CHAPTER-1. GENERAL INTRODUCTIONshodhganga.inflibnet.ac.in/bitstream/10603/111168/2... · CHAPTER-1....

CHAPTER-1. GENERAL INTRODUCTION

1

1. Introduction:

Antibiotics have saved millions of lives and eased the suffering of patients of

all ages for more than 70 years. These “wonder drugs” deserve much of the credit for the

dramatic increase in life expectancy around the world in the 20th

century. As the world’s

population increases, health problems expands, accordingly need to discover new

therapeutics will become even more diring. The design of drug molecules arguably offers

some of the greatest hopes for success in present and future era1. The treatment of

infectious diseases is still an important and challenging problem due to the emergence of

numerous infectious disease and increasing number of multi-drug resistant microbial

pathogens which cause a variety of illnesses ranging from hospital-acquired pneumonia,

bloodstream infections and urinary tract infections from catheters, abdominal infections

and even meningitis. Resistant infections are difficult to treat, tend to spread relatively

rapidly and increase healthcare costs significantly2. Antimicrobial resistance has been

detected in all parts of the world; it is one of the greatest growing challenges to global

public health today.

Fungal infections are life threatening systemic infections and increasing more

and more3. The primary reason for this is the increasing number of patients at risk,

including those, with higher age, major surgery, immunosuppressive therapy, acquired

immunodeficiency syndrome (AIDS), cancer treatment, solid organ and hematopoietic

stem cell transplantation4. The search and development of more effective and safe

antimicrobial agents are compulsory5, 6

. A. brassicae and A. brassicicola are

phytopathogenic fungi that severely affect the production of most cruciferous crops

(broccoli, cauliflower, mustard, turnip, cabbage, and radish). N-(Salicylidene)-

2-hydroxyaniline at the concentration of 500 ppm inhibited the growth of these fungi7 by

67-68%.

Bacterial drug resistance is a fast growing global health challenge. Resistant

infections are difficult to treat, tend to spread relatively rapidly and increase healthcare

costs significantly. Antimicrobial resistance is becoming a global concern with rapid

increase in multi-drug resistant bacteria. Some previously treatable pathogens are now

becoming untreatable, for example methicillin-resistant Staphylococcus aureus (MRSA)

and vancomycin-resistant Enterococcus8 (VRE). Throughout history, there has been a

continual battle between humans and the multitude of micro-organisms that cause infection

and disease. Bubonic plague, tuberculosis, malaria, and more recently, the human


2

immunodeficiency virus, acquired immunodeficiency syndrome pandemic, have affected

substantial portions of the human population, causing significant morbidity and mortality.

Beginning around the middle of the 20th

century, major advances in antibacterial drug

development and other means of infection control helped turn the tide in favour of

humans9.

To overcome the alarming problem of microbial resistance to antibiotics, the

discovery of novel compounds active against new targets is a matter of urgency. Many of

the crude drugs, which are sources of medicinal preparations, still originate from wild

growing material. However, plant based drugs have shortened the life span of the source of

material. There is a continuous search for more potent and cheaper raw materials to feed

the industry. So now a day's pharmaceutical industries are looking for synthesizing the

alternative compounds which can act as drug.

2-Azetidinones or β-lactams are well-known heterocyclic compounds among

the organic and medicinal chemists10

. The biological activity of the famous antibiotics

such as penicillins, cephalosporins and carbapenems are attributed to the presence of 2-aze

tidinone ring in them. Some other types of biological activity besides the antibacterial

activity have been reported in compounds containing 2-azetidinone ring11, 12

. Such

biological activities include antimicrobial13

, anti-tuburcular14

, carbonic anhydrase

inhibitors15

, local anaesthatics16

, anti-inflammatory17

, anthelmintic18

, hypoglycemic

activity19

. The β-lactams also serve as synthons for many biologically important classes of

organic compounds20

. Due to this, the investigation of chemistry and biology of these

compounds continue to appeal the synthetic and medicinal organic chemists. In search for

new biodynamic potent molecule some additional heterocyclic moieties have been

incorporated with the β-lactam nucleus and their biological and pharmacological activity21

studied.

The β-lactam class of compounds has served an important and highly

successful role in the pharmaceutical industry. “Miracle drugs” such as penicillins and

cephalosporins have significantly improved human health and life expectancy. Azetidin-

2-one, a four-membered cyclic lactam (β-lactam) skeleton has been recognized as a useful

building block for the synthesis of a large number of organic molecules by exploiting the

strain energy associated with it. Efforts have been made in exploring such new aspects of

β-lactam chemistry versatile intermediates for their synthesis of aromatic β-amino acid and

their derivatives. The β-lactam heterocyclic are still the most prescribed antibiotics used in

medicine. They are considered as an important contribution of science to humanity22

.


