of sulphamethoxazole and
trimethoprim (Septrin) have been used for the treatment of uncomplicated urinary tract
infections5, scabies, worms, wounds, infections of the eye
2, mucous membrane and skin
2 among
others. Some examples are compounds 2-6:6,7
SN R1
O
O
R3
R2
1
Where R1 = Alkyl, phenyl or aryl
R2 = H, alkyl or aryl
R3 = H, alkyl or aryl
16
1.1BACKGROUND OF THE STUDY
At the beginning of 20th
century, Paul Ehrlich8 showed that various azo dyes were
effective against trypanosomiasis in mice; however, none was effective in man. In the early
1930s, Gerhard Domagk9, Head of Bacteriological and Pathological Research at Baeyer
Company in Germany, who was trying to find an agent against Streptococci, tested a variety of
azo dyes. One of the dyes tested, Prontosil7, showed remarkable positive results when tested on
mice against streptococcal infections. Prontosil's discovery ushered in the era of antibacterial
compound and had a profound impact on pharmaceutical research, drug laws, and medical
history.
In the late 1930’s, working at the Pasteur Institute in Paris in the laboratory of Ernest Fourneau,
Jacques and ThérèseTréfouël, Daniel Bovet and Federico Nitti discovered that Prontosil is
metabolized to sulphanilamide (p-aminobenzenesulphonamide)8, a much simpler and colorless
compound, redefining Prontosil7 as a prodrug.10
It was this compound which was the true
H2N
S
O
NH2
O
H2N
S
O
NH
O
N N N N
CH3
H2N
S
O
NH
O
2Sulphanilamide
(Antibacterial Drug)3
Sulphadiazine(Treatment of Cerebral
Meningitis)
4Sulphamerazine
(Treatment of infections)
HNCCH3
O
S
O
O
HN
N
N
CH3
CH3
H2N S
O
O
NH
NN
S CH3
5Sulphamethazine
(Treatment of Pneumococcal, Sepsis and Gonorrhea)
6
Sulphamethizole(Anticancer Drug)
S
O
O
NH2O2N N
NO2
N
7
17
antibacterial agent. Sulphanilamide was then synthesized in the laboratory and became the first
synthetic antibacterial agent active against a wide range of infections.
In 1940, Woods and Fildes11
improved on the hypothesis by extending the theory to include
other sulphonamides which also proved effective against Gram-positive organisms, especially
pneumococci and meningococci. A retrospective look at sulphonamides11
leaves no doubt that
besides providing the first efficient treatment of bacterial infections; they unleashed a revolution
in chemotherapy to rationally design new therapeutic agents11
.Literally, thousands of chemical
variations were played on the sulphanilamide theme. The best therapeutic results were obtained
from compounds in which one hydrogen of the –SO2NH2 group was replaced by some other
groups, usually a heterocyclic ring.11
Till date, more than twenty thousand sulphanilamide
derivatives, analogs and related compounds especially those related to p-aminobenzoic acid,
have been synthesized. Such syntheses have resulted in the discovery of new compounds with
varying pharmacological properties.11
Further structural modifications, have led to many new
types of antibacterial agents (sulphanilamides), Leprostatic agents (sulphones), diuretics
(heterocyclic sulphonamides), hypoglycemic agents (sulphonylureas), antimalarial, antithyroid,
antitumor and antiviral agents.12
Among the most successful modification are a few derivatives
of sulphanilamide presented as compounds 3, 9,10,11 and 12.
S
O
O
NH2O2N N
NO2
N
7
H2N S
O
O
NH2
8
Reductase
18
Structure of Sulphonamide
Sulphonamides or sulpha drugs have the general structure 1. In this structure 1, R may be alkyl,
aromatic or heteroaromatic and R1,R2 may be hydrogen, alkyl, aromatic or heteroaromatic group.
However, sulphanilamide which is the first known compound of this type has the sulphonamide
base structure 13 in which R1 and R4 are hydrogen.13
Till date, about 15,000 sulphonamide
derivatives, analogues and related compounds have been synthesized.13
This has led to the
discovery of many useful drugs which are effective as diuretics, antimalarial, antithyroid agents
and so on. 13
S
NH2
O O
NH2
S
N
O O
NH2
H N
N
NH2
S OO
N
NO CH3
H
S
NH2
O
O
NH
N
S
NH2
S OO
NH N
NN
S SN
H
C
O
ONH2
R
O
2
3
9Sulphamethizole
10Sulphathalidine
11Sulphalidine
12
2-sulphanilamido-pyridine
(Phthalylsulphathiazole)
19
Classification of Sulphonamide
Moreover, various parameters have been used to classify sulphonamides though it does
not currently have a clear classification.14
These parameters include; chemical structure, duration
of action, spectrum of activity and therapeutic application. However they are grouped as
systematic (absorptive action) and local use. The obtainable one is based on therapeutic usage in
terms of the duration of action.15
They are;
1. Short-lasting Sulphonamides: They have been preferred for systemic infections as they
are rapidly absorbed and rapidly excreted.16
They are considered short lasting if the blood
concentration levels remain higher than 50 g/ml for less than 12h after a single
therapeutic dose.17
Example;
Note: Sulpadiazine, sulphamerazine and sulphamethazine used together constitute the triple
sulphonamide preparation for treating urinary tract infections etc.
N S
R4
O
O
N
H R1
H
13
Sulphonamide based structure
N
N NHSO2 NH2
3
NH2
N
N NHSO2
CH3
4
N
NH3C
CH3
NHSO2 NH2
N
N
S S
S
O
O
HO
O
O
OH
OH
O O
5
14Trisulphopyrimidine
20
2. Moderate or Intermediate-Lasting Sulphonamide: They have been used for infections
requiring prolonged treatment. They are considered lasting if the blood plasma
concentration levels remains higher than 50g/ml are obtained between 12 and 24h.17
Example;
Compound 9 in combination with 16 commonly known as septrin18
inhibits
dihydrofolicreductase, the enzyme that converts both folic and dihydrofolic acid to
tetrahydrofolic acid. Consequently, two steps in the biosynthesis of nucleic acids and proteins
(necessary for bacterial survival) are inhibited. They have been used for various infections such
as recurrent urinary tract infections and are especially active against invasive aspergillosis in
AIDS patients. Other examples are; sulphapyridine, sulphadoxine etc.
3. Long-Lasting Sulphonamide: These sulphonamides are rapidly absorbed and slowly
excreted. They are considered long lasting if the blood plasma concentration levels remains
higher than 50g/ml are obtained 24h after dosing.17
Examples are the following:
H2N SO2NH
NO CH3
H2N SO2NH
S
NN
CH3
N
N
H2N
OCH3
OCH3
OCH3
9 15Sulphamethizole
16Trimethoprim
H2N SO2NH H2N SO2NH
N
NCH3ONN
S CH3
H2N SO2NH
N N
OCH3
C
N N
O
OH
SO2NH
N
617
1819
Sulphalene (Kelfizina)
Sulphamethoxy-pyridazineSulphasalazine
21
Compound 17 is used in combination with other drugs for the treatment of patients with resistant
cases of malaria. Compound 19, has been used for the treatment of ulceration colitis. Compound
6 is used as an anticancer drug.18
Other examples are sulphadoxine, sulphadimetopyrazine etc.
4. Poorly Absorbed Sulphonamides: Some sulphonamides are poorly absorbed from the
gastrointestinal tract. Therefore this group is employed presurgically for patients undergoing
intestinal surgery to diminish the bacterial count.17
Examples are compounds 22 and 23.
