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TRANSCRIPT
PART I
IntroductionIntroductionIntroductionIntroduction
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Literature ReviewLiterature ReviewLiterature ReviewLiterature Review
SECTION I
Studies on QuinolonesStudies on QuinolonesStudies on QuinolonesStudies on Quinolones
1.1.1 Introduction and literature review
“Over a few decades ago, a new milestone in the field of antibacterial drug
discovery was reached by the introduction of a novel class of molecules, known as
quinolones.”
Heterocyclic chemistry has great importance to the medicinal chemists. Large
numbers of various heterocyclic compounds are being used as therapeutic agents and
these compounds are also essential for the human life in which quinolones are most
widely useful as antibacterial agents.
Quinolones comprise a relatively large growing and most interesting group of
antibacterial field of antibacterial chemotherapy particularly in the past few years.
This is because they potentially offer many of the attributes of an antibiotic.
Combining high potency, broad intravenous formulations, high serum levels, a large
volume of distribution indicating concentration in tissues and a potentially low
incidence of side effects; many researchers have attempted to make these potential
attributes real [1-3].
The first quinolone, nalidixic acid (1-ethyl-7-methyl-1,4-dihydro-4-oxo-1,8-
naphthyridine-3-carboxilic acid) I was introduced in 1962. The substance was
discovered by George Lesher and coworkers in a distillate during chloroquine
synthesis, the representative of the quinolones which has found effective against some
Gram negative microorganisms and possessed pharmacokinetic properties for treating
urinary tract infections [4-7].
N N
COOH
O
CH3
CH3
I
Since then structural modifications have resulted in an important class of
fluoroquinolones, which have improved coverage of Gram positive organisms.
Quinolones are classified into four generation based on potency and spectrum of their
antimicrobial activity.
First generation quinolones
First generation agents, which are used less often today, have moderate Gram
negative activity and minimum systemic distribution.
Nalidixic acid II, cinoxacin III, flumequine IV and 7-piperazinyl V
derivative, pipemidic acid are the first generation quinolones.
N N
COOH
O
CH3
CH3
X
COOH
O
R
O
O
II III
N
COOH
O
F
CH3
N
N
N
COOH
O
CH3
N
NH
IV V
Second generation quinolones
Second generation quinolones have expanded Gram negative activity and
typical pathogen coverage, but limited Gram positive activity. These agents are most
active against aerobic Gram negative bacilli.
Lomefloxacin VI, norfloxacin VII and enoxacin VIII are the class-I agents of
2nd generation.
NN
NH F
F
O
COOH
Et
CH3
NN
NH
F COOH
O
Et
VI VII
N NN
NH
F COOH
O
Et
VIII
Ofloxacin IX and ciprofloxacin X are the class-II agents of the 2nd generation
having higher serum, tissue and intracellular drug concentration compared with class-
I agents.
NN
N
F COOH
O
OCH3CH3
NN
NH
F COOH
O
IX X
Third generation quinolones
Sparfloxacin XI, gatifloxacin XII, levofloxacin XIII, moxifloxacin XIV are
the third generation quinolones having expended Gram negative and a typically
intracellular activity but have improved Gram positive coverage.
NN
NH
F COOH
O
F
CH3
CH3
NH2
NN
NH
F COOH
O
O
CH3
CH3
XI XII
NN
N
F COOH
O
OCH3CH3
NN
F COOH
O
OCH3N
HH
H
XIII XIV
Fourth generation quinolones
Fourth generation agents including trovafloxacin XV with improved Gram
positive coverage, while maintain Gram negative coverage and gain anaerobic
coverage. Clinafloxacin XVI investigational fluoroquinolone has the most in vitro
potency against anaerobic bacteria [8-13].
N NN
F COOH
O
F
FNH2
H
H
NN
F COOH
O
Cl
NH2
XV XVI
Fig.1 Chronological development of quinolones
1970 1980 1990 2000
Nalidixic
Acid
Oxolonic acid
Pipemidic acid
Cinoxacin
Flumequine
Norfloxacin
Ciprofloxacin
Ofloxacin
Temafloxacin
Sparfloxacin
Grepafloxacin
Levofloxacin
Trovafloxacin
Gatifloxacin
Moxifloxacin
Gemifloxacin
Garenoxacin
Therapeutic uses of quinolone
Genitourinary infections
Because of their extensive Gram negative coverage, quinolone antibiotics
were initially used to treat urinary tract infections. The higher genitourinary drug
concentrations that occur with renally cleared quinolones promote their effectiveness
in the treatment of genitourinary infections. Ciprofloxacin, ofloxacin, lomefloxacin,
enoxacin, levofloxacin and gatifloxacin have higher renal clearance and greater renal
concentration; they are optimal choice for the treatment of complicated urinary tract
infections.
Prostatitis
Quinolones are effective in the treatment of prostatitis because of their
excellent penetration into prostatitis tissue. When taken for four to six weeks,
norfloxacin, ciprofloxacin, lecofloxacin and ofloxacin have eradication rates of 67 to
91 percent.
Respiratory diseases
The U.S. Food and Drug Administration (USFDA) has labelled gatifloxacin,
moxifloxacin, sparfloxacin and levofloxacin for use in the treatment of acute bacterial
sinusitis. However quinolone should not be used as first line agent in the treatment
acute bacterial sinusitis because of the potential for development of bacterial
resistance.
Sexually transmitted diseases
Based on 1998 guidelines from the CDC (Centers for the Disease Control and
prevention) ceftriaxone is the agent of choice for treatment of uncomplicated neisseria
gonorrhoeae, urethritis and cervicitis. A single dose of ciprofloxacin or ofloxacin
should be considered as alternative treatment in, for example, patients with penicillin
allergy.
Gastroenteritis
Prophylactic antimicrobial therapy is not recommended for the prevention of
diarrhea in travelers. Norfloxacin or ciprofloxacin has been found to be comparable to
trimethoprim-sulfamethoxazole in the treatment of traveler’s diarrhea.
Ciprofloxacin and ofloxacin are the agents of choice for treatment of enteric
typhoid fever. Norfloxacin is superior in the treatment of vibrio cholerae infections.
Skin and soft tissue infections.
Because of limited data, the role of quinolones in the treatment of skin and
soft tissue infections remains uncertain. Diabetic foot infections, which are
polymicrobial, can be treated with quinolones in combination with other antibiotics
[14-19].
Adeverse events
Although quinolones are well tolerated and relatively safe, certain adverse
effects are common with all agents in this antibiotic class. Gastrointestinal and central
nervous system (CNS) effects are the most frequent adverse events, occurring in 2 to
20 percent of patients treated with quinolones.
Quinolones have few adverse effects, most notably nausea, headache,
dizziness, and confusion. Less common but more serious adverse events include
prolongation of the corrected QT interval, phototoxicity, liver enzyme abnormalities,
arthropathy and cartilage and tendon abnormalities the spectrum of antibacterial
activity [20-24].
Mechanism of action and pharmacokinetics
Quinolones rapidly inhibit DNA synthesis by promoting cleavage of bacterial
DNA gyrase and type-IV topoisomerase, resulting in rapid bacterial death. The
molecular organization of the complex is presently unknown although several models
have been suggested. According to one model, four quinolone molecules bound as
two pair of noncovalently associated drug dimmers in a single standard DNA bubble
opened up by topoisomerase action. Based on another model the affinity of
quinolones to metal ions seems to be an important prerequisite of their antibacterial
activity; probably quinolones bind to the DNA enzyme-complex via a magnesium ion.
As a general rule, Gram negative bacterial activity correlates with inhibition of DNA
gyrase and Gram positive bacterial activity corresponds with inhibition of DNA type-
IV topoisomerase.
Like amino glycosides, the quinolones exhibit concentration dependent
bacterial killing. Bactericidal activity becomes more pronounced as the serum drug
concentration increases to approximately 30 times the minimum inhibitory
concentration (MIC). Higher drug concentration paradoxically inhibits RNA and
protein synthesis, thereby reducing bactericidal activity. Quinolones have a
postantibiotic effect about one to two hours.
Quinolones are well absorbed following oral administration, with moderate to
excellent bioavailability. Serum drug levels achieved after oral administration are
comparable to those with intravenous dosing, which allow an early transition from
intravenous to oral therapy and a potential reduction of treatment costs.