3

The discovery of monocyclic β-lactams e.g. monocardins (1) sulphazecin etc.

from saprophytic soil bacteria in Japan and USA around 1980’s unravelled the existence of

a novel class of β-lactams, which contains a single β-lactam23

, not fused to any other ring

system. The biological activity of norcardicins and monobactams against antimicrobial era,

have highlighted the importance of developing efficient methods for the preparation of

manocyclic 4-substituted β-lactams.

N

COOH

OH

H

NHO

ONH2

HOOC NH

O

(1)

Thus it creates interest in the synthesis of heterocyclic compounds, containing single

β-lacat m. Literature also reveals that several natural ‘monocyclic β-lactams’ and their

synthetic derivatives exhibit potent therapeutic efficacy, now it appears in the medicinal

field that the minimum requirement for biological activity is a suitable β-lactam ring24-26

.

Some novel monocyclic β-lactams have also been evaluated for anti-hyperglycemic25

, anti-

inflammatory and analgesic activities26

.

Aztreonam27

2-({[(1Z)-1-(2-amino-1,3-thiazole-4-yl)-2-{[2S,3S)-2-methyl-4-

oxo-1-sulfoazetidin-3-yl]amino}-2-oxo-ethyledine]amino}oxy)-2-methylpropanoic acid

(2) is a totally synthetic bactericidal antibiotic. It is a monobactam, having a unique

monocyclic β-lactam nucleus, active against a wide variety of Gram “-”ve aerobic

pathogens28, 29

.

N

CH3

SO3HO

S

N

NH2

NO

CH3CH3

O

OH

NH

O

HH

(2)


4

Ezetimibe (3), the first licensed azetidinone drug has been promoted as an

adjunct to statin therapy and to achieve greater reductions in blood cholesterol

concentrations than occur with a statin alone. These drugs represent a new class of

pharmaceutical agents that can be used to treat patients with hypercholesterolemia.

Chemically ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypro-

pyl]-4(S)-(4-hydroxyphenyl-2-azetidinone30-33

.

N

O

F

OH

OH

F

(3)

Superior stability of β-lactam antibiotic carbacephems34

over cephalosporin

and the ease with which it can be derivatized at 3-position, is synthetically attractive. With

the approval of first carbacephem (lorabid) (4) for clinical use the interest is continued

further. Tricyclic β-lactam antibiotics called trienems35

(5) are also a class of tricyclic

carbapenems, a highly potent, broad-spectrum antibacterial agent effective against Gram

“+”ve, Gram “-“ve and anaerobic pathogenic bacteria has attracted the attention of

synthetic as well as biological community.

N

RCONH

Cl

OH

O

O

NOMe

CO2H

H

OH

CH3

O

(4) (5)

This work has lead to the development of 4-[(4-carboxyphenyl)-oxy]-3,3-diethyl-1-

[phenyl-methyl)amino]carbonyl]-2-azetidinone (6) the first orally active human leucocyte

elastase (HLE) inhibitor. Compound with a methoxy or a methyl group on benzene ring

were found to be very potent HLE inhibitors as well as effective against hamster lung

hemorrhage36

. Further the alkyl substitution on the benzyleurea afforded enhanced HLE


5

inhibition and in-vivo efficacy37

. Works of Firestone et al. established the substituted

2-azetidinone ring as minimal structure necessary for effective HLE inhibition38

.

H

NH

OH

N

R

R

O

OCOOH

(6)

The β-lactam class of antibiotics is well known for their neurotoxicity39

. Since

the first report of epilaptogenic properties of penicillin in 1945 by the classic work of

Jonson and Walker40, 41

adverse effect of penicillin and other β-lactam antibiotics on the

central nervous system have become more widely recognized42, 43

. Mittal and Goel have

reported antidepressant activity of some 1,3,4-trisubstituted azetidinone derivatives in

mice44

.

In search for new potent bioactive molecule, some additional heterocyclic

moieties were also incorporated in the β-lactam nucleus and their biological and

pharmacological activities45

were studied. Vijay Kumar et al. prompted by the review of

literature revealed to synthesize substituted 4(m-hydroxy-p-methoxyphenyl)-1[(6’-fluoro-

7’-substituted (1,3)-benzothiazole-2’-yl)amido-2-phenyl]3-chloro-azetidinone (7) and

screened for anticonvulsant activity by pentylene tetrazole (PTZ) induced method. The

animal of control group (PTZ) 1ml/100g was administered and action like straubs tail,

jerky movement of whole body and conclusion were observed46

.