1.2 STATEMENT OF THE PROBLEM
Although many sulphonamides have being prepared, tested and found active, further
modifications of these structures are still necessary. The sulphonamides thus produced by these
modifications may prove to be more active and hence useful as antimicrobial agents.
1.3 OBJECTIVE OF THE STUDY
The specific objectives of this research work were to:
i. Synthesize some new sulphonamides with different substituents on the aromatic ring.
ii. Synthesize some new sulphonamides with different substituents on the amino group.
iii. Characterize them using spectrophotometric methods, namely, FT-IR, 1H-NMR,and
13C-NMR spectroscopy.
iv. Carry out biological evaluation of their antimicrobial activities.
H2N SO2NH
20Sulphaphenazole
N
N
H2N S
O
O
NH
N N
OCH3H3CO
21Sulphadimethoxine
HO
HOOC
N N SO2NHN
C
C
O
OH
O
NH SO2NH
S
N
22Salicylazosulphapyridine (Azulphidine) 23
Phthalylsulphathiazole (Sulphathalidine)
22
1.4 JUSTIFICATION OF STUDY
A survey of the literature reveals that despite the various hazardous effects posed by deadly
microbes, it is sad to note that very few new antimicrobial drugs have been discovered in recent
times. Therefore, there is a great need to design and synthesize new antimicrobial drugs for the
control of the rapid spread of harmful microbes. Although many benzenoidsulphonamides have
been synthesized, only a few p-toluenesulphonamides were synthesized and evaluated to the best
of my knowledge. For this reason, there is the need to carry out the synthesis of such categories
of sulphonamides for the evaluation of their antimicrobial potentials.
23
CHAPTER TWO
2.0 LITERATURE REVIEW
Sulphonamides are a widely used classof organic compoundsin medicine.19
Because of their
importance in medicine; many workers have synthesized over five thousand compounds of this
class. Many of these derivatives, after series of biological evaluations, are currently used as
drugs. The synthesis and biological activities of known sulphonamides are presented below.
2.1. Synthesis of Sulphonamides as Antibacterialand Antifungal Agents.
Shivanandaet al.20
synthesized a series of sulphonamides26 derived from naphthofurans
by treating the appropriate sulphonamides25 with the naphthofurans-2-carboxylic acid at 60-
70oC. The products obtained were screened for biological activity and many of them showed
appreciable antibacterial and antifungal activities.
Priteshet al.21
synthesized a novel series of 4-acetamido-N-(substituted 1,3-benzothiazol-
2-yl) benzenesulphonamides 30and N-(substituted 1,3-benzothiazol-2-yl)-4-(substituted
aryldiazenyl) benzenesulphonamide31 inorder to determine their antibacterial and antifungal
activity. In this reaction, substituted 2-aminobenzothiazole 27 was treated with 4-acetamido
phenyl sulphonyl chloride 28 to produce the acetate sulphonamide29. This was followed by acid-
catalysed hydrolysis to the free amine 30. Diazotization of compound 30 followed by diazo-
coupling with 2-naphthol gave the final product 31 as in Scheme 1. When compounds 30 and 31
were tested for their microbial activities, they were found to possess a broad spectrum of
antibacterial and antifungal activities against some microorganisms.
O
COOH
R
S R'H2N
O
O
O
NH
O
S R'
O
O
25
24 26
POCl3,
24
More complex sulphonamides were also prepared by Navinet al.22
as in Scheme 2. The
series of quinazolonyl derivatives of 4-oxo-thiazolidinyl sulphonamides37 were screened for
antibacterial and antifungal activity and were found to have a remarkable antibacterial as well as
antifungal activity.
S
N
NH S
O
O
N=N Ar
N
S
NH2 +
NHCOCH3
SO O
Cl
N
S
NH S
O
O
NHCOCH3Pyridine, Ac2O
, 2hR R
Substituted 2-aminobenzothiazole27
284-acetamidophenylsulphonyl chloride
4-acetamido-N-(substituted 1,3-benzothiazol-2-yl)benzenesulphonamide
29
R
NH2
N
S
NH S
O
O
Acetic acid(80%)
reflux, 6h
R 4-amino-N-(substituted 1,3-benzothiazol-2-yl)30
benzenesulphonamide
HCl, NaNO2
Naphthol in NaOH
31N-(substituted 1,3-benzothiazol-2-yl)
4-(substituted aryl diazenyl) benzenesulphonamide
SCHEME 1: Synthesis of 4-Acetamido-N-(substituted 1,3-benzothiazol-2-yl) benzenesulphonamides
25
Saba and Akhyar23
synthesized two novel sulphonamides (N-(2-methoxyphenyl)-4-
methyl benzenesulphonamide40 and N-ethyl-4-methyl-N-(3-methylphenyl)
benzenesulphonamide41 by reacting the appropriate amines 39 with 4-Methyl benzenesulphonyl
chloride 38 as in Scheme 3.The products obtained in good yields were again bio-assayed to
determine their biological activities and found to be active against gram-positive and gram-
negative bacteria.
Cl
NH
Cl
CH2COOH
SOCl2Benzene
SO2-
CH2COClCl
NH
Cl
COOH
NH2
PyridineH2OHCl-
-
Cl
NH
Cl
O
N
O
H2NHNSO 2S NH2
-H2OPyridine
N
N
O
NH O2S
Cl
NH
Cl
NH2
N=CH
Cl
NH
Cl
N
N
O
NH O2SR
ROHC
MethanolH2O-
RCHN
SO
N
N
O
NH O2S
Cl
NH
Cl
DMF
ZnCl2HSCH2COOH
H2O-
37
36
34 35
32 33
SCHEME 2: Synthesis of Quinazolonyl Derivatives of 4-oxo-thiazolidinyl sulphonamides
26
Deepikaet al.,24
synthesized various derivatives of sulphonamide linked Moxifloxacinas
in Scheme 4and screened them to check the biological activities. They found the compounds to
have moderate to good antibacterial activity.
S
O
O
ClNH
O
OH
+i. Na2CO3/H2O, stir at rt, 4h
ii. 2M HCl, pH 2
S
O
O
N
OOH
NHEt2, heatS
O
O
N
N
O
CH3CH3
5051 52 53
S
O
O
Cl
+
NH2
OH
R
O50
54
i. Na2CO3/H2O, stir at rt, 4h
ii. 2M HCl, pH 2
S
O
O
NHO
OH
R
55
NHEt2, heat S
O
O
NHO
N
R
CH3CH3
56
Scheme 4: Synthesis of Derivatives of Sulphonamide Linked Moxifloxacin
Naga et al.25
synthesized a class of novel N-((2-(1H-tetrazol-5-yl) methyl substituted
sulphonamide46 from (2-(1H-tetrazol-5-yl)-biphenyl-4-yl) methanamine44, and appropriately
CH3
SO O
Cl
+
NH2
O CH3
CH3
SO O
NH
O CH3
CH3
SO O
Cl
+
N
CH3
CH3
H
CH3
SO O
HN
CH3
CH3
384-Methyl benzenesulphonyl chloride
392-Methoxy aniline
40N-(2-Methoxy phenyl)-4-methyl
benzenesulphonamide
38
39
41N-ethyl-4-methyl-N-(3-methylphenyl)
benzenesulphonamide
N-ethyl-3-methyl aniline
SCHEME 3: Synthesis of (N-(2-Methoxy phenyl)-4-methyl and N-Ethyl-methyl-N-(3-methylphenyl) benzenesulphonamides
27
substituted benzenesulphonyl chlorides 45 in the presence of mild basic conditions. They were
screened and found to have good antibacterial and antifungal activities.
