Quinoline-based azetidinone and thiazolidinone analogues as antimicrobial and antituberculosis agents

Article abstract of DOI:10.1007/s00044-012-0061-7

New azetidinone and thiazolidinone class of bioactive agents based on quinoline nucleus have been synthesized. 2-Chloroquinoline-3-carbaldehyde reacted with various substituted amine to form the corresponding Schiff base intermediates. We have derived final azetidinone and thiazolidinone analogues from Schiff bases using chloroacetyl chloride and 2-mercaptoacetic acid, respectively. The newly synthesized analogues were then examined for their antimicrobial activity against some bacterial and fungal strains as two gram -ve bacteria (Escherichia coli MTCC 739 and Pseudomonas aeruginosa MTCC 741), two gram +ve bacteria (Staphylococcus aureus MTCC 96 and Bacillus subtilis MTCC 430), two fungal species (Aspergillus niger MTCC 282 and Candida albicans MTCC 183) as well as against Mycobacterium tuberculosis strain H37Rv to develop a novel class of bioactive agents. The results of bioassay showed that some of the newly synthesized azetidinones and thiazolidinones emerged as lead molecules with excellent MIC (mg/mL) values against mentioned microorganisms compared to standard drugs. The structure of the final analogues has been confirmed on the basis of IR, ¹H NMR, ¹³C NMR, and elemental analysis.

Full text of DOI:10.1007/s00044-012-0061-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0061-7
ORIGINAL RESEARCH
Quinoline-based azetidinone and thiazolidinone analogues
as antimicrobial and antituberculosis agents
•
Bhupendra M. Mistry Smita Jauhari
Received: 8 December 2011 / Accepted: 9 April 2012
Ó Springer Science+Business Media, LLC 2012
Abstract New azetidinone and thiazolidinone class of
bioactive agents based on quinoline nucleus have been
synthesized. 2-Chloroquinoline-3-carbaldehyde reacted
with various substituted amine to form the corresponding
Schiff base intermediates. We have derived final azetidi-
none and thiazolidinone analogues from Schiff bases using
chloroacetyl chloride and 2-mercaptoacetic acid, respec-
tively. The newly synthesized analogues were then exam-
ined for their antimicrobial activity against some bacterial
and fungal strains as two gram -ve bacteria (Escherichia
coli MTCC 739 and Pseudomonas aeruginosa MTCC
741), two gram ?ve bacteria (Staphylococcus aureus
MTCC 96 and Bacillus subtilis MTCC 430), two fungal
species (Aspergillus niger MTCC 282 and Candida albi-
cans MTCC 183) as well as against Mycobacterium
tuberculosis strain H37Rv to develop a novel class of
bioactive agents. The results of bioassay showed that some
of the newly synthesized azetidinones and thiazolidinones
emerged as lead molecules with excellent MIC (mg/mL)
values against mentioned microorganisms compared to
standard drugs. The structure of the final analogues has
been confirmed on the basis of IR, 1H NMR, 13C NMR, and
elemental analysis.
Introduction
Quinoline is a heterocyclic scaffold of paramount impor-
tance to human race. Several quinoline derivatives isolated
from natural resources or prepared synthetically are sig-
nificant with respect to medicinal chemistry and biomedi-
cal use. Indeed quinoline derivatives are some of the oldest
compounds which have been utilized for the treatment of a
variety of diseases. The bark of Cinchona plant containing
quinine was utilized to treat palpitations (Samuel levy and
Salomon Azoulay, 1994), fevers, and tertians since more
than 200 years ago. Quinidine, a diastereoisomer of qui-
nine was in the early twentieth century, acknowledged as
the most potent of the ant arrhythmic compounds isolated
from the Cinchona plant (Wenckebach, 1923). The quin-
oline skeleton is often used for the design of many syn-
thetic compounds with diverse pharmacological properties
such as antimicrobial agents (Donnell et al., 2010),
antituberculosis (Mungra et al., 2010), antibacterial
(Makawana et al., 2011). There are many methods avail-
able for fused quinolines, the Vilsmeier approach has been
recently, explored by Katritzky and others. More recently,
synthesis of functionalized quinoline and their benzo/het-
ero-fused analogues has been reported from the reaction of
a-oxoketen-N, S-acetals with Vilsmeier reagent. It will
suffice to mention here that currently available antimicrobial
drugs such as norfloxacin, ciprofloxacin, ketoconazole con-
tain quinoline ring in their structures. In fact, 2-chlor-
oquinoline-3-carbaldehyde, the primary intermediate, is a
good starting material for the preparation of different quin-
oline derivatives. In addition, literature survey revealed that
quinoline-based azetidinones (Ross et al., 2004; Halve et al.,
2007; Wang et al., 2009; Rajasekaran et al., 2010; Dua et al.,
2010; Rokade and Dongare, 2010; Bhat et al., 2011) and
thiazolidinones (Kumar et al., 2007; Bhati and Kumar, 2008;
Keywords 2-Chloroquinoline-3-carbaldehyde ꢀ
Substituted anilines ꢀ Azetidinone ꢀ Thiazolidinone ꢀ
Antimicrobial activity
B. M. Mistry (&) ꢀ S. Jauhari (&)
Department of Applied Chemistry, S.V. National Institute
of Technology, Surat 395007, Gujarat, India
e-mail: bhupendra.mistry84@gmail.com
S. Jauhari
e-mail: smitajauhari2011@gmail.com
123