OH

OCH3

N

Cl

O

NH

ON

S

F

NH

Cl

(7)

Isatin is an endogenous compound identified in humans; possess a wide range

of biological activities. Biological properties of isatin include a range of action in the brain

and offer protection against certain types of infections. Shrivastava47

et al. synthesized (8)


6

a series of compounds from carbazole, which on condensation with chloroacetylchloride in

presence of triethylamine afforded azetidinone, exhibiting promising antibacterial,

antifungal, anti-inflammatory and anticonvulsant activities48

.

NCl

C6H5

S

NN

N

O

(8)

Smith and Rombo49, 50

reported the synthesis of first β-lacatm derivative of

orlistat that exhibit inhibition of re-combinant form of fatty acid synthase (FAS-TE) as

potential therapeutics. FDA approved over-the-counter weight-loss medication51-59

.

Synthesis of palmitate, human fatty acid synthetase (FAS) has recently attracted attention

as a drug target in oncology for its well-documented up-regulation in cancer cells60-62

. The

pharmacological inhibition of FAS has also been shown to enhance the effectiveness of

current anti-neoplastic therapies such as a paclitaxel63

and trastuzumab64

. In the last few

years, microwave-induced organic reaction enhancement (MORE) has gained popularity

as a non conventional technique for rapid organic synthesis65-68

, which is termed as

“e-chemistry” because it is easy, effective, economical and eco-friendly. It is believed to

be a step towards achieving ‘Green Chemistry’ objectives. Within the framework of green

chemistry, now environmentally benign and novel approaches for the synthesis of azetidin-

2-ones69-72

are being developed.

Gilman73

et al. reported the first preparation of β-lactam by the condensation

of Reformatsky reagents with simple imines. β-Lactams have occupied a central role in the

vigil against bacterial infections over the past few decades74

. 5-membered organo-thio and

4-mem-bered organo-azo heterocyclic compounds and their derivatives75-77

have been

extensively explored for their application in the field of antimicrobials and considered as a

key component of many biologically active compound such as penicillin (9) and

cephalosporins78

(10).


7

N

SCH3

CH3

COOH

O

NO

R

H

N

S

COOH

O

N

RO

O

CH3

O

H

(9) (10)

Various substituted 3-chloro-4-(substituted-phenyl)-1-{4-[7-chloro-2-(3-

chloropropyl)-4-oxoquinazolin-3(4H)-yl}azetidin-2-ones (11) containing different

functional groups have been synthesized by Lokhandwala79

et al. by treating 7-chloro-2-

(3-chloropropyl)-3-{4-[(substituted-benzylidene)amino]phenyl}quinazolin-4-(3H)-ones

with chloroacetylchloride in presence of triethylamine at reflux temperature. Compounds

were tested for significant antimicrobial activity. IIango80

reported synthesized of a series

of 4-aryl-3-chloro-N-(3,4,5-trihydroxybenzamido)-2-azetidinones (12) which has been

screened in-vitro for biological activities and found that compounds with chlorophenyl

group and 4-dimethylaminophenyl group exhibited good antimicrobial and anti-tubercular

activity.

N

N

Cl

Cl

O

N Cl

O

R OH

OH

OH

NH N

O

Cl

O

R

(11) (12)

Wang81

et al. have discovered azetidinone (2-Chloro-3-(1,3-dioxoisoindolin-2-

yl)-4-oxoazeti-din-1-yl)-5,5-dimethyl-3-oxoisothiazolidin-2-yl)-2-phenylaceticacid) (13)

for the treatment of diabetes and dyslipidemia and a high-yielding method for N-arylation

of azetidinone esters were also described. Rokade82

obtained some azetidinone derivatives:

N-(3-chloro-2-(substituted-phenyl)-4-oxoazetidin-1-yl)-2-(naphthalene-2-yl-oxy)-acetami-

de (14) with the β-naphthol and evaluated them for antimicrobial activity.

N

Cl

O

Pht

N

S

O

CH3

CH3

HOOC

R1

N Cl

O

Ar-

NH

O O

(13) (14)


8

Rangappa83

et al. reported a simple, one-pot and efficient three-component

synthesis of novel 3-chloro-4-[4-(2-oxo-2H-chromen-4-yl-methoxy)phenyl]-1-phenylazeti-

din-2-one derivatives (15) using 4-(2-oxo-2H-chromen-4-ylmethoxy)benzaldehydes with

the merits of simple operation, convenient work-up, environmentally benign and providing

good yields. A novel method for the synthesis of 3-Chloro-4(4-chloro-phenyl-1-(4-{1-[2'-

(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-1H-benzimidazol-2yl}-phenyl)-azetidin-2-one

(16) derivatives have been reported by Sharma84

et al. Azetidin-2-one derived from the

nitro, chloro, hydroxy, fluoro and iodo containing biphenyl tetrazole azomethines shows

good angiotensin-II (AT1) receptor antagonist activity.

