Page 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
Page 2
CHAPTER-1. GENERAL INTRODUCTION
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
.
Page 3
CHAPTER-1. GENERAL INTRODUCTION
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)
Page 4
CHAPTER-1. GENERAL INTRODUCTION
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
Page 5
CHAPTER-1. GENERAL INTRODUCTION
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)
Page 6
CHAPTER-1. GENERAL INTRODUCTION
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).
Page 7
CHAPTER-1. GENERAL INTRODUCTION
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-
chlorop- ropyl)-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)
Page 8
CHAPTER-1. GENERAL INTRODUCTION
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
.
Page 9
CHAPTER-1. GENERAL INTRODUCTION
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
Page 10
CHAPTER-1. GENERAL INTRODUCTION
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.
Page 11
CHAPTER-1. GENERAL INTRODUCTION
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.
Page 12
CHAPTER-1. GENERAL INTRODUCTION
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
Page 13
CHAPTER-1. GENERAL INTRODUCTION
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.
Page 14
CHAPTER-1. GENERAL INTRODUCTION
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
Page 15
CHAPTER-1. GENERAL INTRODUCTION
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)
Page 16
CHAPTER-1. GENERAL INTRODUCTION
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.
Page 17
CHAPTER-1. GENERAL INTRODUCTION
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
Page 18
CHAPTER-1. GENERAL INTRODUCTION
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)
Page 19
CHAPTER-1. GENERAL INTRODUCTION
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.
Page 20
CHAPTER-1. GENERAL INTRODUCTION
20
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