In a similar reaction, Argyropoulouet al.26
acylated some benzo[d]thiazol-2-amines 47
with benzene sulphonyl chlorides 48 to give N-(benzo[d]thiazol-2-yl) benzenesulphonamides49.
The products were found to have antibacterial activities.
Ajani et al.27
synthesized a series of N,N-diethylamide bearing sulphonamides53, 56 by
amidation of easily prepared benzenesulphonamides precursors52, 55 as in Scheme 5. They also
screened the synthesized compounds for antimicrobial activity and found the compounds
exhibited marked potency as antibacterial agents.
S
O
O
ClNH
O
OH
+i. Na2CO3/H2O, stir at rt, 4h
ii. 2M HCl, pH 2
S
O
O
N
OOH
NHEt2, heatS
O
O
N
N
O
CH3CH3
5051 52 53
S
O
O
Cl
+
NH2
OH
R
O50
54
i. Na2CO3/H2O, stir at rt, 4h
ii. 2M HCl, pH 2
S
O
O
NHO
OH
R
55
NHEt2, heat S
O
O
NHO
N
R
CH3CH3
56
Scheme 5: Synthesis of N,N-dimethylamide bearing sulphonamides
NH2
N
N
NHN
+S
O
O
R ClEt3N, THF
50-60oC
N
N
NHN
HN S
O
O
R
4445 46
N
SNH2
R+ ClO2S R1
RN
SN
H
S R1
O
OPyridine
60oC
4748 49
Benzo[d ]thiazol-2-amine
28
2.1.2. Synthesis of Sulphonamides as Antimalarial Agents.
Boechatet al.28
used a rational approach to synthesized a new set of 15 1H-1,2,4-triazol-
3-yl benzenesulphonamide derivatives with the aim of developing new antimalarial lead
compounds. They synthesized 1H-1,2,4-triazol-3-yl benzenesulphonamide derivatives 60by
preparing 3-amine-1H-1,2,4-triazoles 59in excellent yield (91-99%) using aminoguanidine
bicarbonate 57to undergo condensation followed by cyclization with the appropriate carboxylic
acid 58. An equimolar mixture of the 3-amino-1H-1,2,4-triazoles59and the appropriate sulphonyl
chloride derivative 48was stirred in the presence of acetonitrile or DMF at room temperature and
yield the desired 1H-1,2,4-triazol-3-yl benzenesulphonamides60 as in Scheme 6. These
compounds possessed antimalarial activities.
Ryckebuschet al.29
synthesized and evaluated a library of 31 sulphonamides as inhibitors
of a chloroquine-resistant strain of Plasmodium falciparum according to Scheme 7. They
reported that the most potent compound displayed an activity 100-fold better than chloroquine.
They synthesized thesesulphonamides66 by amine 62obtained by aromatic substitution of 4,7-
dichloroquinoline63 by 1,4-bis(3-chloropropyl)-piperazine64, and reacted with commercially
available sulphochlorides65 or sulphofluorides.
H2N N
NH
NH2 . H2CO3
H
+R' OH
O
R'
N N
NH2
N
H
H
N
R'
N N
N
H
O2S R
S
O
O
ClR
DMF or rt, 6hCH3CN,
i. Toluene, reflux, 24h
57 58 59
48
60
SCHEME 6: Synthesis of 1H-1,2,4-triazol-3-yl benzenesulphonamide Derivatives
29
2.1.3. Synthesis of sulphonamides as an Antioxidant Agent
Further derivatives of sulphonamide bearing carbazole rings were reported by Reddy et
al.30
These compounds were prepared as in Scheme 8. They were further screened to determine
their biological activities and found to exhibit moderate to potent antimicrobial activities and
good antioxidant activities.
SCHEME 8: Synthesis of Sulphonamide Bearing Carbazole
Rindhe, et al.31
synthesized 3(Z)-{4-[4-(arylsulphonyl)piperazin-1-ylbenzylidene)-1,3-
dihydro-2H-indol-2-one 74by firstly producing t-butyl-4-{4 [Z]- (2-oxo-1,2-dihydro-3H-indol-3-
ylidene)methyl]phenyl}piperazine-1-carboxylate 72which was converted to (3Z)-3-(4-piperazin-
1-yl benzylidene)-1,3-dihydro-2H-indol-2-one 73as shown in Scheme 9. Compound 73were
dissolved in tetrahydrofuran (THF) in the presence of pyridine and catalytic amount of dimethyl
aminopyridine. The reaction mixture was stirred at room temperature for 8h and then poured in
water. The aqueous layer extracted with ethyl acetate. The ethyl acetate layer that separatedout,
N Cl
R
+ NN
NH2
H2N
N N
R
NN
NH2
H
Pentanol, reflux
18h, 85%
63 +
N
N
Cl
Cl
+ S
O
O
R Cl
HNN
N S
O O
RN N
R
H
6162
63
6465
66
CH2Cl2
r.t, 3h
SCHEME 7: Synthesis of Sulphonamide as Inhibitors of a Chloroquine-resistant
N
O
H
O O
N-
O
O
N
O
SO
O R
Na+
NaH
THF, 0-5oC
R SO2 Cl
2-3h
6768
69
30
was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product obtained
was crystallized in alcohol.
2.1.4 Synthesis of Sulphonamides as Anticancer andAntitumor Agents
Another highly substituted sulphonamide was prepared by Ghorab, et al.32
They obtained
4-oxothiazolidine benzenesulphonamides79as described earlier.33
by refluxing the Schiff base
with thioglycolic acid in dry benzene for additional 12h. In addition, one pot reaction can be
conducted via refluxing sulphanilamide8 with the required aldehyde and thioglycolic acid 78 in
dry benzene for 48h. These reactions are summarized in Scheme 10. They found these
synthesized compounds to have anticancer activities.
N
O
H
+
O
NN
O
OHN
O
NN
O
O
NHN
N
O
HHN
O
NN SR
O O
Ammonimum acetateToluene, 80o
TEA, DCM, R.T
RSO2Cl, R.T
Pyridine, THF
70 71
72
7374
SCHEME 9: Synthesis of 3(Z)-{4-(arylsulphonyl)piperazin-1-ylbenzylidene)-1,3-dihydro-2H-indol-2-one
NH2
SO O
NH2
+
CHO
R
EtOHS
O
O
H2N N=CH R
NH2
SO O
NH2
+
CHO
R3
R1
R2
+
HS
OH
O
SO O
NH2
HS
OH
O
N
SR1 R2
R3
Dry benzene12h
Dry benzene
48h
8
8
75
77
76
78
79
SCHEME 10: Synthesis of 4-Oxothiazolidine benzenesulphonamides
31
Babu34
synthesized 1-((4-chlorophenyl)(phenyl)methyl)-4-(sulphonyl)piperazine84 as
shown in Scheme 11 and N-(5-Bromo-2-chlorobenzyl)-N-cyclopropylsulphonamide derivatives
87as shown in Scheme 12. He found the synthesized compounds to have anticancer activities.
2.1.5. Synthesis of Sulphonamides as Anti-inflammatory Agent
Sondhiet al35
synthesized some methanesulphonamide derivatives89 by condensation of
3,4-diaryl-2-imino-4-thiazolines 88with methanesulphonyl chloride. They found the
compounds to have anti- inflammatory and anticancer activities.