OO

N

R1

O

O

ClH

H

R

N

NN

R1

R2

R3

O

Cl

CN

(15) (16)

2. Review on halogenated compounds:

The new generation antibiotics like Norfloxacin, Ciproflaxacin and

Flufloxacin, incorporated with fluorobenzene85

moiety had proved their efficacy as potent

bioactive molecules. A wide range of biodynamic properties have been shown by

fluorobenzenes 2-substituted benzothiazoles86-88

while, sulfonamide89-91

drugs were the

first effective chemotherapeutics employed systemically for the prevention and cure of

bacterial infection in human. Encouraged by some observations Jagtap et al. have

synthesized fluoro substituted sulphonamide benzothiazoles (17) incorporated with

2-azetidinones92, 93

, in looking for pharmacological agents with broad-spectrum anti-

mycobacterial activity94, 95

. Fluoro-benzothiazolo-sulphonamidoquinazoline derivatives

have been reported to synthesize in hope of getting pharmacological agents with broad

spectrum of anti-tubercular activity96-99

.


9

N

Cl

O

NO2S

O

O

NH

N

SR

F

(17)

The new generation antibiotics incorporated with fluorobenzene moiety proved

their efficacy as potent bioactive molecules99

. Now a day’s vast number of compounds

with fluorobenzene moiety featured in different areas like antibacterial, antifungal, anti-

inflammatory, psychoactive, pesticides and herbicides100

etc.

Sulphonamides elicit wide varieties of anti-tubercular101

and antimicrobial

activity102, 103

. It has been found that 1-(4-methoxyphenyl)-3-chloro-4-(2-hydroxy-3-iodo-

5-chlorophenyl)-2-azetidinones (18) exhibited good antibacterial activity104

. 2-Azeti-

dinones (19) having methoxy group are endowed with antibacterial activity105

.

N

Cl

O

Cl

I

OH

H3CO

N

H

Cl

HO

H3CO OH

I

(18) (19)

Variously substituted 4-(m-hydroxy-p-methoxyphenyl)-1[(6'-fluoro-7'-substituted(1,3)-

benzothiazol-2'-yl)amido-2-phenyl]3-chloro-azetidin-2-one (20) containing different

functional groups have been synthesized by Vijaya Kumar106

et al. and were reported

possessing significant anticonvulsant activity.

NHS

NO

NH

OH

H3CO N

Cl

O

F

R or R'

(20)

The synthesis or a new series of quinoxaline 2,3-dione derivatives containing

4-thiazolidinone, 2-azetidinone and imidazolinones nucleus by reacting N-substituted

arylidene/heteroarylidene quinoxaline-2,3-dione with thioglycollic acid in the presence of


10

dry benzene, with chloroacetylchloride in the presence of triethylamine and with

4-benzylidene-2-methyloxazole-5-one in the presence of pyridine respectively, reported

by Sankari107

et al. It was concluded from antibacterial activity of the compounds with

chloro, hydroxy and nitro substitution in the three derivatives showed better activity as

compared to bromo and fluoro substitution. 2-Hydroxy-5-phenylbenzaldehyde on

iodination yielded 2-Hydroxy-3-iodo-5-phenylbenzaldehyde. This aldehyde on

condensation with substituted aromatic amines in presence of catalytic amount of acetic

acid afforded a series of azomethines. These azomethines on reaction with

chloroacetylchloride afforded a biologically active 2-azetidinone derivatives (21) reported

by Junne108

et al.

NR

R1

R2 R

3

R4

O

ClOH

I

(21)

Various substituted 4-(m-hydroxy-p-methoxyphenyl)-1-[(6'-fluoro-7'-substitu

ted (1,3)-benzothiazol-2'-yl)amido-2-phenyl]-3-chloroazetidin-2-one containing different

functional groups have been synthesized by Vijay Kumar109

et al. via treating fluoro chloro

aniline with KSCN in presence of bromine in glacial acetic acid and ammonia to get

2-amino-6-fluoro-7-chloro-(1,3)-benzothiazole, which was treated with anthranillic acid in

presence of dry pyridine to get 2-amino-N-(6-fluoro-7-chloro-(1,3)-benzothiazol-2-yl)-

benzamide. To the above, refluxed with vanillin and alcohol in presence of concentrated

HCl to get 2-(3-hydroxy-4-methoxybenzylidene-amino-phenyl-amido)-6-fluoro-7-chloro-

(1,3)-benzothiazole or azomethines. A solution of azomethine in 1, 4-dioxane was added to

well-stirred mixture of chloroacetylchloride and triethylamine to get azetidinone (22). To

the above product was treated with different primary and secondary aromatic amines in

presence of DMF to get newly targeted compound through replacing at 7th

position

chlorine. The compounds were tested for in-vitro anti-inflammatory activity and showed

significant activity.