Elimination half-lives for the quinolones vary from 1.5 to 16 hours. Therefore,
most of these drugs are administrated every 12 to 24 hours. The quinolones are
eliminated by renal and nonrenal routes. To avoid toxicity, dosage often needs to
adjust in patients with renal or hepatic impairment. The majority of quinolones are
excreted renally; however sparfloxacin, moxifloxacin and trovafloxacin are exctreted
hepatically [25-31].
Structure activity relationship
The minimum pharmacophore required for significant antibacterial activity
consist of the pyridone ring at C-4 with a carboxylic acid group at C-3 position. The
structure-activity relationship (SAR) of quinolones have been the subject of extensive
review [32-38]. The antibacterial activity of peripheral substituents and their spatial
arrangements play a major role to influence the antibacterial activity and
pharmacokinetic properties through affinity for binding with bacterial enzymes [39].
The purpose of our brief discussion is to demonstrate the changes or effects
occur due to modifications or manipulation of different substituents in particular
position of the pharmacophore, and their influence on the chemotherapeutic
properties, as well as side effects of quinolone class.
Position N-1
Antibacterial activity is greatly influenced by the steric bulk of N-1 substituent
and optimal groups in order of activity being cyclopropyl, ethyl followed by
fluorosubstituted phenyl and t-butyl [37]. It is also found that substituted with more
steric bulk group have also enhanced activity against anaerobes from the X-ray
crystallography and molecular modeling studies. It has been observed that in N-1 aryl
substituted quinolones, the N-1 aryl ring is twisted out of the plane of the quinolone
nucleus [40-41]. Another structure at this position is found in ofloxacin, levofloxacin,
pazufloxacin, nalidixicacid and rufloxacin which has fused ring between position-1
and 8.
Position 2
Very little is known about the SAR of quinolone having substituents at C-2
position; as loss of bioactivity has been found with methyl, hydroxyl or methylthio
substituents. However a ring between C-1 and C-2 position was shown to have
biological activity. The C-2 position is left unsubstituted because of its proximity to
the enzyme binding site [33-37].
Position 5
Introduction of some substituents such as halogen, nitro, amino, hydroxy and
alkyl groups at C-5 were initially thought to reduce antibacterial activity of the
quinolones. However 5-amino substitution in the 6,8-diflouro quinolone series having
N-1-cyclopropyl group showed enhanced in vitro activity, especially against Gram
positive organisms.
Thus substitutions at this position one thought to contribute to potency against
Gram positive organisms. The influence of 5-amino depends on the substitution
pattern at C-8 and N-1 and a few potent analogues in this series are sparfloxacin XVII
and having Gram positive activity as well as anaerobic activity. Moreover
grepafloxacin XVIII with a methyl group at C-5 exhibits increased activity [33-37].
N
NH
N
F
NH2 O
COOH
F
CH3
CH3
N
O
COOH
CH3
F
N
NH
CH3
XVII XVIII
Position 6
Several substituents besides fluorine have been introduced into position-6. All
of the quinolones having those substituents were less active than C-6
fluoroquinolones. The influence of fluorine at C-6 is essential for high activity as
evidenced by its enhanced gyrase inhibition and cell penetration which has become
the basis for generic name fluoroquinolones. However, these have been a recent
interest in quinolones without fluorine at this position.
Position 7
Substituent at position-7 is closely associated with properties of the quinolone
such as their antibacterial spectrum, bioavailability and side effects. Introduction of a
basic group at C-7 of the quinolone ring was found to enhance antibacterial activity,
as this substituent greatly influences antibacterial and pharmacokinetic properties. A
five or six member cyclo amino moiety (e.g. pyrrolidine or piperazine rings) is the
most commonly used substitution at C-7 position.
In a series of compounds it was shown antibacterial activity against Gram
negative bacteria increased in the following order 4-methyl piperazine-1-yl < 3-
methyl piperazine-1-yl < piperazine-1-yl < 3-aminopyrolidine-1-yl; whereas the Gram
positive activity follows the sequence piperazine-1-yl < 3-methyl piperazine-1-yl < 4-
methyl piperazine-1-yl < 3-amino pyrrolidine-1-yl [42].
The addition of azobicyclo groups in to position 7 has resulted in agents with
significant anti-Gram positive activity and marked lipophilicity.
Position 8
Manipulation of the group at position 8 has also been shown to play a role on
oral pharmacokinetics and broadening the spectrum of activity [43-47]. Among many
modification investigated in C-8 position, a new substituent such as fluoro, chloro,
methyl and methoxy group offered good antibacterial activity, especially against
Gram positive bacteria while other substituents tend to decrease the activity.
Different methods for the preparation of 4-quinolone have been described in
literature [48-52].
Narayanan et al [53] synthesized a series 7-substituted 5-amino-l-cyclopropy1-
6,8- difluoro- 1,4-dihydro-4-oxo-3 quinolinecarboxylic acids XIX and XX. All the
synthesized compounds were studied for their biological evaluation.
X N
O
COOHF
R1
R3
R2
N
O
COOHF
R2
R1
XCH3
XIX XX
Dax and Wei [54] have prepared quinolones XXI, XXII and XXIII as
antibacterials and studied their spectral analysis.
N
O
COOEtF
N
F
OCH3
N
O
COOEtF
N
N
OCH3CH3COHN
XXI XXII
N
O
COOHF
N
N
OCH3NH2
XXIII
Tetracyclic pyridone carboxylic acids XXIV have been synthesized by Jinbo
et al [55] and studied their antibacterial activity.
N
O
O
OH
F
X
N
NCH3
Y
XXIV
7-Azetidinylquinolones XXV, XXVI and XXVII have been prepared by
Frigola et al [56] to study the effects on potency and physicochemical properties of
the substituent at position 2 of the azetidine moiety. The in vitro activity of the
synthesized compounds has been determined against Gram positive and Gram
negative bacteria and the in vivo efficacy of selected derivatives have been determined
using a mouse infection model.
A N
O O
OHF
N
R2
R1
R3
R4
R5
A N
O O
R3
F
R1
N
R5
NH2
CH3
R2
XXV XXVI
A N
O O
OHF
R1
N
R3
R4
R5
R2
XXVII
Hagihara et al [57] have synthesized arylpiperazinyl fluoroquinolones XXVIII
and studied their anti-HIV activity.
N
O
COOH
R1 R2
N
N
F
R3
XXVIII
6-Desfluoroquinolones XXIX have been synthesized by Massari et al [58] and
represented as anti-HIV agent act on transcription regulation.
N
COOHF3C
O
CH3
N
N
XXIX
Anti-HIV 4-quinolones XXX and XXXI have been synthesized by Dayam and
coworkers [59] for inhibiting the transcription from the 5 L promoter a crucial step in
the anti-HIV replication cycle.
NN
N
O
COOH
CH3F3C
XXX
NN
N
O
COOH
CH3
S
N
XXXI
Pasquini et al [60] have synthesized 4-quinolone-3-carboxylic acid XXXII
bearing different substituents on the condensed phenyl ring as potential HIV-1
integrase inhibitor.
O
COOH
(CH2)2OAC
CH3
Cl
Cl
XXXII
Recently 4-quinolone keto acids XXXIII have been designed and synthesized
as integrase inhibitors, selectively active against the strand transfer (ST) for HIV
integration process [61].
N
H
O
COOH
OHO
Cl
XXXIII
Moreover several research works have been carried out for anti-HIV activity
[62-65] of quinolones and significant anti-HIV activity was observed for variety of
derivatives.
Eukaryotic type II topoisomerase and prokaryotic type II topoisomerase is
cellular target for anticancer drug and antibacterial agent. Both are structurally
similar. Therefore, new antitumor 4-quinolone XXXIV have been synthesized as
topoisomerase inhibitors [66].
N
O
COOH
CH3
F
N
N
NH
S
XXXIV
2-Phenyl-4-quinolones XXXV have been synthesized by Nakamura and
coworkers [67] as cytotoxic agents demonstrated significant antitumor-promoting
activity.
N
H
O
NH
N
CH3
CH3
O
XXXV
Xai et al [68] have synthesized methyl ester analogous of 2-phenyl-4-
quinolone acetic acid XXXVI and XXXVII. Both of them showed moderate
antitumor activity.