Cl
O
NaH4
60-65oC
Cl
OH
Co
60-65Toluene
Conc. HCl
Cl
Cl
Cl
Cl
N
N
H
N
N
H
N
N
S
R
O O
RSO2Cl, TEA
35-40oC
DMF,Kl, KOH
80-85oC
80(4-Chlorophenyl)(phenyl)
methanone
81(4-Chlorophenyl)(phenyl)
methanol
821-Chloro-4-(chloro(phenyl
methyl) benzene
83
1-((4-Chlorophenyl)(phenyl)methyl) piperazine
84
SCHEME 11: Synthesis of 1-((4-Chlorophenyl)(phenyl)methyl)-4-(sulphonyl)piperazine
OH
Cl
Br
O
N
Cl
Br
O
N
Cl
Br
N
Cl
Br
SO O
R
RSO2Cl
H HBF3, etherate,THF
NaBH4, 60-65oC
TEA, 35-40oC
Oxalychloride
Cyclopropane amine
0-5oC
845-Bromo-2-chloro
benzenoic acid
5-Bromo-2-chloro-N-cyclopropyl
benzamide
85 86
87
SCHEME 12: Synthesis of N-(5-Bromo-2-chlorobenzyl)-N-cyclopropyl sulphonamide
32
Husain et al.36
synthesized various amide derivatives of sulphonamide by condensing them
with appropriate 4-oxo-4(4-substituted phenyl)butanoic acid moiety as shown in Scheme 13. The
compounds were found to have significant anti-inflammatory and antibacterial activities.
SCHEME 13: Synthesis of Amide Derivatives of Sulphonamide
2.1.6. Synthesis of Sulphonanamides as Antiviral and Anti- HIV Agent
In a six-steps synthesis, Chen et al.37
synthesized 5-(4-chlorophenyl)-N-substituted-N-1,3,4-
thiadiazole-2-sulphonamide derivatives 100. Esterification of 4-chlorobenzoic acid94 with
methanol and subsequent hydrazination, followed by reaction with carbon disulphide and
hydrogen tetraoxosulphate(vi) acid afforded 5-(4-chlorophenyl)-1,3,4-thiadiazole-2-thiol 98.
Conversion of this intermediate into its sulphonyl chloride 99, followed by nucleophilic attack of
the amines gave the title sulphonamides100 as in Scheme 14. The bioassay tests they carried out
showed that the compounds possessed certain anti-tobacco mosaic virus activity.
N
S NH
R1
R2
R3
R1
R2
R3
N
S N S
O
O
CH3
CH3SO2/K2CO3
Dry THF, r.t., stir4h
8988
R'
R +
O O
R'
R
OH
O
O
R'
SO2R'' N
O
OH
R'
R
SO2R'' NH2
POCl3
Anhyd. AlCl3
Pyridine
90 91 92
93
33
SCHEME 14: Synthesis of 5-(4-Chlorophenyl)-N-substituted-N-1,3,4-thiadiazole-2-sulphonamide
Igbalet al.38
synthesized some novel primary benzenesulphonamides bearing 2,5-
disubstituted-1,3,4-oxadiazole moiety 103 by direct chlorosulphonation at the 2-position of the
phenyl ring 102 leading to 5- mercapto-1,3,4-oxadiazoles 101 as shown in Scheme
15.Interestingly, they found the synthesized compound to have anti-HIV activity.
SCHEME 15: Synthesis of Benzenesulphonamides Bearing 2,5-disubstituted-1,3,4-oxadiazole
2.1.7. Synthesis of Sulphonamides as Diuretics Agent
A sulphonamide that has diuretic activity was reported by Vardanyan and Hruby.39
The
compound 4-chloro-N-(2-methyl-1-indolinyl)-3-sulphonylbenzamide108which he named
Inapamide was obtained from2-methylindoline104 by nitrosation to give 2-methyl-1-
nitrosoindoline 105. Reduction of compound 105 with lithium aluminum hydride led to the
formation of 1-amino-2-methyl indoline106. Acylation with 3-sulphonyl amino-4-chlorobenzoic
acid chloride107 led to compound108.40
as in Scheme 16.
Cl CO2H Cl CO2CH3 Cl CONHNH2
Cl CONHNH.CS2K Cl
N N
SSH
98
N N
SS
O
O
ClCl
N N
SS
O
O
N
R2
R1
Cl
94 95 96
97 98
99 100
reflux reflux
r.t 0oC
-2-0 oC
MeOH, H2SO4NH2NH2, H2O, EtOH
KOH, CS2, EtOH H2SO4
ClCH2CH2Cl, H2O, HCl,ClNHR1R2
CH3CN, Et3Nr.t
CR
O
NH NH2
R
SO O
Cl
NN
O SH
NN
O SHR
SO O
NHR'
CS2, KOH
EtOH,reflux
Dry NH3
CHCl3, r.t, 1.5h
101 102 103
34
SCHEME 16: Synthesis of 4-chloro-N-(2-methyl-1-indolinyl)-3-sulphonyl benzamide.
2.1.8. Synthesis of Sulphonamides as Analgesic Agent
Monoterpene-based p-toluenesulphonamide was reported by De Sousa et al.41
starting
with the naturally occurring (R)-(-)-carvone109. This was followed by 1,2-addition of KCN and
then reduction with lithium aluminum hydride to afford the amino alcohols. Tosylation of this
mixture with p-toluenesulphonyl chloride furnished thesulphonamide112(Scheme 17). The
compound was screened and found to haveanalgestic-like psychopharmacological activity.
SCHEME 17: Synthesis of Monoterpene-based p-toluenesulphonamide
N H
CH3
N NO
CH3
N NH2
CH3
Cl
SO2 NH2
C
O
Cl
N NH
CH3
O
C
SO2NH2
Cl
104 105106
107
108
Inapamide
NaNO2 LiAlH4
O O CN
CH2NH S
O
O
KCN, EtOH,
acetic acid, 0oC, 90%
H2O LiAlH4, THF
p TsCl
r.t., 89%
120oC, 69%
109 110 111
112
-
35
2.1.9. Synthesis of Sulphonamides as Anticonvulsant Agent
Devendraet al.42
synthesized 4-phthalimido-N-(4-substituted phenyl)
benzenesulphonamide119 and 4-succinimido-N-(4-substituted phenyl)
benzenesulphonamide120by condensation of substituted anilines113 with p-
acetamidobenzenesulphonyl chloride114 in the presence of dry pyridine and acetic anhydride by
heating for 2hours to give substituted 4-acetamido-N-phenyl benzenesulphonamide115. This
product, 115 was further hydrolysed in the presence of glacial acetic acid for 6hours to give
substituted 4-amino-N-phenyl benzenesulphonamide116. The products were further refluxed
with phthalic117and succinic118 anhydrides in the presence of glacial acetic acid to give the
final products 119 and 120(Scheme 18). Biological evaluation of these compounds showed that
they have anticonvulsant activities.
SCHEME 18: Synthesis of 4-phthalimido-N-(4-substituted phenyl) benzenesulphonamide
2.1.10. Synthesis of Sulphonamides as Inhibitors of Butyryl Cholinesterase
Rehmanet al.43
synthesized a series of N-substituted derivatives of 2-phenylethylamine
125 by reacting of 2-phenylethylamine 121with benzene sulphonyl chloride 122toyieldN-(2-
phenylethyl) benzenesulphonamide123, which on further on treatment with alkyl and acyl
R NH2 + ClO2S NHCOCH3 NHCOCH3R NHSO2
R NHSO2 N
O
O
N
O
O
O
O
O
O
O
O
NH2R NHSO2
R NHSO2
113 114115
116
117118
119 120
PyridineAcetic Anhydride
, 2h
Hydrolysis,
Glacial Acetic acid
36
halides 124in the present of sodium hydride gaveN-substituted sulphonamides125 (Scheme 19).