11

N

S

NHF

NH O

N

O

Cl

OH

OCH3R

(22)

R= o-, m-, p-(-H, -NO2, -Cl, -OCH3, -COOH) and Piperazino

In the last few decades, organic cyano compounds have, found extensive

utilization in the synthesis of heterocycles. The cyano-β-lactams were derived by a N-to-C

1,3-rearrangement of the kete-nimine intermediates, while the carbamoyl-β-lactams were

the hydrolysis products of the intermediates. The chemistry of these compounds is very

rapidly developing110

and enormous number of reports, reviews and monographs111-113

has

been written to cover the developments in this area. Some authors were interested in

synthesizing azetidinone derivatives with different substituent specially halogens, which

are known for their activity. These derivatives have shown promising activities as

antibacterial, antifungal and anti-tubercular agents. Patel et al. have synthesized some new

3-chloro-4-(substituted-phenyl)-1-(4-(2-oxo-2H-chromen-4-yl-amino)-phenyl)-azetidin-

2-one (23) containing coumarin moiety and evaluated for antimicrobial activity114

.

O

NH

N

Cl

O

O

(23)

Patel et al. have synthesized azomethines and 2-azetidinones (6-bromo-3-(3-chloro-2-(sub

stitutedphenyl)-4-oxo-azetidin-1-yl)-2-(2-(2,6-dichloro-phenylamino)benzyl)-quinazolin-

4(3H)-one) (24) derived from quinazolin-4(3H)-one and evaluated for antimicrobial

activity115

. Some of these compounds having chloro and methoxy group exhibited good

antimicrobial activity.


12

N

N

NNH

Cl

Cl

O

Cl

O

Br

(24)

4-Chloro-1-(4-chlorophenyl)-4-(4-methoxyphenyl)-azetidin-2-one derivatives (25)

prepared by Thakare116

from 4-chloro-N-(4-substitutedbenzylidene)aniline by

condensation with different aromatic aldehyde. Charbe et al. synthesized some novel

2-azetidinone derivatives (26) and evaluated them for cholesterol absorption inhibition and

antibacterial activity117

.

N

O Cl

RCl

NH

O

N

O

NR

1

R

R2

OCH3

(25) (26)

A new series of 4-[3-chloro-2-(4-hydroxy-3-methoxybenzyllidene)-

4-oxoazetidin-1-yl] amino-N-(substituted)benzenesulfonamide derivatives (27) has been

synthesized by Apoorva118

et al.

N

O

Cl

OCH3

S

O

O

R"HN

R'

(27)

3. Review on azomethines:

Azomethines are highly useful precursors for the synthesis of secondary

amines, chiral amines and important biological molecules such as alkaloids119

. Recently a

large variety of aryl and heterocyclic chiral and achiral azomethines were generated by

Andrew120

et al. The literature survey revealed that azomethines have engaged in


13

recreation and development of the synthetic chemistry. It is also well recognized that the

compounds containing azomethine functional group have a broad range of biological

activities. Many azomethines are known to be medicinally important and used to design

medicinal compounds121

. Azomethines are the compounds which possess an azomethine

linkage and are found to attribute various pharmacological activities122-128

and also serve as

a back bone for the synthesis of various heterocyclic compounds. Azomethines are also

used as protective groups in organic synthesis for amino groups129

.

Pawar et al. have synthesized some new azetidinone derivatives and screened

for anticonvulsant activity130

. It was reported that p-aminobenzoic acids on addition with

different aromatic aldehydes give azomethines. These azomethines on treatment with

chloroacetylchloride and triethylamine gave various substituted 4-[3-chloro-4-substituted

phenyl-2-oxo-azetidin-1-yl]-benzoic acid (28) containing different functional groups.

Reddy131

et al. have synthesized 6-fluorobenzothiazole substituted pyrazolo azetidinones.

2-aminobenzothiazoles were synthesized from 3-chloro-4-fluoroaniline and further

condensed with 3-methyl-1-phenyl-5-pyrazolone to yield the corresponding azomethines.