N
H
F
O
H3COOC
N
H
O
H3COOC
F
XXXVI XXXVII
Series of 1,2,3,4-tetrahydro-2-phenyl-4-quinolones have been synthesized and
evaluated as anti-cytotoxic agents, XXXVIII demonstrated potent cytotoxic and
antitubulin effect [69].
NH
O
OCH3
XXXVIII
7-substituted quinolones XXIX and XL have been synthesized by Chen et al
[70] and evaluated for antibacterial and cytotoxic activities.
N
O
COOHF
CH3
X
N
N
O
R
XXXIX
N
O
COOHF
CH3
X
N
N
NR2
R1
XL
Several research works have been carried out and synthesized 2-phenyl-4-
quinolones [71-74] and oxadiazole based 4-thiazolidinones [75] and evaluated for
antitumor activity. Most of the compounds were demonstrated significant activity.
Fluoroquinolones have been synthesized by Kamal et al [76] and linked to
DC-81 at C-8 position through different alkyl chain, XLI was exhibited good DNA
binding affinity and showed promising in vitro anticancer activity.
O N
N
OH
CH3
N
O
COOEtF
F
XLI
4-Quinolone-3-carboxylic acids [77, 78] and 2-phenyl-4-quinolones [79] have
been synthesized and evaluated for anticancer activity. Majority of compounds were
demonstrated significant activity.
7-Substituted ciprofloxacin derivatives XLII have been synthesized and
evaluated for antimycobacterial activity against Mycobacterium tuberculosis and for
inhibition of the activity of DNA gyrase. Some of them demonstrated potent activity
comparable with ciprofloxacin [80].
N
NN
N
ClR'
O
F
O
COOH
XLII
Agrawal et al [81] have synthesized quinolones XLIII to study their
antitubercular activity.
N
F
O
COOH
R
F
F
XLIII
4-Quinolones XLIV have been demonstrated antimalarial activity. According
to Sachonhofer theory of antimalarial action of aminoquinolines, it convert in to 4-
quinolone by hydrolysis of the 4-imino intermediate in vivo to show a high
antimalarial activity [82].
NH
O
CH3 CH3
(CH2)8 CH3
XLIV
Wang and Vince [83] have synthesized some benzothiazine quinolones. All
derivatives were investigated for there antimalarial activity as inhibitor of hematin
formation. Compound XLV were found as an inhibitor of hemoglobin hydrolysis.
N S
ONH2
OCH3
XLV
4-Quinolones have been reported as β-adrenergic blocking agents by Willard
and coworkers [84]. Compound XLVI showed diuretics activity.
N
H
O
O
Cl O
COOEt
OH
NH(H3C)3C
XLVI
Simand et al [85] have synthesized dihydro quinolone carboxamides XLVII
and XLVIII which are used as anticonvulsant and psychotropic agents.
N
O
CONHR
CH2OR1
N
O
CONHR
R1
XLVII XLVIII
Asahina et al [86] have synthesized 4-quinolone-3-carboxylic acids XLIX
having a trifluoromethyl group as a novel N-1 substituent and studied their
antibacterial activity.
O
COOH
CF3
R
F
XLIX
4-Quinolones with bone-binding bisphosphate group at C-7 have been
reported by Herczegh and coworkers, L was found effectively active against Gram
negative bacteria [87].
NN
N
PP
OH
OH
O
OH
OH
O
F
O
COOH
L
Patel et al [88] have synthesized amides of quinolone LI, LII, LIII and LIV
by using substituted arylamine at C-3 position and piperazine, imidazole and
morpholine at C-7 position of newly synthesized quinolone. Antibacterial activity of
all synthesized compounds has been studied against four different strains.
NCl
F
O O
NH
R
N
O O
NHF
N
NR1
R2
LI LII
N
O O
NHF
N
OR
N
O O
NHF
RN
N
LIII LIV
Novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acids LV and LVII
carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10
position have been synthesized and their in vitro antibacterial activity, intravenous
single-dose toxicity, convulsion inductive ability and phototoxicity have been
evaluated by asahina et al [89].
N
O
COOHF
N
OCH3R1 R2
NH
N
O
COOHF
N
O
R1 R2
NH
F
LV LVI
Reddy et al [90] have synthesized 7,8 and 1,8 Imidazo fused quinolone
carboxamides LVII, LVIII and LIX and evaluated against antibacterial activity.
CONHCH3
O
F
NHCH3
N
Ar
CONHCH3
O
Et
F
NH
N
Ar
CH3
LVII LVIII
CONHCH3
O
Et
F
NH
N
R
CH3
LIX
Huang et al [91] have done a modification at the C-7 position of the quinolone
nucleus 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3
carboxylic acid LX. The antibacterial activity of these new fluoroquinolones was
evaluated and results compared with the standard drugs.
N N
O
COOHF
R
LX
Patel and Patel [92] have synthesized 4-thiazolidinones containing
fluoroquinolone analogous LXI and evaluate their antimicrobial studies.
NN
N
O
FNH
O
N
S
O
R
CH3
LXI
Patel and Patel have synthesized [93] 2-phenyl-3-{1-cyclopropyl-6-fluoro-7-
[4-methylpiperazin-1-yl]-4-quinolone}carboxamido-3-thiazolidin-4-ones LXII. All
the synthesized compounds were studied for their biological evaluation.
NN
N
O
FNH
O
N
S
O
R
CH3
LXII
Patel et al [94] have synthesized thioureido amides of fluoroquinolone LXIII
and observed their biological activity.
NN
N
O
FNH
O
NHS
RR1
R1= -H, -CH3, -C2H4OH LXIII
Studies of molecular modeling of 8-methoxy quinolone analogues LXIV by
using quantitative structure activity relationship have done by Srivastva et al [95].
N
O O
OH
R1
F
R2
OCH3
LXIV
Al-trawneh et al [96] have synthesized 6-fluoro-4-oxopyrido[2,3-a]carbazole-
3-carboxylic acids LXV via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-
oxoquinoline-3-carboxylate. The synthesized compounds were tested for their in vitro
antimicrobial, antiproliferative activity and ability to inhibit the activity of DNA
gyrase and topoisomerase IV was also investigated.
N
O
COOHF
NH
R2R1
R2
LXV
Srinivasan et al [97] have synthesized 1-Ethyl-6,8-difluoro-4-oxo-7(4-
arylpiperazin-1-yl)1,4-dihydro-quinoline-3-carboxylic acids LXVI and 1-ethyl-6,8-
difluoro-4-oxo-7(4-piperidin-1-yl)-1,4-dihydro-quinoline-3-carboxylic acids LXVII
and evaluated for antibacterial and antifungal activities.
O O
OH
CH3
F
F
N
NR
O O
OH
CH3
F
F
N
R
LXVI LXVII
Zhang et al [98] have synthesized 7-(3-alkoxyimino-5-amino/methylamino
piperidin-1-yl)fluoroquinolones LXVIII and evaluated in vitro antibacterial activity.
X
O O
OH
R3
F
N
NOR1
R2NH
LXVIII
Literature survey shows that the fluorinated 4-quinolones have also been
synthesized so far and their microbial activities have also been cited. Survey also
found that few research workers have developed 4-quinolones without fluorine atom
at C-6 position and also tested them against microorganisms for their activities.
HIV-1 Integrase inhibitors derived from quinolone antibiotics LXIX by Sato
et al [99].
R3 N
R4
O
O
OR5R1
R2
LXIX
7-(1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazin-7-yl)quinolones LXX have been
designed and synthesized by Zhu B et al [100]. Antibacterial activity of all
synthesized compounds has been determined against Gram positive and Gram
negative pathogens.
X N
O O
OH
NNH
R2
R3
R1
Y
LXX
Zhang et al [101] have synthesized 4-oxo-3-carboxyl quinolones LXXI and
studied their antimalarial activity and cytotoxicity.
N
H
O
O
O
R
MeO
LXXI
Nagasawa et al [102] have done the SAR studies on the 4-oxo-1,4-
dihydroquinoline carboxylic acid LXXII class of HIV-I integrase inhibitors.
N
O O
OH
CH3 OH
CH3
F
Cl
O
CH3
LXXII
Pyrroloquinolones LXXIII and LXXIV have been synthesized by Mentel et al
[103] and studied the reaction intermediates and the characterization of derivatives.
N
H
N
H
O
R
N
H
N
HR
O
Br
LXXIII LXXIV
Lee et al [104-106] have synthesized pyrido[3,2-h] qunolines LXXV, LXXVI,
LXXVII and LXXVIII. Activity of all synthesized compounds was compared with
nalidixic acid and ciprofloxacin. These compounds showed comparable antimicrobial
activities.