The synthesized compounds were found to be inhibitors of butyryl cholinesterase.
SCHEME 19:Synthesis of N-substituted derivatives of 2-phenylethylamine
2.2.0. Applications of Sulphonamides in Synthetic Organic Chemistry
Sulphonamides have been used in the field of synthetic chemistry, especially in highly
versatile and stereo- selective reactions. Some of these are elaborated below.
� Sulphonamides are used as a basis for distinguishing between primary, secondary and
tertiary amines. The sulphonamides formed from primary and secondary amines are
usually crystalline solids.44
Because of the remaining hydrogen atom on the nitrogen, the sulphonamide from a primary
amine is soluble in alkali, forming a salt.
CH2
CH2
NH2
+S
OO
Cl
CH2
H2C
NS
OO
H
SOOCH2
H2C
N
R
1'3'
5'
1
3
5
NaHStir at r.t
R-X (124)
121 122123
125
H2O
NaCO3
SO2Cl + RNH2
Na+OH
-
SO2NHR + Na+Cl
-+ H2O
H2O+Na+Cl
-+SO2NHR2
Na+OH
-
R2NH+SO2Cl
SO2Cl + R3NNa
+OH
-
No reaction
126
Alkylsulphonamide(soluble in base)
127Dialkylsulphonamide(insoluble in base)
SO2NHR + Na OH-. . . .
. .SO2NR
-
Na+
+ H2O
128 129
37
In practice, the amine is shaken with benzenesulphonyl chloride and alkali. Primary amines yield
clear solutions which, on acidification, precipitate the alkylsulphonamide. Secondary amines
yield an insoluble compound which is unaffected by acid. Tertiary amines also give an insoluble
compound (the unreacted amine) which, however, dissolves on acidification (forming a soluble
amine salt). This test for distinguishing between the three classes of amines is known as the
Hinsberg reaction.45
� Fukuyama and coworkers introduced the 2-nitrobenzenesulphonyl group as a new amine
protecting and activating group. As a selected example, Bowman46
reported a
monoalkylation of amino group using α-amino esters facilitated by the use of
nitrophenylsulphonamide protecting group. Formation of anion of the sulphonamide
using CS2CO3 and subsequent alkylation gave an intermediate 131. Facile removal of the
sulphonyl group using phenylthiolate anion yielded the desired secondary amine 132 as
below;
� Wang et al.47
reported that various α-ketoesters have been reduced into the corresponding
1,2- diols in high enatioselectivities using the NaBH4/ Me3SiCl system.
� Jones and coworkers48
synthesized tran-2,5-disubstituted-3-iodopyrrolidines136 from 5-
endo-trig iodocydization of the (E)-homollylicsulphonamides135 in presence of
potassium carbonate in excellent yields.
S N
H
O
O
NO2
COOR2
R1
S N
O
O
NO2
COOR2
R1
R3
R3 N
H
CO2R2
R1
ii. R3 X
i. CS2CO3, DMF, 30mins PhS-
DMF, r.t,24h, (-S )O2
130131
132
R
OR1
O
O
R
OH
OH
NaBH4/MeSiCl, DMF, reflux
Cat (25mmol)
Polymer- supported chiral sulphonamide
133134
38
2.2.1. Miscellaneous Applications of Sulphonamides
Therapeutic importance of sulphonamides, in various areas of medicinal chemistry, can be
judged from some reported examples such as: anti-apoptosis (cell death), epilepsy 13749
,dual
action receptor antagonist (DARA) for the treatment of hypertension 13850
, anti-HCV 14251
;
serotonin 5- HT (5- hydroxytryptamin) receptor, potential therapeutic agents for depression,
sleep disorder, migraine pain and hypertension 13952
; anti-cocaine-induced convulsion and
lethality 14053.
Mesoionicoxatriazoles (MOTA) 14154
, selective antiplatelet, antithrombotic
(MOTA have “NO” (nitric Oxide) donating ability). “NO” is unique messenger, play vital role in
regulation of cardio vascular system, transmission in central and peripheral nervous system and
host defense mechanism, Sivelestat (ONO-5046); Elsanol (injectable formation) 14354
, has been
reported for the treatment of lung damage.
NR1R2
SO2R3
N
SO2R3
R2
I
R1
3aq. I2
MeCNK2CO3
135 136
N
O
H
S S
O
O
N
R
S
O O
N
H
N
O
NH3C
OMe
NO CH3
CH3
137
138
S
O O
N
N
NH
N
OO
NO
O
SO O
NH2
HCH3
Cl
+N
N N
H
N
S
O
O139
140
141
40
CHAPTER THREE
3.0 EXPERIMENTAL SECTION
3.1. GENERAL
All the starting materials and reagents were obtained from commercial sources and were
used without further purification. The melting points were determined with Fischer John’s
melting point apparatus and are uncorrected. IR spectra were recorded on 8400s Fourier
Transform Infrared (FTIR) spectrophotometer and are reported in wave number (cm-1
). IR
analysis was done at National Research Institute for Chemical Technology (NARICT), Zaria,
Kaduna State. Nuclear Magnetic Resonance (1H-NMR and
13C-NMR) were determined using
Jeol 400MHz at Strathclyde University, Scotland. Chemical shifts are reported in (δ) scale. Tests
for biological activities were carried out in the Laboratories of the Faculty of Pharmacy Sciences,
University of Nigeria Nsukka. All reagents were of technical grade. p-toluenesulphonyl chloride
and some derivatives of aminopyridine used are purchased from Sigma chemical company while
some are from Aldrich chemical company. The solvents used such as dimethylformamide
(DMF), methanol and acetone were purchased from Aldrich in sure-seal bottles and were used as
received.
3.2. General Procedure for the Preparation of the Sulphonamides
The preparation of 4-methyl-N-(pyridin-2-yl) benzenesulphonamide146a described below is a
typical procedure for the preparation of these new p-toluenesulphonamides. 2-Amino pyridine
(0.94g, 10.0mmol) was dissolved in a mixture of anhydrous acetone (20.00ml) and dry pyridine
(2.00ml). p-toluenesulphonyl chloride (1.91g, 10.0mmol) was then added later. The reaction
mixture was warmed to room temperature and allowed to stir. The reaction was left for 24 hours
and 1.50g of 4-methyl-N-(pyridin-2-yl) benzenesulphonamide146a (product) was filtered off
using suction filtration. On diluting the filtrate with distilled water, a further crop (1.25g) was
obtained. The total product was recrystallized from dimethylformamide (DMF). 4-Methyl-N-(5-
nitro pyridin-2-yl) benzenesulphonamide146c and 4-methyl-N-(3-nitro pyridin-2-yl)
benzenesulphonamide146d were recrystallized from methanol solvent and N-(3-hydroxypyridin-
41
2-yl)-4-methyl benzenesulphonamide146ewas recrystallized from ethanol solvent. The products
were dried in a hot air oven at 50oC for 6 hours.
Properties and Characteristics of these New Sulphonamides Prepared
3.2.1. 4-Methyl-N-(pyridin-2-yl) benzenesulphonamide
The compound weighed (1.64g, 66.1%) as a white needle-like solid melting at 205oC- 206
oC. IR
(KBr) Ѵmax: 3236cm-1
(N-H stret.), 3042cm-1
(Ar C-H), 1133cm-1
(SO2- functional group). 1H-
NMR [DMSO-d6] δ: 8.01 (d, J = 5.25Hz, 1H, NH), 7.76 (d, J = 8.14Hz, 2H, Ar-H), 7.70 (m, 4H,
phenyl-H), 7.33 (d, J = 8.14Hz, 2H, Ar-H), 7.14 (d, J = 8.70Hz, 1H, Ar-H), 6.86 (m, 4H, pyridyl-
H), 2.32(s, 3H, CH3-phenyl). 13
C-NMR [DMSO-d6] δ: 153.57- 144.10 (C1-C9, Ar-C), 21.49 (C10,
aliphatic carbon).