The azomethines were cyclised with chloroacetylchloride in triethylamine to yield

2-azetidinones1-(7-substitutedamino-6-fluorobenzo[d]thiazol-2-yl)-3-chloro-7-methyl-5-

phe nyl-1,5,6-triaza spiro[3.4]oct-6-en-2-one (29).

HOOC

N

ClO

R

N

S

N

Cl

O

N

NH

H5C6

CH3

RF

(28) (29)

Azomethines derived from the reaction of aromatic aldehydes and aliphatic or

aromatic amines represented an important series of widely-studied organic ligands. A

variety of applications of azomethines and their metal complexes such as biological132

,

clinical133

, analytical134

, industrial135

and catalytical136

have been reported. The

condensation of o-hydroxy azo-aldehydes and diaminomaleonitrile in the presence of a

catalytic amount of acetic acid produced aszomethines in high yields reported by

Yahyazadeh137

et al. Parmar138

et al. have synthesized novel 3-chloro-[1-(3,6-

(diphenyl)[1,2,4]triazolo[3,4b] [1,3,4]thiadia-zole)]-4-(3,4-diethoxyphenyl azetidin-2-one

(30) with their derivatives and screened for their antibacterial activity.


14

NN

N

N

S

OCl

H

H

(30)

A series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one-containing

azomethines were synthesized by Asiri et al. antibacterial screening results revealed that

compounds showed moderate to good antibacterial activity139

. Iqbal140

et al. have

synthesized a series of azomethine derivatives by reacting 2-formyl-phenoxyacetic acid

with aromatic amines. Among the compounds, 2-(4-acetamidophenyliminomethyl)

phenoxyacetic acid, 2-(4-methylpyridin-2-yliminomethyl)phenoxyacetic acid, 2-(2,3-

dichlorophenyliminomethyl) phenolxyacetic acid, (2-{[4-(2′-chlorophenyl)-thiazole-2-

ylimino]methyl}phenoxy) acetic acid and 2-{2-[(3-imidazol-1-ylpropylimino)methyl]

phenoxy}acetic acid exhibited good activity against S. aureus and E. coli.

As a part of ongoing studies in developing antimicrobials, a series of N-(1,3-

benzothiazol-2-yl)-2-[(2Z)-2-(substituted-arylidene)hydrazinyl]acetamide was synthesized

by Soni141

et al. and examined their antimicrobial activities in-vitro against some bacterial

strains and found that compounds containing azomethine linkage were possessing better

broad-spectrum antibacterial activity. Mathew142

et al. concentrated in a research on the

synthesis of some azomethines of 5-phenyl-substituted, 2-amino1,3,4-thiadiazole derivates

by the reaction between various aryl carboxylic acids with thiosemicarbazide to form

5-phenylsubstituted and 2-amino-1,3,4-thiadiazole derivatives, which on further treatment

with various aldehydes gave azomethines of anthelmintic activity.

4. Review on cyano-compounds:

A clinical application of synthetic cyanoacrylate in various medical devices

was approved by the US food and drug administration (FDA). It includes cyanoacrylates

as liquid bandages and dental cements etc.143

. A technique of latent fingerprints using

controlled cyanoacrylate vapour exposure in fuming cabinets is used for artefacts

recovered in investigations of forensic crime-scene. The possible effect of un-reacted

monomer and other polycyanoacrylate film impurities on spectral analalysis is also

highlighted144

. Nanoparticles of poly (isobutylcyanoacrylate) with dispersed insulin in

pluronic acid solution have been reported145

. Polybutylcyanoacrylate nanoparticles were


15

delivered to the lungs via carrier particles that dissolve after contact with the aqueous

environment of lung epithelium146

.

Cheng147

et al. gained deeper insight into the unique reactivity of β-lactam

carbenes and further explored their synthetic applications they isolated two different types

of β-lactam derivatives 4-cyano- or 4-carbamoyl- β-lactams, depending upon the nature of

the alkyl group of the isonitriles. This work provided a very simple and efficient route to

4-cyano- or 4-carbamoyl- β-lactams, which are versatile synthetic intermediates and new

chemical entities of potential biological activity.

β-Lactam derivatives have attracted continued interests not only for their

diverse and potent antibiotic activity148, 149

, but also for their great utility as versatile

synthetic intermediates150, 151

ie., some 4-carbamoyl- and 4-alkoxycarbonyl- β-lactams

were found to be inhibitors of HIV-1 protease152

or human leukocyte elastase and porcine

pancreatic elastase153

. On the other hand, 4-cyano and 4-carbamoyl β-lactams have been

used as precursor of thienamycin and isopenam154

. Over the past decades, many synthetic

methods155-158

, such as Kinugasa reaction of alkynes with nitrones158

, Ugi

threecomponent/four-centre condensation of β-amino acids with aldehydes and

isonitriles159

, cyclization reactions of β-amino acids160

and reactions of chromium carbene

complexes with azomethines161

, have been developed for the construction of the β-lactam

skeleton. However, the Staudinger reaction162, 163

still remains the most efficient route to

β-lactams.