N
NEt
O
COOH
R1
N
NEt
O
COOH
R1
R2
R3
LXXV LXXVI
N
N
COOH
C2H5
CH3
O
N
N
COOH
C2H5
OF
LXXVII LXXVIII
Coscia and Dickerman [107] have first synthesized pyrido quinolone LXXIX
from1-acetyl-3-ethoxy carbonyl-4-piperidine and aniline.
NH2
R
+
N
O
COCH3
COOC2H5
CuSO4
CH3COOHN
NCOCH3
OH5C2OR
N
H
NCOCH3R
O
N
H
NHR
O
H2O
Pd(C)
N
H
NR
O
250oC
LXXIX
Pyrido[3,2,1-ij]cinnoline ring System-1,8-bridged tricyclic quinolones LXXX
have been synthesized by Barett et al [108].
N
N
F
F
CH3
COOR
O
LXXX
Chevalier et al [109] have prepared pyridoquinolines LXXXI as potential
inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes
strains.
NCH3 N
CH3
CH3
XXRR
LXXXI
Otto Meth-Cohn [110] have described the synthesis of a simple one-pot rout
for pyrido[2,3-h]quinoline-2-ones LXXXII from anilides.
CHO
CH3
CH3NH
Ph
CH2
N N O
Ph
+
LXXXII
Patel et al have synthesized nonfluorinated pyridoquinolones LXXXIII,
LXXXIV and LXXXV by incorporating amides at C-3 position and studied their in
vitro biological evaluation [111].
N
X
N
O
O
NH(CH2)2OH
R
NH
N
X
N
O
NH
O(CH2)2OH
SO2
R
LXXXIII LXXXIV
N
X
N
O
NH
S(CH2)2OH
R
LXXXV
Patel et al [112,113] have synthesized carbonyl pyridoquinolones LXXXVI,
LXXXVII and LXXXVIII by incorporating the various substituted carbonyl
piperazine and carbonyl urea derivatives at C-3 position of pyridoquinolone and
studied their antimicrobial activity.
N
OH
NCONHCONH
O
R1
R
N
OH
NCO
O
R1
NH
N
LXXXVI LXXXVII
N
OH
NCONH
O
R1 N N CH3
R1= H, CH3. LXXXVIII
Patel and chauhan [114] have synthesized 6-chloro-4-oxo pyridoquinolones
LXXXIX and XC by incorporating the various substituted carbonyl piperazine and
carbonyl urea derivatives at C-3 position of pyridoquinolone and studied their
antimicrobial activity.
N
NH
O
Cl
CONH C NH
S
R
N
NH
O
Cl
CONH
R
LXXXIX XC
Angular-pyridoquinolones XCI have been efficiently synthesized by
Majumdar et al [115] in 60–95% yields by molecular iodine-mediated cyclization of
easily available starting materials, 6-(N-propargyl) amino quinolone derivatives.
N
X O
R
I
XCI
1.1.2 Scope of the present work
Quinolones have been a valuable addition to the array of antimicrobial agents
that are used to treat human infections. Combination of two biological active moieties
in one molecule might results in an overall enhanced the biological activity.
Limited work has been seen in the literature for non C-6 fluoro pyrido-4-oxo-
quinolone; considering all these facts, in the present work we have synthesized
several new derivatives of substituted Schiff bases by incorporating the various
aldehydes at C-3 position of 4-oxo-pyrido[2,3-h]quinoline-3-carboxylate and 4-oxo-
1,4-dihydro-(4′-methyl-6′-chloropyrido[2,3-h])quinoline carboxylate respectively,
followed by synthesis of azetidinones, thiazolidinones and methyl thiazolidinones and
studied their antimicrobial activities as well as antitubercular activity against
Mycobacterium tuberculosis H37Rv.
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SECTION II
Studies on AzetidinonesStudies on AzetidinonesStudies on AzetidinonesStudies on Azetidinones
1.2.1 Introduction and literature review
2-Azetidinones, commonly known as β-lactams, are well - known heterocyclic
compounds among the organic and medicinal chemist. The synthesis of heterocylic
compound has always drawn the attention of chemist over the years mainly because
of their important biological properties. The role of β-lactam is endowed with unique
structure and potent antibacterial activity. The 2-azetidinone (β-lactam) ring system is
the common structural feature of a number of broad spectrum β-lactam antibiotics,
including penicillins, cephalosporins, carbapenems, nocardicins, monobactams,
clavulanic acid, sulbactams and tazobactams, which have been widely used as
chemotherapeutic agents to treat bacterial infections and microbial diseases [1-12].
Among the various methods for constructing this pharmaceutically important
four member ring the ketene-imine cycloaddition, also known as the staudinger
reaction. Staudinger’s keteneeimine reaction is the most common method for the
synthesis of monocyclic 2-azetidinone [13-16]. Numerous monocyclic β-lactams have
been prepared by the reaction of acid chloride and imine in the presence of a tertiary
amine or α-diazoketone as ketene precursor [17-20].
(Et)3N, solvent
R1 Cl
O
NR1
R2
N
O Cl
R1R2
+
I
The four membered 2-azetidinone rings are also known as β-lactam ring.
It possesses good pharmacological and biological activities. For many years
azetidinone II has been of great practical significant as the centre of penicillin III and
cephalosporins IV reactivity.
N
O
CH3
CH3
CH3
CH3
CH3
S
O
CH3
CH3
COOR1
RCOHN
N
S
O
COOH
CH2COOH
RCOHN
II III IV
No authentic β-lactams were known until the beginning of 20th century. The
first β-lactams were prepared by Staudinger [13] in 1907. Prior to 1940, the chemistry
of β-lactam has received little attention and it was subject of minor interest. β-lactam
as a class acquired importance only after 1943 when it was established that an
important antibiotic which was known as “Penicillin” III contains a β-lactam ring
[21].
Biological importance of 2-azetidinone
The 2-azetidinone scaffold is extremely versatile and has featured in a number
of clinically used drugs. The wide range of pharmacological profile shown by 2-
azetidinone can be classified into the following categories.
2-Azetidinone showed a broad spectrum of activity on various pathogens and
a considerable research has been done on the synthesis of new potent antibacterial and
antifungal 2-azetidinones [19, 20]. The discovery of monobactams by Squibb and
Takeda disclosed new horizons for the clinical application of β-lactam antibiotics,
since some of them, like aztreonam and carumonam possess a specific activity against
Gram negative bacteria. These molecules inhibit construction of cell wall and
eventually lead to cell lysis and death. Moreover, due to their β-lactamase inhibitory
action, 2-azetidinone-based heterocycles represent an attractive target of
contemporary organic synthesis. Almost all the positions of 2-azetidinone have been
explored to enhance the antibacterial and antifungal activity of this versatile nucleus.
The structure activity relationship studies on different azetidinone derivatives shows
that they are more effective on Gram negative bacteria as compared to Gram positive
bacteria. The presence of electron withdrawing substitution on aromatic ring increases
the antimicrobial activity of different derivatives.
Patel and Patel [22] have synthesized 2-azetidinyl-4-quinazolinones V of
diclofenac analogue and studied their antimicrobial activities.
N
N
O
NH
Cl
Cl
BrN CH
R
ClO
V
Novel azetidinones VI containing aryl sulfonyloxy group have been prepared
by Patel and Desai [23] and studied the biological evaluation of all synthesized
compounds.
O2N O S
O
O
N
OH
H
R
Cl
VI
1,4-Diaryl 2-azetidinones VII have been synthesized by Guner et al [24]. The
synthesized compounds were screened to an antimicrobial screening procedure
against Gram positive and Gram negative strains.
N
O
Cl
Cl
R1 R2
VII
Pathak et al [25] have synthesized a series of 1-butyl-3-substituted-4-(2-aryl-
1H-indol-3-yl)-2-azetidinones VIII and were screened for their antimicrobial activity.
NH
Br
NCH3
O
HCl
H
VIII
Optically active analogues of carumonam and its methoxyimino derivatives
IX have been synthesized by Guanti et al [26]. These monobactams bearing
sulfamoyloxymethyl or N-alkyl substituted sulfamoyloxymethyl groups at position 4
and were tested for in vitro antibacterial activity. The substitution of a
carbamoyloxymethyl with a sulfamoyloxymethyl group gives a new class of
monobactams with a certain antibacterial activity.