3.2.2. 4-Methyl-N-(4-methyl pyridin-2-yl) benzenesulphonamide.
This compound weighed (1.52g, 58.0%) as a white solid melting at 217oC- 218
oC. IR
(KBr)Ѵmax: 3229cm-1
(N-H stret.), 3037cm-1
(Ar C-H), 1141cm-1
(SO2- functional group). 1H-
NMR [DMSO-d6] δ: 7.81 (d, J = 5.87Hz, 2H, Ar- H), 7.74 (d, J = 8.20Hz, 2H, Ar-H), 7.31 (d, J
= 8.09Hz, 1H, Ar- H), 6.99 (s, 1H, Ar- H), 6.67 (d, J = 5.86Hz, 1H, Ar-H), 3.39 (s, 1H, NH),
2.32 (s, 3H, CH3-pyridyl), 2.22 (s, 3H, CH3-phenyl).
3.2.3. 4-Methyl-N-(5-nitropyridin-2-yl) benzenesulphonamide.
This compound weighed (1.58g, 53.9%) as a milky needle-like solid melting at 183oC- 184
oC. IR
(KBr)Ѵmax: 3259cm-1
(N-H stret.), 3096cm-1
(Ar C-H), 1518- 1349cm-1
(NO2stret.), 1198cm-1
(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.92 (d, J = 2.64Hz, 1H, Ar- H),8.26 (dd, J1=
2.75Hz, J2 = 9.46Hz, 1H, Ar- H), 7.50 (d, J = 8.05Hz, 2H, Ar- H), 7.13 (d, J = 7.90Hz, 2H, Ar-
H), 6.71 (d, J = 9.46Hz, 1H, Ar-H), 5.30 (s,b, 1H, NH), 2.29 (s, 3H, CH3-phenyl).
3.2.4. 4-Methyl-N-(3-nitropyridin-2-yl) benzenesulphonamide.
This compound weighed (2.14g, 73.0%) as a yellowish needle-like solid melting at 153oC-
154oC. IR (KBr)Ѵmax: 3454cm
-1- 3268cm
-1 (N-H stret.), 3110cm
-1 (Ar C-H), 1333cm
-1
(NO2stret.), 1162cm-1
(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.41 (m, 7H,
42
heteroaromatic-H), 8.00 (s, b, 1H, NH), 7.51 (dt, J = 2.65Hz, J1 = 8.07Hz, J2 = 8.07Hz, 2H, Ar-
H), 7.13 (d, J = 8.00Hz, 1H, Ar-H), 6.77 (dd, J1= 4.58Hz, J2 = 8.31Hz, 1H, Ar-H), 2.29 (s,
3H,CH3-phenyl).
3.2.5. N-(3-Hydroxy pyridin-2-yl)-4–methyl benzenesulphonamide.
This compound weighed (1.92g, 72.7%) as a pale-white needle-like solid melting at 105oC-
106oC. IR (KBr)Ѵmax: 3474cm
-1 (OH stret.), 3287cm
-1 (N-H stret.), 3138cm
-1 (Ar C-H),
1164cm-1
(SO2- functional group). 1H-NMR [DMSO-d6] δ: 7.82 (m, 7H, heteroaryl-H), 7.43 (d, J
= 8.15Hz, 1H, NH), 7.29 (dd, J1 = 1.39Hz, J2 = 7.89Hz, 1H, Ar-H), 6.50 (dd, J1 = 4.85Hz, J2 =
7.85Hz, 1H, Ar-H), 5.97 (s, 1H, OH), 2.40 (s, 3H, CH3-phenyl).13
C-NMR [DMSO-d6] δ: 153.10
– 112.40 (C1-C9, Ar-C), 21.74 (C10, aliphatic carbon).
3.2.6. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide.
This compound weighed (1.66g, 63.3%) as an orange liquid (oil). IR (KBr)Ѵmax: 3311cm-1
(N-
H stret.), 3161cm-1
(Ar C-H), 1154cm-1
(SO2- functional group). 1H-NMR [DMSO-d6] δ: 8.09
(m, 7H, heteroaryl-H), 8.0 (s, b, 1H, NH), 7.74 (t, J = 8.06Hz, 1H, Ar-H), 7.52 (d, 8.02Hz, 1H,
Ar-H), 7.25 (d, J = 7.84Hz, 1H, Ar-H), 7.12 (d, J = 7.86Hz, 1H, Ar-H), 6.83 (d, J = 8.83Hz, 1H,
Ar-H), 6.62 (d, J = 7.03Hz, 1H, Ar-H), 2.35 (s, 3H, CH3- pyridyl), 2.24 (s, 3H, CH3- phenyl).
3.2.7. 4-Methyl -N- (pyridin-2-yl) benzenesulphonamide.
This compound weighed (1.25g, 50.4%) as a white solid melting at 213oC- 214
oC. IR
(KBr)Ѵmax: 3227cm-1
(N-H stret.), 3061cm-1
(Ar C-H), 1164cm-1
(SO2- functional group). 1H-
NMR [DMSO-d6] δ: 8.53 (d, J = 7.15Hz, 2H, Ar-H), 7.87 (d, J = 8.31Hz, Ar-H), 7.50 (d, J =
8.07Hz, 2H, Ar-H), 7.44 (m, 4H, heteroaromatic-H), 7.12 (d, J = 7.91Hz, NH), 2.28 (s, 3H, CH3-
phenyl).
3.3. Antimicrobial Activity
The antimicrobial properties of the sulphonamides were investigated in form of the
general sensitivity testing and minimium inhibitory concentration (MIC) with respect to freshly
cultured targeted organisms. The eight organismsused in this present study are Bacillus subtilis,
Bacillus cereus and Staphylococcus aureus as gram-positive bacteria,Klebsiellapneumoniae,
43
Pseudomonas aeruginosa and Escherichia coli as gram-negative bacteria, Candida albicansand
Asperigellusniger as fungi organisms.
3.3.1. Sensitivity Testing of Compounds.
Agar diffusion technique method as describe by Vincent (2005)55
, was used to determine
the antimicrobial activities of the synthesized compounds. Sensitivity test agar plates were
seeded with 0.1ml of 24 hours culture of each micro-organism into its corresponding petri-dish
previously labeled using the molten agar already prepared. The plates were allowed to set after
which cups were made in each sector previously drawn on the backside of the bottom- plate
using marker. Using the pipette (sterile), each cup was filled with six drops of their
corresponding antimicrobial agent in appropriate solvent at a concentration of 2mg/ml. The
plates were finally incubated at 37oC for 24 hours for bacteria and 48 hours for fungi. It should
be noted that the solubilizing solvent used was dimethyl formamide (DMF). Mueller Hinton agar
was prepared in 20ml portions kept molten at 45oC. The zone of inhibition (clearance) produced
after 24 hours on incubation at 37oC was measured.Muller Hinton agar was used for the fungi in
place of nutrient agar for bacteria. The procedure was repeated for Tetracycline and Fluconazole
drugs (bacteria and fungi standard respectively).