2-Azetidinone-4-ylidenes are β-lactam carbenes reported by Warkentin and

co-workers164

. The work by Abbas165

et al. involved in the preparation of [5-cyano-(1,3,4-

thiadiazole-1-2-yl)thio]aceto-hydrazides which were condensed with carbonyle

compounds to give azomethines. Nagai166

et al. studied that the reactions of benzaldehyde

and analogues with ethyl cyanoacetate in ethanolic ammonia produce

α-cyanohydrocinnaniamides, 2,6-dihy- droxy-3,5-dicyano-4-phenypyridines and dimeric

products. Le Moal167

and Nagai168

et al. reported the Cope-Knoevenagel condensation of

p-substituted benzaldehydes with ethyl cyanoacetate to produce ethyl α-cyano-

p-substituted cinnamates (31).

H

H

CONH2NC

NC COOEt

XX

(31)


16

3-Cyano-6-phenyl-4-(3`-pyridyl)pyridine-2(1H)-thione,2,2`-bis-pyridyldisulfi-

de, 2-alkylthio pyridines and 2-aminothieno[2,3-b]pyridines were synthesized and their

neurotropic activities were examined by Krauze169

et al., bispyridyldisulfide exhibited low

toxicity and selective antiamesic activity. A new series of 2-amino-3-cyano-4-tetrazolo

quinolinylpyridine derivatives has been synthesized by Mungra170

et al. and were

subjected to in-vitro antimicrobial screening against pathogenic strains of bacteria and

fungi, results were found to be equipotent or more potent than commercial antibiotics.

Recently, azomethines N'-(4-cyanobenzylidene)-2-cyanoacetohydrazide derivatives were

prepared by Shah171

et al. from the cyanoacetohydrazide with the condensation of 4-cyano

benzaldehyde (32). 4-cyano and 4-carbamoyl β-lactams have been used as precursors of

thienamycin and isopenam172

.

NC

N NH

CNO

(32)

Azomethines containing chloro and cyano group at the C-2 position display

enhanced antibacterial effects173, 174

in pyrazol-3-ones and are found in numerous

biologically active molecules having an important role in the animal and plant kingdoms.

Tertiaryaminobenzaldehydes have been found significantly important on account of their

role in the synthesis of chemotherapeutics175, 176

and analytical reagents177

.

The cyanomethyl group together with the adjoining formyl group are suitably

arranged in a molecule of 2-cyanomethylbenzaldehyde178

to participate in the formation of

fused-ring compounds. Indeed, the reaction of aldehyde with ammonia, primary or

secondary amines, catalyzed by trifluoroacetic acid, gives 3-amino substituted

isoquinolines, usually in good yields179

. Mohamed180

et al. have synthesized of a series of

6-aryl-5-cyano-2-thiouracil derivatives by the reaction of ethyl cyanoacetate with thiourea

and aldehydes which were used as an intermediate compound for the synthesis of a

number of thiouracil derivatives.6-(4-fluorophenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyri

midine-5-carbo-xamide, 4-oxo-2-thio-xo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-

pyrimidine-5-carboxamide, 6-(4-fluorophenyl)-4-hydrazino-2-thioxo-1,2-dihydropyrimi

dine-5-cabonitrile and 4-hydrazino-2-thioxo-6-(3,4,5-trimethoxyphenyl)-1,2-dihydropyri-

midine-5-carbonitrile were revealed to exhibit promising antimicrobial activity.


17

Pore181

and co-workers have synthesized a series of 5-cyano N1, 6-disub-

stituted, 2-thouracil derivatives exhibiting antinociceptic and analgesic activity with

conclusion that compounds bearing bulkier and lipophilic substituents on phenyl group,

located at C-6 of thiouracil nucleus, were more active than hydrophilic substituents on

phenyl group at the same position.