N
S
N
O
NH
OMe
N
O SO3Na+
NH2
O S
O
O
NH CH3
O
IX
Phillips et al [27] have reported the synthesis of two monobactams. They
observed the effect of introduction of (N-methyl-l,2,3-triazol-4-yl) methylene at the
C-3 position of the azetidinone nucleus X on the β-lactamase inhibitory activity of
the monobactam.
NN
N
H
N
O
SO3
-K+
N
N
N
CH3
X
Desai et al have carried out the synthesis of some novel azetidin-2-ones by
both microwave and conventional condensation method [28]. The synthesized
derivatives were screened for their in vitro antibacterial activity. Among all these
compound, XI exhibited potent antibacterial activity against both Gram positive and
Gram negative bacteria.
N
H
N
S
NH
O
N
Cl
O
Cl
H
XI
2-Azetidinones from chalcones of 4-hydroxy coumarin have been synthesized
by Pawar et al [29]. All the compounds were screened in vitro for their antimicrobial
activity against a variety of bacterial strains. The antimicrobial data of the compounds
revealed that compounds having the methoxy group XII showed most significant
activity.
O
CH3 N N
O NH
O
Cl
OCH3
XII
Halve et al [30] have developed a series of 3-chloro-4-(3-methoxy-4-acetyloxy
phenyl)-1-[3-oxo-3-(phenylamino)propanamido] azetidin-2-ones, and 3-chloro-4-[2-
hydroxy-5-(nitro substituted phenylazo)phenyl]-1-phenylazetidin-2-ones. All the
newly obtained azetidin-2-ones XIII were assayed in vitro for their growth inhibitory
activity against pathogenic micro-organisms.
Cl NH NHN
O
Cl
OCH3
CH3
O
O
O O
XIII
The emergence of multi-drug resistant tuberculosis, coupled with the
increasing overlap of the AIDS and tuberculosis pandemics has brought tuberculosis
to the forefront as a major worldwide health concern.
Kagthara et al [31] have synthesized 2-azetidinones XIV which showed a
potential antitubercular activity. The synthesized compounds were tested in vitro for
their antitubercular activity against M. tuberculosis H37RV. Those compounds
demonstrating atleast >90% inhibition in the primary screen have been retested at
lower concentration to determine the minimum inhibitory concentration in CABTEC
460. The data were compared with the standard drug rifampicin at 0.031 mg/ml
concentration which showed 97% inhibition.
N
N
H
OC
NH
O Cl
R
XIV
Trivedi et al have prepared several 1,3,7,9-tetrabromo-10 [a-(4-aryl-3-chloro-
2-oxo-1-azetidinylamino)acetyl]-10H-phenothiazines XV [32]. All the synthesized
compounds were screened for antitubercular activity against H37RV strain of M.
tuberculosis in Lowenstein-Jensen egg medium by serial two-fold dilution method.
S
N
Br Br
Br Br
OC
NH
N
O
Cl
R
XV
Vashi et al [33] have synthesized various 4-aryl-3-chloro-1-(4'-hydroxy-5'-
isopropyl-2'-methylphenyl)-2-azetidinones XVI and screened for their antitubercular
activity against M. tuberculosis H37RV.
OH
CH3
N
Cl
O
R
CH3
CH3
XVI
Thakre et al [34] have prepared various 2-azetidinone bearing benzo (b)
thiophene nucleus as potential antitubercular agent. The compound with 3,4 di
methoxyphenyl substitution XVII showed highest % of inhibition.
S
O
NH
Cl
Cl
N
O
R
Cl
XVII
Udipi et al have carried out the synthesis of 2-(6-methoxynaphthyl)
propionamido azetidine-2-ones and evaluated them for antitubercular activity [35].
The compound with methoxy substitution at para position XVIII showed better
activity.
OH3CO
CH3
NHN
O
OCH3
XVIII
Burnett et al [36] have described the evolution of the design of iodinated
analogues of SCH48461 and SCH58235 and the synthesis of those analogues
containing 2-azetidinone XIX.
N
OH
I
O
OH
F
XIX Heek et al [37] have discovered a potent cholesterol absorption inhibitor,
SCH58235 XX, through the identification of the active metabolites of SCH48461.
N
OH
F
O
OH
F
XX
Azetidinones are the important pharmacodynamic heterocyclic nuclei which
when incorporated in different heterocyclic templates have been reported to possess
potent anti-inflammatory activity.
Kumar et al [38] have prepared 2-[(4'-oxo-3'-chloro-2'-phenylazetidin-1'-yl)
aminomethyl]-3-[4''-(p-chlorophenyl)thiazol-2''-yl]-6-bromoquinazolin-4-ones XXI.
All the compounds have been screened for their anti-inflammatory and analgesic
activities.
N
N
O N
S
NH
Cl
Cl
O
Br
R
XXI
Bhati [39] has prepared various 3-chloro-4-aryl-1-{5-[{[1,3,4]thiadiazino[6,5-
b]indol-3-ylamino]methyl]-1,3,4-thiadiazol-2-yl}azetidin-2-ones XXII. The
synthesized compounds were evaluated for their anti-inflammatory, ulcerogenic and
analgesic activities
N
N N
SNH
S
N
N
N
O
Cl
R
XXII
Vijay Kumar et al [40] have synthesized N-substituted-3-chloro-2-
azetidinones XXIII. The compounds were tested for in vitro anti-inflammatory
activity by protein denaturation method and showed significant activity at low and
high concentration compared to standard
N
S
NH
NH
ON
O
ClOH
H3CO
F
R
XXIII
Azetidinone based quinazolin-4-ones XXIV have been synthesized by Kumar
et al [41] for their anti-inflammatory activity.
N
N
O
SO
N N
N
N
O
Cl
RX
XXIV
Azetidinones are capable of suppressing the in vitro growth of various types of
tumor cells.
4-Sulfonylazetidinones-2 has been synthesized by the reaction of DBU and
organic halides with the esters of penicillin sulfones [42]. 4-Sulfonylthio- and 4-
sulfothioazetidinones-2 have been synthesized by nucleophilic substitution of the 2-
benzothiazolylthio groups in 4-(benzothiazolylthio)azetidinones-2 using sodium
sulfinates or sodium hydrogen sulfite. A study of their cytotoxic activities revealed
the anticancer effect of compounds containing methylsulphonylthio-, 4-
tolylsulfonylthio-, and 4-methoxycarbonylamin ophenylsulphon-ylthio-substituents
XXV at position 4 of the β-lactam ring relative to a wide range of monolayer cultures
of cancer cells in vitro.
N
S
OCOOCHPh2
CH2CH3
S
O
O NHCOOCH3
XXV
A series of 1,3,4-trisubstituted and 3,4-disubstituted 2-azetidinones XXVI and
XXVII, XXVIII, XIX and XXX have been synthesized in order to study the relation
between their structure and biological characteristics. Study of the cytotoxic activity
of these compounds revealed an anticancer effect in (3S,4S)-1-(4-methoxyphenyl)-3-
methyl-2-azetidinones containing 2-acetoxybenzoyloxymethyl and 2,2-dicyanovinyl
substituents at position 4 in vitro with respect to a wide range of monolayer cultures
of cancer cells [43].
N
CH3
O
OCH3
H
NO2
N
CH3
O
OCH3
O
O
OCOCH3
XXVI XXVII
N
CH3
O
OCH3
H
OCOCH3
N
CH3
O
CH2OH
OCH3
N
CH3
O
OCH3
CN
CN
XXVIII XXIX XXX
A series of novel 1,4-diaryl-2-azetidinones XXXI have been prepared by
stereospecific Staudinger reaction as conformationally restricted analogues of
combretastatin A-4 by Sun et al [44]. All synthesized compounds were tested for
cytotoxic activity against human neuroblastoma cells (IMR32). Selected compounds
were additionally tested against a panel of 12 human and rat tumor cells and normal
CHO cells.
O OH
OCH3NH2
XXXI
2-Oxo-1-azetidinylacetamides XXXII have been synthesized by the four-
component condensation of β-amino acids with aldehydes and isonitriles by Veinberg
et al [45]. Study of their cytotoxic activity in vitro revealed a cytotoxic effect of
individual compounds in relation to cancer cells of human fibrosarcoma, mouse
hepatoma, and mouse neuroblastoma and also their ability to initiate the biosynthesis
of nitric oxide radical (TG100).