3.3.2. Minimium Inhibitory Concentration (MIC) Testing of Compounds.
The MIC was determined by further dilution of the test sample found to be sensitive
against a particular organism. Serial dilutions of the sulphonamides were prepared from 2mg/ml
solution of the sulphonamides to give 2.0-0.125mg/ml. After dilution, the test solutions were
added into their corresponding cups previsously made in the molten agar starting from the lowest
concentration (0.125- 1.0mg/ml). This was followed by incubation at the appropriate incubation
temperature and time. The resultant inhibition zones of diameter (IZD) were measured and the
value subtracted from the diameter of the borer (8mm) to give the inhibition zone diameter
(IZD). The MIC was also determined using graph of logarithm of concentration against IZD 2
for
each plate containing a specific compound and a microorganism. The anti-logarithm of the
intercept on x-axis gives the MIC.
44
CHAPTER FOUR
4.0. RESULTS AND DISCUSSION
4.1.0 4-Methyl –N- (pyridin-2-yl) benzenesulphonamide 146a.
On condensation reaction of p-toluene sulphonylchloride 144 and2-aminopyridine 145a in dry
pyridine and acetone at room temperature for 24hours, 4-methyl-N-(pyridin-2-yl)
benzenesulphonamide146a was obtained as a white needle-like solid with a melting point of
205oC- 206
oC.
SCl
O O
+N
NH2
-HCl
H3C
SNH
H3C
OO
N
1
2
3
4
5
6
7
7
89
10
8
Acetone, dry pyridine, r.t, 24h
144 145a146a
The proposed mechanism of this reaction is as shown in Scheme 20.
H3C
SO
O
Cl N
NH2
..
+R
Dry pyridine
H3C
SO
O
R
N+
H
H Cl-
N -HClH3C
SO
O
R
N
N
H
SCHEME 20: Proposed Mechanism of Reaction of New Synthesized Sulphonamides.
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3236cm-1
is due to NH, 3042cm-1
is due to aromatic C-H and 1133cm-1
is due to SO2-
functional group. In the1H-NMR spectrum, the peaks at δ8.01 is assigned to NH-proton, δ7.76 is
assigned to C7–proton, δ7.70 and δ6.86 (m, 8H) are due to heteroaromatic protons, δ7.33 is
assigned to C8 – proton, δ7.14 is assigned to C9 – proton and δ2.32 is due to CH3, aliphatic
45
hydrogen. In the13
C-NMR spectrum, peaks at δ153.57- δ114.10 are due to aromatic carbons (C1-
C9) and δ21.49 is due to aliphatic carbon (CH3). The spectrum agrees with the assigned structure.
4.1.1.4-Methyl –N-(4-methyl pyridin-2-yl) benzenesulphonamide 146b.
On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-4-methyl pyridine
145b in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(4-methyl
pyridin-2-yl) benzenesulphonamide146b was obtained as a white solid with a melting point of
217oC- 218
oC.
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3229cm-1
is due to NH, 3037cm-1
is assigned to Aromatic C- H and 1141cm-1
is due to SO2-
functional group. In the 1H-NMR spectrum, the peaks at δ7.81 is assigned to C7 – proton, δ7.74
is assigned to C8 – proton, δ7.31 is assigned to C3 – proton, δ6.99 is assigned to C9- proton, δ6.67
is assigned to C4- proton, δ3.39 is due to NH- proton, δ2.32 is due to C10- proton and δ2.22 is due
to C11- proton. The spectrum agrees with the assigned structure.
4.1.2. 4-Methyl -N-(5–nitro pyridin-2-yl) benznesulphonamide 146c.
On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-5-nitro pyridine 145c
in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(5-nitro pyridin-2-yl)
benzenesulphonamide146c was obtained as a milky needle-like solid with a melting point of
183oC- 184
oC.
H3C
S
O O
Cl+
N
NH2
H3C
SO O
NH
H3CN
H3C
- HCl
acetone, dry pyridine, r.t., 144 145b
146b
24h
12
34
5
6
7
8
9
10
7
8
11
46
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3259cm-1
is due to NH, 3096cm-1
is assigned to Aromatic C- H 1518cm-1
- 1349cm-1
is due to
NO2 group and 1198cm-1
is due to SO2- functional group. In the1H-NMR spectrum, the peaks at
δ8.92 is assigned to C4 – proton, δ8.26 is assigned to C9 – proton, δ7.50 is assigned to C7 –
proton, δ7.13 is assigned to C8- proton, δ6.71 is assigned to C6- proton, δ5.30 (s, b, 1H) is due to
NH- proton and δ2.29 is due to C10- proton. The spectrum agrees with the assigned structure.
4.1.3. 4-Methyl-N-(3–nitro pyridin-2-yl) benznesulphonamide 146d.
On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-3-nitro pyridine 145d
in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(3-nitro pyridin-2-yl)
benzenesulphonamide146d was obtained as a yellowish needle-like solid with a melting point of
153oC- 154
oC.
SNH
H3C
OO
NO2N
1
2
3
4
5
6
7
8
9
10
8
9H3C
SO O
Cl + N
NH2
O2N-HCl
Acetone, dry pyridine, r.t
24h144 145d146d
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3454cm-1
is due to NH, 3110cm-1
is assigned to Aromatic C- H, 1536cm-1
- 1333cm-1
is due to
NO2 group and 1162cm-1
is due to SO2- functional group. In the1H-NMR spectrum, the peaks at
δ8.41 (m, 7H) is due to heteroaromatic – protons, δ8.00 (s, b, 1H) is due to NH – proton, δ7.51 is
assigned to C9 – proton, δ7.13 is assigned to C4- proton, δ6.77 is assigned to C5- proton, and
δ2.29 is due to C10- proton. The spectrum agrees with the assigned structure.
H3C
S
O O
Cl+
N
NH2
NO2
SO O
NH
H3CN
NO2
- HCl
acetone, dry pyridine, r.t., 144
145c146c
24h
12
3
4
5
6
7
8
97
8
10
47
4.1.4 N-(3-Hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide 146e.
On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-3-hydroxyl pyridine
145e in acetone/DMF (in mol ratio of 2:1) and dry pyridine at room temperature for 24 hours, N-
(3-hydroxy pyridin-2-yl)-4-methyl benzenesulphonamide146e was obtained as a pale white
needle-like solid with a melting point of 105oC- 106
oC.
SNH
H3C
OO
NHO
1
2
3
45
6
7
8
9
109
8H3C
SO O
Cl + N
NH2
-HCl
Acetone, dry pyridine, r.t
24h144
HO
145e
146e
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3474cm-1
is due to OH, 3287cm-1
is due to NH, 3138cm-1
is assigned to Aromatic C- H and
1164cm-1
is due to SO2- functional group. In the1H-NMR spectrum, the peaks at δ7.82 (m, 7H) is
due to heteroaromatic – protons, δ7.43 is due to NH – proton, δ7.29 is assigned to C6 – proton,
δ6.50 is assigned to C7- proton, δ5.97 is due to OH and δ2.40 is due to C10- proton. In the13
C-
NMR spectrum, peaks at δ153.10- δ112.40 are due to aromatic carbons (C1- C9) and δ21.74 is
due to aliphatic carbon (CH3). The spectrum agrees with the assigned structure.
4.1.5. 4-Methyl–N-(6-methyl pyridin-2-yl) benzenesulphonamide 146f.
On condensation reaction of p-toluenesulphonyl chloride 144 and 2-amino-6-methyl pyridine
145f in acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(6-methyl
pyridin-2-yl) benzenesulphonamide146f was obtained as a yellowish liquid (oil).