Dicyanoethylation of m-toluidine was carried out by treating the aromatic

primary amine with acryonitrile in acetic acid in presence of cuprous chloride by Arora182

et al. The cyanoethylated amine on formylation gave 2-methyl-4-N’N-bis-2'-cyanoethyl

aminobenzaldehyde. The resulted aldehyde gave azomethines: 2-methyl-4-N’N-bis-2′-

cyanoethylaminobenzylidineaniline, 2-methyl-4-N’N-bis-2′-cyanoethylaminobenzylidine-

p-chloroaniline, 2-methyl-4-N’N-bis-2′-cyanoethylaminobenzylidine-p-toludine and

2-methyl-4-N’N-bis-2′-cyanoethylaminobenzylidine-p-fluoroaniline with aniline and three

different substituted anilines. Cyano derivatives (33) of N-alkyl and N-aryl piperazine

have been synthesized by Kumar183

et al. which of them (a), (b) and (c) showed mild to

moderate antibacterial and antifungal activity against different pathogenic strains.

N NH2CH5C6

CN

N NCH3

CN

N N

CNOH

(a) (b) (c)

(33)

Synthesis and anti-AIDS, anticancer, anti-tubercular, fungicidal and

antibacterial activities of 2-methyl-4-N-2’-cyanoethyl-N-methane/benzenesulphonyl

aminobenzaldehyde and their hydrazones have been reported by Dhingra184

et al. In

addition, 2-azetidinones also display a broad range of enzyme inhibitory activity and they

have attracted considerable attention due to a wide range of pharmaceutical activities.

The β-lactams have played a vital role in human medicine. Despite of

enormous volume of literature currently available on the subject, modification of the side

chain around the main skeleton of β-lactam ring is challenging in the medicinal era hence,

there is scope for investigation, for the feasibility of constructing alternative structure type

and testing the resulting molecules for biological activity.

5. Aims and objective of the research work:

Keeping in view the diverse biological activity of azomethine group and

azetidinone nucleus, it is planned to synthesise the azomethines and target compounds


18

followed by in-vitro biological screening for their possible antimicrobial activities. All

compounds were prepared following reported procedures. This piece of research work

records the experiments conducted, observations made and interferences drawn by us with

the following chapters:

Chapter-1. General introduction: This part of the thesis covers overall ground of the

relevant literature concerning the β-lactam antibiotics, azomethines, cyano substituted

compounds, halogen moiety containing compounds and their derivatives with biological

and pharmacological significance revealing pertinent literature.

Chapter-2. Synthesis of precursors: Four-cyanoethylatedtertiaryaminobezaldehydes

(34), A, B, C and D, have been selected as precursors for the present study. Synthesis of

precursors afforded by the cyanoethylation of the corresponding aromatic primary amines

by acrylonitrile and glacial acetic acid followed by formylation in presence of POCl3 and

DMF.

R

O

NNC CN

O

NS

O

O

NC

H

R = -H (A), -CH3 (B), -OCH3 (C) and (D)

(34)

Chapter-3. Synthesis of intermediate-azomethines: Synthesis and characterization of a

series of twenty-eight new intermediate-azomethines (35) have been carried out by the

condensation of cyanoethylatedtertiaryaminobenzaldehydes with aniline or o-, m-, p-

fluoro/chloro primary aromatic amines.

N

R

N

NC CN

N

NSNC

O

O

H

R1

R1

R = -H, -CH3, -OCH3 R1 = Aniline or o-, m-, p- (Fluoro/Chloro) anilines

(SB1-SB21) and (SB22-SB28)

(35)


19

Chapter-4. Synthesis of 2-azetidinones:

Twenty-eight new 4-membered heterocyclic 2-Azetidinones (36) have been synthesized by

incorporation of β-lactam ring at the imine linkage of azomethines.

N

R

N

NC CN

O

Cl N

H

NSNC

O

O

Cl

O

R1

R1

R = -H, -CH3, -OCH3 R1 = Aniline or o-, m-, p- (Fluoro/Chloro) anilines

(BL1-BL21) and (BL22-BL28)

(36)

Chapter-5. In-vitro antimicrobial susceptibility testing: Some of the fluoro and chloro

substituted derivatives of newly synthesized azomethines and 2-azetidinones were

screened in-vitro for their efficacy evaluation against selected pathogens, by disc diffusion

method and results are summarized in the form of tables.

6. Instrumentation:

Melting points were determined in an open capillary tube and are uncorrected.

The chemicals and solvents used were of laboratory grade and were purified. Completion

of the reaction was monitored by thin layer chromatography on pre-coated sheets of 25 DC

alufolin Kieselgel 60 F254 silica gel 60 F254 (Merck) using uv-vis florescence analysis

chamber for detection. FT-IR spectra were recorded in KBr on a Perkin-Elmer

spectrometer-2. 1H NMR spectra were recorded in DMSO-d6 with an advanced

spectrometer (Bruker) at 400-MHz frequency using TMS (tetramethylsilane) as an internal

standard. Elemental analyses were performed on a Perkin-Elmer-240 elemental analyzer.


20

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