N
O
HNH
C6H11NH
OO
O
Ph
Cl
XXXII
Sunil kumar et al [46] have synthesized azetidinone XXXIII containing
quinazolin-4(3H)-ones and screened for antiparkinsonian activity
N
NNH
O
N
O
Cl
R
X
XXXIII
Tozser et al [47] have synthesized arylpiperazinyl fluoroquinolones XXXIV
and studied their anti-HIV activity.
N
O
O
O
O
NHN
NN
XXXIV
For the past decade, peroxisome proliferator-activated receptors (PPARs),
which are members of a nuclear hormone receptor superfamily, have attracted much
attention as novel therapeutic targets for the treatment of diabetes and dyslipidemia
[48-50].
Goel has synthesized a novel series of 2-azetidinones XXXV [51] via {2+2}
cycloaddition (Staudinger) reaction of imines with ketenes. The synthesized
compounds were evaluated for antihyperglycemic activity. In alloxan-induced
diabetic rats, high glucose levels and depression in hepatic glycogen contents were
observed which could be attributed to the less availability of active form of enzyme
glycogen synthetase.
N
O
O
NO
CH3
CH3
XXXV
A series of conformationally constrained azetidinone XXXVI [52] acid-
derived dual PPAR a/l agonists has been synthesized by Wei Wang et al. for the
treatment of diabetes and dyslipidemia.
N
OCH3
O
N
O
OH
CH3
CH3
CH3CH3
XXXVI
Vijay kumar et al [53] has synthesized N-substituted-3-chloro-2-azetidinones
XXXVII and XXXVIII. The compounds were tested for anticonvulsant studies by
PTZ induced method.
N
S
NH
NH
ON
Cl
O
OH
H3CO
F
R
XXXVII
N
S
R
NH
ON
Cl
O
OH
H3CO
F
XXXVIII
A series of 3-(3-guanidinopropyl)-azetidin-2-ones [54] have been synthesized
by Han et al. and evaluated as inhibitors of cleavage of synthetic substrates in vitro by
the serine proteases thrombin, trypsin and plasmin. Acetylation of the β-lactam N
atom afforded trans-4-(2-phenylethyl)- 3-(3-guanidinopropyl)-1-acetyl-2-azetidinone
XXXIX, an effective, time-dependent inhibitor of thrombin and a potent inhibitor of
plasmin.
NH
NH.HCl
N
NH2
O
Ph
O
CH3
XXXIX
Vasopressin is perhaps best-known for its role in the cardiovascular system, it
also has actions in the central nervous system (CNS), and several CNS applications of
vasopressin receptor antagonists have been suggested. A number of research groups
have prepared antagonists directed at the vasopressin V1 receptor [55, 56].
A novel series of vasopressin V1a antagonists has been designed from the
unique monocyclic azetidinone platform by Guillon et al [57]. Subnanomolar
affinities at the human V1a receptor have been achieved. The azetidinone LY307174
XL was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM
at the human V1a receptor) based on molecular similarity to ketoconazole, a known
antagonist of the luteinizing hormone releasing hormone receptor.
O
N
O
O
CH3
O
O
O
O
XL
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SECTION III
Studies on ThiazolidinonesStudies on ThiazolidinonesStudies on ThiazolidinonesStudies on Thiazolidinones
1.3.1 Introduction and literature review
Thiazolidinones are the derivatives of thiazolidine, which belong to an
important group of heterocyclic compounds. Thiazolidinones with carbonyl group at
position 2 I, 4 II, or 5 III have been subject of extensive study. Among these three
types, Thiazolidinone II is an important scaffold known to be associated with several
biological activities which contains 4-oxothiazolidin or 4-thiazolidinone [1-4].
NH
SO
N
H
S
O
N
H
SO
I II III
Numerous reports have been appeared in literatures which highlight the
chemistry and use of 4-thiazolidinones. A comprehensive review has been written on
4-thiazolidinone in 1961 by Brown [1]. Then the chemistry and biological importance
of 4-thiazolidinones has been reviewed in depth by Newkome [2] and Singh [3].
Many researchers have been synthesized the thiazolidinones by various
methods [4-11], among them most convenient method is the cyclization of Schiff base
with α–mercapto alkonic acid [12-15].
4-Thiazolidinones can be synthesized easily by addition of mercapto acetic
acid to the C=N bond of Schiff base. Different methods for the preparation of 4-
thiazolidinones have been described.
Synthesis:
Substituted 2-imino-4-thiazolidinones VI are obtained in good yield by the
reaction of symmetrical and unsymmetrical thioureas IV with various substituted and
unsubstituted α-haloalkanoic acids, their esters, acid chlorides, amides or carbamates
V [4-6].
CH3
NH C
S
NH R1
+ X
Y
OR2
R3
N
S
R
R3
R2N
R1
O
IV V VI
Various N-substituted acetyl thioacetamides VIII on treatment with mono
chloroacetic acid VII yield 2-acetyl methylene-3-substituted-4-thiazolidinones IX [7].
Cl CH2
COOH+
R NH
C CH2
CH3
O
S
N
S
R
C
CCH3
OO
VII VIII IX
2-Imino- 4-oxo-5-thiazolidineacetic acid XII can synthesized in good yield by
refluxing equimolor amounts of substitcuted or unsubstituted thioureas XI and maleic
anhydride X in acetone [8, 9].
O
O
O
+
CH3
NH C
S
NH R1 N
S
R
N
R1
O
CH2
HOOC
X XI XII
3-Carboxyalkyl -2-thiono-4-thiazolidinones have been synthesized from long
chain amino acids, NH2-(CH2) n-COOH. The amino acids XIII react with CS2 in the
presence of bases to give the corresponding N-substituted-4-thiazolidinones XIV [10,
11].
NH2 (CH2)n
COOH
CS2+KOH
S
N
O
S
(CH2)n COOH
XIII XIV
α-Mercapto alkanoic acid has been extensively used for the synthesis of 4-
thiazolidinones. The substituted and unsubstituted α-mercaptoalkanoic acids XV react
conveniently with Schiff base XVI of aromatic or heterocyclic aldehydes and
aliphatic or aromatic amines in different solvents to give a variety of 2-substituted-4-
thiazolidinones XVII [12-15].
N
HC
R
R1
+ SH C
R2
R3
COOH
S
N
R
R1
R2
R3
O
XVI XV XVII
R=alkyl or aryl; R1= aryl or heterocyclic; R2, R3= H or alkyl
Mechanism:
The reaction proceeds by the attack of mercapto acetic acid upon the C=N
group. Here, HS-CH2-COOH group attached to the carbon atom of C=N group which
is followed by capture of proton by nitrogen and subsequent cyclization.
In this reaction, the acyclic intermediate is formed. In several cases, the
uncyclized product has been isolated [16]. Phosphorous pentoxide in dioxane was
used for subsequent cyclization of certain uncyclized product [17].
+
CH2HOOC SHS
N
R
R1
O
NH
CH
R
R1
OC
OH
H2C
S
-H2O
N CH
R R1
Biological importance of 4-thiazolidinone:
The 4-thiazolidinone scaffold is extremely versatile and has featured in a
number of clinically used drugs. The wide range of pharmacological profile shown by
4-thiazolidinone can be classified into the following categories.
Thiazolidinone and its derivatives XVIII interact with MurB enzyme and
inhibit the peptidoglycan biosynthesis, essential component of cell wall of both Gram
positive and Gram negative bacteria [18].
N
S
O
H9C4
HOOC
O
CH3CH3
CH3
CH3
XVIII
Goel et al [19] have synthesized new anthranilic acid derivatives, 2-
substituted-3-(4-bromo-2-carboxyphenyl)-5-methyl-4-thiazolidinone IXX and
evaluated for their anti-inflammatory activity against carrageenan-induced oedema in
albino rats.
N
S
COOHBr
O
CH3
R
IXX
New substituted azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino(6,5-b)
indoles XX have been synthesized by Bhati and Kumar [20]. The compounds were
evaluated for their anti-inflammatory, ulcerogenic and analgesic activities.
N
NN
S NHCH2
N
S
N
N
S
R
O
XX
Kumar and Rajput [21] synthesized series of quinazolin-4-one based 4-
thiazolidinones and screened for anti-inflammatory activity, XXI demonstrated
significant activity.