H3C
S
O O
Cl+
N
NH2
CH3
SO O
H3CN
CH3
- HCl
acetone, dry pyridine, r.t., 144 145f
146f
24h
1
2
3
4
56
89
7
8
10
9
11
NH
48
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3311cm-1
is due to NH, 3161cm-1
is assigned to Aromatic C- H and 1154cm-1
is due to SO2-
functional group. In the1H-NMR spectrum, the peaks at δ8.91 is assigned to NH –proton, δ862 is
assigned to C9- proton, δ8.09 (m, 7H) is due to heteroaromatic – protons, δ7.74 is assigned to C5
– proton, δ7.52 is assigned to C6 – proton, δ7.25 is assigned to C7- proton, δ6.83 is assigned to
C8- proton, δ2.35 is due to C10- proton and δ2.21 is due to C11- proton. The spectrum agrees with
the assigned structure.
4.1.6. 4-Methyl–N-( pyridin-4-yl) benzenesulphonamide 146g.
On condensation reaction of p-toluenesulphonyl chloride 144 and 4-amino pyridine 145g in
acetone and dry pyridine at room temperature for 24 hours, 4-methyl-N-(pyridin-4-yl)
benzenesulphonamide146g was obtained as a white solid with a melting point of 213oC- 214
oC.
The assigned structure is supported by spectra analysis. In the IR spectrum, the absorption bands
at 3227cm-1
is due to NH, 3061cm-1
is assigned to Aromatic C- H, and 1164cm-1
is due to SO2-
functional group. In the1H-NMR spectrum, the peaks at δ8.53 is assigned to C7 – proton, δ7.87 is
assigned to C8 – proton, δ7.44 (m, 8H) is due to heteroaromatic – protons and δ2.28 is due to
C10- proton, aliphatic proton. The spectrum agrees with the assigned structure.
4.2. Antimicrobial Activity Evaluation
The obtained new compounds were screened in vitro for their antibacterial activities
against gram-positive bacteria (B. subtilis, B. cereus and S. aureus), gram-negative bacteria (P.
aeruginosa, E. coli and K. pneumoniae) and antifungal activities against fungi organisms (C.
albicansand Asp. niger), using the agar diffusion techniques.55
The choice of gram-positive and
gram-negative bacteria were because they are easily transmissible through soil, food, water,
H3C
S
O O
Cl+
SO O
H3C
- HCl
acetone, dry pyridine, r.t., 144 145g
146g
24h
1
2
34
5 68
9
7
8
10
NH
N
NH2
N
7
49
animal and human.56
Bacillus subtilis is commonly found in soil and inhibits the gut, considered
as a normal gut commensal.57
It is used in laboratory studies directed at discovering the
fundamental properties and characteristics of gram-positive spore-forming bacteria.58
Bacillus
cereus is an endemic, soil-dwelling, gram-positive, rod-shaped, beta hemolytic bacterium. Some
of its strains are harmful to humans and cause food borne illness.59
S. aureus is a bacterium that is
frequently found in the human respiratory tract and on the skin. It is a common cause of skin
infections (e.g. boils), respiratory diseases (e.g. Sinusitis) and food poisoning.60
E. coli is a
normal flora of human body which causes a lot of vancomycin-resistant Enterococci and
Methicillin-resistant Staphylococcus aureus.61
E. coli is a gram-negative, rod shaped bacterium
that is commonly found in the lower intestine of warm- blooded organisms (endotherms). It can
cause serious food poisoning in humans and are occasionally responsible for product recalls.62
K.
pneumoniae is a gram-negative, non-motile, encapsulated, lactose fermenting, facultative
anaerobic, rod shape bacterium. It is found in the normal flora of the mouth, skin and
intestines.63
P. aeruginosa is a gram negative, aerobic, coccobacillus with unipolar motility that
can cause disease such as urinary tract, burns, wounds and blood infections in animals, including
humans.60
It is found in soil, water, skin flora and most man- made environments throughout the
world.64
The choice of C. albicansand Asp. niger as fungal organisms are that they diploid
fungus that grows both as yeast and filamentous cell and a causal agent of opportunistic oral and
gential infections in humans.60
The choice of Tetracycline and Fluconazole as Clinical standards
is due to the fact that they possesses broad spectrum of antibacterial and antifungal activities
respectively.65
The results of the antibacterial and antifungal activities tests are shown in Table 1.
4.2.1. Results of Sensitivity Testing of Compounds.
Compound
Nos.
Gram-Positive Bacteria Gram-NegativeBacteria Fungi Organisms
B.Subtilis B.
Cereus
S.
Aureus
P.
Aeruginosa
E. coli K.
Pneumoniae
C.
Albicans
Asp.
Niger
146a - - - - - - - -
146b - - +++ - - - - -
146c - ++ +++ - - - ++ -
146d - - - - - - ++ -
50
146e + ++ +++ - - - ++ -
146f - - - - - - - -
146g - ++ +++ - - - - -
TCN + ++ + +++ + +++ - -
Flu - - - - - - +++ +++
TABLE 1: Results of General Sensitivity Test.
+ = Less Sensitive, ++ = Moderately Sensitive, +++ = Highly Sensitive and - = Resistance.
From the result of sensitivity testing, it was observed that compounds 146a and 146f are
not sensitive to the organisms under test. Compound 146d is not sensitive to bacteria. The
sensitive compounds 146b, 146c, 146e and 146g were only active against gram-positive bacteria.
Compounds 146c, 146d and 146e were sensitive to Candida albicans(fungi organism) only.
TCN is sensitive to bacteria only and Flu is sensitive to fungi organisms.
4.2.2. Results of Minimium Inhibitory Concentration (MIC) Testing of Compounds.
The compounds found sensitive on the tested organisms were further diluted to get the
MIC results as in Table 2.
Compound
Nos.
Gram-Positive Bacteria Gram-Negative Bacteria Fungi Organisms
B.
Subtilis
B.
Cereus
S.
Aureus
P.
Aeruginosa
E. coli K.
Pneumoniae
C.
Albicans
Asp.
Niger
146b - - 0.20 - - - - -
146c - 0.23 0.19 - - - 0.23 -
146d - - - - - - 0.30 -
146e 0.24 0.13 0.17 - - - 0.23 -
146g - 0.19 0.20 - - - - -
TCN 5.62 11.48 5.31 15.85 3.16 17.78 - -
Flu - - - - - - 24.00 27.00
TABLE 2: Results of MIC Test
51
From the point of view of B. subtilis as shown in table 2, compound 146e is the most active at
MIC value of 0.24mg/ml. From B. cereus, compounds 146e and 146g are the most active at MIC
value of 0.13mg/ml and 0.19mg/ml respectively, From S. aureus, compounds 146c and 146e are
the most active at MIC value of 0.19mg/ml and 0.17mg/ml respectively. From P. aeruginosa, E.
coli and K. pneumoniae, none of the synthesized compounds showed activity. TCN is active at
MIC values of 15.85mg/ml, 3.16mg/ml and 17.78mg/ml respectively. From C. albicans,
compounds 146c and 146e are the most active at MIC value of 0.23mg/ml and 0.23mg/ml
respectively. From Asp.niger, none of the synthesized compounds also showed activity. Flu is
active at MIC value of 27.00mg/ml.
52
CHAPTER FIVE
5.0 CONCLUSION
The synthesis of N-(heteroaryl-substituted)-p-toluenesulphonamides has been achieved
successfully. The assigned structures were supported by spectra analysis. The sulphonamides
have good antimicrobial properties against some of the tested organisms.
53
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