N
N
O
N
S
S
O
N
N
N
O
XXI
New thiazolidinonyl-4-aryl-oxymethylcoumarins have been synthesized and
screened for in vitro antimicrobial and in vivo anti-inflammatory activity. Compound
XXII showed potent antibacterial, antifungal and anti-inflammatory activity [22].
O
O
CH3
S N
O
Br
XXII
Indole based thiazolidinones have been designed and synthesized by Uchoa et
al [23]; XXIII demonstrated the significant anti-inflammatory activity.
N
H
S
N
O
O
O
Cl
XXIII
Taranalli et al have synthesized thiazolidine-4-ones and evaluated for anti-
inflammatory, analgesic and anti-ulcer activity [24].
OH N
SO
R
R3 R2
R1
XXIV
Geronikaki and coworkers [25] have synthesized 2-(thiazole-2-ylamino)-5-
phenylidene-4-thiazolidinones XXV and screened for anti-inflammatory and majority
of the compounds were dual COX / LOX inhibitors.
N
S
NH
S
N
R2
R1O
Aakash et al [26] have synthesized biphenyl-4-carboxylic acid 5-(arylidene)-2-
(aryl)-4-oxothiazolidin-3-yl amides XXVI and evaluated for anti-inflammatory
activity
NH
O
NS
O
Ar
Ar'
XXVI
Benzothiazole based 4-thiazolidinones have been synthesized and screened to
anti-inflammatory activity by Gurupadayya et al [27] XXVII demonstrated significant
anti-inflammatory activity.
N
S
NS
F
Cl O
NO2
XXVII
Naphtho-[2,1-b] furan based thiazolidinones XXVIII have been synthesized
and evaluated for anti-inflammatory activity. Some of the compounds demonstrated
significant anti-inflammatory activity [28].
O
N
S N S
O
R2
R1
XXVIII
The 2,3-diaryl-1,3thiazolidin-4-ones XIX have been synthesized and few of
them demonstrated anti-inflammatory activity by inhibiting the activity of COX-2
enzyme [29].
S
N
H2NO2S
O
R
XIX
Vigorita and coworkers [30] have synthesized 3,3-(1,2-ethane-diyl)-bis[2-aryl-
4-thiazolidinones] for anti-inflammatory activity. Good activity observed for XXX.
S NN S
Cl
Cl
Cl
Cl
O
O
XXX
4-Thiazolidinones have been synthesized by Look et al [31] and evaluated as
cyclooxygenase-1(COX-1) inhibitor; XXXI demonstrated significant inhibition of
COX-1.
N S
O
H3COOC
O C4H9
Cl
XXXI
Moreover several 4-thiazolidinones [32-34] have been synthesized and
evaluated for their anti-inflammatory activity. Majority of them were demonstrated
significant activity.
The emergence of multi-drug resistant tuberculosis, coupled with the
increasing overlap of AIDS and tuberculosis pandemics has brought tuberculosis to
the forefront as a major worldwide health concern.
Dave and co-workers [35] have synthesized series of thiazolidinones XXXII
and studied their biological evalutaiton.
N
N
N
N
N
S
SH
R
O
XXXII
The novel 4-thiazolidinones XXXIII have been synthesized and evaluated
against M. tubercular H37RV by Kucukguzel et al, some of them demonstrated good
activity [36].
NH
O
NHN
S
O
O
H3CO
R1
R2 .
XXXIII
Patel and coworkers [37] have synthesized series of pyrimidine based
thiazolidinones and screened for antimicrobial and antitubercular activity. Compound
XXXIV demonstrated excellent antibacterial and antitubercular activity.
NN
NH
O
NH
N
S
F
OCH3
Cl
O
OCH3
OCH3
XXXIV
Some pyrazole based 4-thiazolidinones XXXV have been synthesized and
screened for their in vitro antibacterial activity against various bacterial strains.
Majority of the compounds were demonstrated antitubercular activity [38].
O
N N
NH
N
S
O
R
OH
O
R1
R2
XXXV
Spiro indole based thiazolidinones XXXVI have been synthesized and
evaluated for antimicrobial and antitubercular activity by Dandia et al [39].
N
S
N
N O
O
OR1R2
XXXVI
Novel thiazolidinones have been synthesized by Oza et al [40] and evaluated
for their antitubercular activity, compound XXXVII demonstrated potent activity.
O CH2 NH
N
S
NHCH3
O
Cl
O
O
CH3
XXXVII
Various 4-thiazolidinones have been synthesized by several workers [41-43]
and evaluated for antitubercular activity. Majority of them were demonstrated
significant activity.
A new series of clubbed thiazolidinone-triazoles XXXVIII were synthesized
and studied the effect of hydrophobic unit, hydrogen bonding domain and electron
donor group on the compounds for anticonvulsant activity. Some of them exhibited
excellent anticonvulsant activity [44].
N
H
N N
SN
S
N
O
O O
CH3
R1
R2
XXXVIII
Quinazoline based thiazolidinones XXXIX were synthesized and screened for
anticonvulsant activity by Gursoy and Terzioglu [45].
S
NH N
N
SO
O
CH3
C2H5
N
N
O
CH3
XXXIX
Malawska [46] has synthesized new thiazolidinonyl-quinazolin-4-(3H)-ones
XL for selective anticonvulsant activity with lower toxicity.
N
N
NH
S
NN
N
S
O
O
R1
R2
XL
Terrett [47] has synthesized some 4-thiazolidinones and give relief in pain
associated with arthritis, headache and terminal cancer. Compounds were evaluated
for anticonvulsant activity as sodium channel agonist; XLI demonstrated significant
activity.
S
N
O
N
CF3
O
XLI
Isatin based thiazolidinones [48, 49] have been synthesized. Some of the
compounds demonstrated significant anticonvulsant activity.
Structure activity relationship was performed on 4-thiazolidinones XLII for
anti-cancer activity. Ten of them selectively killed both non-small cell lung cancer
line H-460, while demonstrated less toxicity to normal human fiber blasts [50].
N
NH
S
R1
R2
O
XLII
Gududuru and coworkers have synthesized the amides of 4-thiazolidinone
XLIII as phosphate mimic with less cytotoxicity in prostate cancer cell, despite
improved selectivity over RH 7777 cells [51].
S N
NH (CH2)17CH3
O
O
XLIII
Triazine based thiazolidinones have been synthesized and screened for
anticancer activity, XLIV showed significant anticancer activity [52].
NHN
N
N
S
O
O
O S
XLIV
Some novel thiazolidin-4-ones XLV bearing a lipophilic adamantly
substituents at position 2 or 3 were synthesized with modest anti-HIV activity [53].
N
S
O
R
XLV
Quantitative structure activity relationship studies were performed on 1,3-
thiazolidin-4-ones XLVI for anti-HIV activity. Study showed that substitution of
electronegative groups and hydrophobic groups leads better anti-HIV activity [54].
N
S F
OCH3
CH3
O
XLVI
4-Thiazolidinones XLVII have been designed and synthesized by Rao et al
All the compounds were subjected to anti-HIV activity, the high-active anti-retroviral
therapy based on a combination of HIV-1 reverse transcriptase and protease inhibitor,
some compounds demonstrated potent anti-HIV activity [55].
N
N
S
N
O
R1
R2
R1
XLVII
2,3-Diaryl-1,3-thiazolidin-4-ones XLVIII have been synthesized and
performed the structure activity relationship study. These compounds were proved to
be minimum cytotoxic and acting as nonnucleoside HIV-1 RT inhibitors (NNRTIs)
[56].
N
S
N Cl
Cl
O
CH3
XLVIII
Chandrappa et al [57] have synthesized series of thiazolidinone-2,4-diones and
evaluated for antiproliferative activity, XLIX was found significantly active.
CH
S
N
O
O NO2
XLIX
Series of sulfonamide based 4-thiazolidinones L have been synthesized and
demonstrated as new class of promising anti tumor agents [58].
N
N
N
SO2
NN
S
R
O
L
Ali and Hassan have synthesized the series of clubbed tetrahydro naphthalene-
thiazolidinones and performed antitumor activity by intraperitoneal administration; LI
demonstrated good activity [59].
N
S
N S
NH
O
LI
Indolinones containing thiazolidinone moiety LII have been synthesized and
evaluated for antiviral activity. Majority of the compounds showed potent antiviral
activity [60].
N
H
N N
N
S
O
CH3
O
CH3
O2N
LII
Diurno and coworkers [61] have synthesized 4-Thiazolidinones LIII and
investigated as inhibitor of the contractions induced by histamine.
S N N
OCH3
O
CH3
CH3
LIII
Surrey [62] has synthesized 4-thiazolidinones LIV. Most of the compounds
showed high local anesthetic activity.
N
S
(CH2)n N
OR2
R1
LIV
Some new arylidenes based thiazolidinones have been synthesized by Raikwar
et al [63], LV demonstrated potent diuretic activity.
S
N
S
N
N
Cl
Br
O
Br
LV
Methylele-bis-thiazolidinones have been synthesized by Srinivas and
coworkers [64] and performed the nematicidal activity, LVI showed potent
nematicidal activity.
S
N
S N
O Cl
H3CO
Cl
O
OCH3
LVI
Imran et al [65] have synthesized naphthyl based 4-thiazolidinone acetic acid
derivatives LVII, and screened for antihyperglycemic activity.
N
S
NHN S
COOH
R1
LVII
Tenorio et al [66] have synthesized 4-thiazolidinones and evaluated host cells
infected with Toxoplasma gondi, compound LVIII was found significantly active.
N
NN
H
S
COOH
O2N
O
LVIII
Some potential steroidal antiestrogens have been synthesized containing 4-
thiazolidinone moiety LIX and tested for antiuterotrophic activity [67].
N
S
N
CH3OR
ONH
OR
LIX
Fluorobenzothiophen based 4-thiazolidinones designed and synthesized for
antipsychotic activity; LX possessed application in treatment of schizophrenia [68].
N
SCH3
CH3N
N
S
CH3
O
F
LX
The pseudo nucleoside based 4-thiazolidinones LXI have been synthesized by
Rauter and Padilha [69] and evaluated as inhibitor of amphiphilic acetylcholine
sterase and butyrylcholinesterase.
NS
O
O
O
H
H
O
LXI
Patel et al [71] have synthesized and studied microbial activity of (4-oxo-
thiazolidinyl) sulfonamides bearing quinazolin-4(3H)ones LXIII.
NNH
O
SO2
NS
ONH
Cl
Cl
LXIII
Patel and Patel [72] have synthesized new (4-oxo-thiazolidinyl)quinazolin-
4(3H)ones LXIV and studied their antimicrobial activity.
N
N
O
NH
Cl
Cl
BrN CH
R
SO
LXIV
Patel and Shaikh [73] have synthesized 4-thiazolidinones LXV of nicotinic
acid with 2-amino-6-methylbenzothiazole and studied their antimicrobial activity.
S
N
N
NH
S
N
O
NH
CH3
O
R
LXV
Fuloria and coworkers [74] have synthesized series of thiazolidinones LXVI
and evaluated for antimicrobial activity. All the compounds demonstrated significant
antibacterial and antifungal activity.
O
NH N S
Cl
CH3
OO
R
LXVI
Pyridothiazolidinones have been designed and synthesized for antibacterial
and antifungal activity by Mehta et al [75]; significant activity was observed for
compound LXVII.
N
O
NHNH
O
Cl
CH3 CH3
NN S
NHNH
S
O O
LXVII
Quinoline based thiazolidinones have been synthesized by Keshk et al [76]
and tested for their antimicrobial activity, LXVIII was significantly active.
NNH
O
N
S
NO
CH2C6H5
LXVIII
Rana et al [77] have synthesized quinoline based thiazolidinones and screened
for antimicrobial activity; compound LXIX showed significant antibacterial and
antifungal activity.
N
S
N N N
CH3
O
OH
F
H3CO Cl
LXIX
3-(1,2,4-Triazol-3-yl)-4-thiazolidinonones LXX have been synthesized and
screened against fungal and bacterial species. Some of the compounds were found
active against clinically important pathogens [78].
S
N
N
N
O
CH3H
R1
R2 R3
LXX
1,2,4-Triazole based 4-thiazolidinones have been designed and synthesized by
Patel and Patel [79]. All the compounds have been evaluated for antifungal and
antimicrobial activity. Compound LXXI possessed significant antibacterial activity.
NN
NN
S
Cl
O
LXXI
Patel and Patel have synthesized [80] fluoroquinolone based 4-
thiazolidinones and screened for biological evaluation.
N
NHF
O
N
N
H3CO
O
N
SO
R
LXXII
A series of 4H-chromen-4-ones with 4-thiazolidinones have been designed
and synthesized for antifungal activity. Compound LXXIII inhibited the growth of
fungal species [81].
O
Cl
O
N NS
S
O
LXXIII
Vyas and coworkers [82] have synthesized quinoxaline based thiazolidinones
and evaluated for antimicrobial activity, LXXIV demonstrated significant antifungal
and antibacterial activity.
N
N NH
N
S
CH3
OH
O
LXXIV
Mishra et al [83] have synthesized pyridine based 4-thiaozolidinones and
screened for antimicrobial activity, LXXV significantly improved the biological
activity.
N
CO NH N
S Br
Br
O
NH
Cl
LXXV
Venlafaxine analogous of thiazolidin-4-ones LXXVI has been designed and
synthesized by Kavita and coworkers [84] and screened for antimicrobial activity.
Significant antimicrobial activity observed for all compounds.
NSOH
H3CO
O
R1
R2
LXXVI
4-Thiazolidinones have been synthesized by Dandia et al [85] and evaluated
for their anti-fungal activity. Excellent activity was observered for LXXVII.
N
H
S
NN
NH
O
CH3
O
CH3
CH3
LXXVII
Benzothiazole based 4-thiazolidionones LXXVIII have been designed and
synthesized; all compounds were evaluated for antimicrobial activity, majority of
them demonstrated significant antifungal and anti bacterial activity [86].
S
N
S CH2 NH
N
S
RO
O
LXXVIII
Khalafallah et al [87] have synthesized fused and spiro thiazolidinones from
cycloaddition and cyclocondensation reaction of mercaptoacetic acid for antimicrobial
activity. Compound LXXIX demonstrated significant antibacterial activity.
N
H
S
N S
O
O O
OH
O
O
LXXIX
Spiro thiazolidinones have been synthesized and evaluated for antimicrobial
activity by El-Kanzi et al [88]; compound LXXX demonstrated good to moderate
antimicrobial activity.
N
H
NH
N
NS
NH2O
O
CH3
O
LXXX
The aryloxy-4-thiazolidinones LXXXI have been prepared by Ravi et al [89]
and evaluated for antimicrobial activity. Excellent inhibition of bacterial and fungal
growth was observed for some compounds.
O NH
S
N
R
O
O
LXXXI
Bhoot and coworkers [90] have synthesized series of 4-thiazolidinones and
evaluated for antimicrobial activity, LXXXII showed potent antibacterial and
antifungal activity.
ON
S
NH
O
Cl
Cl
LXXXII
Series of spiro-thiazolidinones LXXXIII have been synthesized to evaluate
for biological activity, majority of them demonstrated good antimicrobial activity
[91].
N
H
S
O O
O N
O
S
R1
R
LXXXIII
Patel and Mehta [92] have synthesized thiazole based 4-thiazolidinones
LXXXIV for antimicrobial activity; majority of them found potent as inhibitors of
bacterial and fungal growth.
S
N
S
N
O
R
LXXXIV
Semisynthetic latranculins have been designed and synthesized by El Sayed
and coworkers [93], LXXXV showed potent antimicrobial activity.
N
S
O
H
O
O
COCH3
CH3
O
H
LXXXV
1,3,4-Thiadiazole based 4-thiazolidinones have been synthesized and
evaluated for antimicrobial activity by Aly and El-sayed [94], LXXXVI showed
potent antibacterial activity.
SS
NN
N
S
Cl
O
LXXXVI
Some thiazolidinones have been synthesized by Sattigeri et al [95]. All
compounds were evaluated for antimicrobial activity and LXXXVII demonstrated the
potent antifungal activity.
N S
O
NH
O
CH3
LXXXVII
Indole, thiazole, sulphone, furan and thiadiazole based thiazolidinones have
been synthesized by several workers [96-105] and evaluated for antimicrobial
activity. Most of the compounds were demonstrated significant antimicrobial activity.
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