Med Chem Res
Shingade et al., 2011; Desai et al., 2011; Pawar and Mulwad,
2004; Patel and Patel, 2010; Pareek et al., 2011) are proved
promising antimicrobial agents.
respectively. 13C NMR spectral assigned signals in the range
between 162.71 and 166.58 due to presence of ketone
(–C=O) functional group of azetidinone ring, 60.20–62.65
range showed the presence of (–C–Cl) group of azetidinone
ring, 147.56–149.51 ppm range indicates the presence of
(–C–Cl) group of quinoline ring, 67.37–69.98 range showed
the linkage of azetidinone ring, while remaining all aromatic
carbons resonated in the range of 112–150.62. The same
Schiff base derivatives 4a–l were heated with 2-mercapto-
acetic acid in the presence of anhydrous zinc chloride which
acts as a catalyst and solvent DMF undergo cyclization to
give quinoline thiazolidin-4-one derivatives 6a–l. The IR
spectrum of compounds 6a–l showed sharp peak near
1,734 cm-1 indicates the presence of ketone (–C=O) func-
tional group of azetidinone ring. It also showed corre-
sponding peak of C–N–CO at 1,536 cm-1 and showed peak
of C–S–C at 621 cm-1. Chlorine functional group showed a
peak at 761 cm-1. The 1H NMR spectra of compounds 6a–l
showed the signal at 6.49 ppm due to –CH–N on thiazolid-
inone ring. Doublets of doublet were observed at 3.93 ppm
due to CH–S proton on thiazolidinone ring, 2.24 ppm due to
the presence of –CH3 group at phenyl ring, and aromatic
protons resonated in the range of 6.90–8.20 ppm. Moreover,
proton positional assignment for the final compounds 6a–l
was found to be in agreement as per the interpretation of
compounds 5a–l. 13C NMR spectral assigned signals in the
range between 172.35 and 178.37 due to presence of ketone
(–C=O) functional group of thiazolidinone ring, 56.93–
59.66 range showed the linkage of thiazolidinone ring,
149.68–151.65 ppm range indicates the presence of (–C–Cl)
group of quinoline ring, 35.23–37.58 ppm indicates the
presence of –CH2 group in thiazolidinone ring, while
remaining all aromatic carbons resonated in the range of
115.57–149.81.
Results and discussion
Chemistry
Various routes have been developed for the synthesis of
functionalized quinolines, the Vilsmeier (Meth-Cohn and
Bramha, 1978) approach is found to be most efficient. Thus,
in this communication the synthesis of 2-chloro-quinoline
3-carbaldehyde 2 from N-aryl acetamides followed by
reaction with Vilsmeier reagent and transformation into
different functionalities. The required acetanilide 1 was
readily prepared from the reaction of corresponding ani-
lines with acetic anhydride in aqueous medium. The
Vilsmeier cyclization of acetanilide 1 was carried out by
adding phosphorus oxychloride to the N-aryl acetamides in
DMF at 0–5°C followed by heating at 90°C to afford
2-chloro 3-carbaldehyde 2 in good yield. The IR spectra of
compound 2 showed a strong absorption in the range of
1,680–1,696 cm-1 for the aldehydic group. The carbalde-
hyde group in quinolines 2 was also transformed into other
functionalities to afford new quinolines which are equally
important synthons for the synthesis of fused quinoline
systems. Thus, carbaldehyde group in quinolines 2 was
converted into substituted quinoline Schiff base derivatives
4a–l in ethanol at refluxed temperature. Schiff base com-
pounds 4a–l showed most prominent peak of imine func-
tion group (–C=N–) at 1,658 cm-1.The substituted Schiff
base derivatives 4a–l also reacted with chloroacetylchlo-
ride in the presence of triethylamine which act as a catalyst
in 1,4 dioxane to undergo cyclization to obtain quinoline
azetidin-2-one derivatives 5a–l. The IR spectrum of com-
pounds 5a–l showed sharp peak near 1,731 cm-1 indicates
the presence of ketone (–C=O) functional group of aze-
tidinone ring. A corresponding peak of C–N–CO was
observed at 1,530 cm-1. Chlorine functional group exhib-
Antimicrobial activity
The antimicrobial bioassay results summarized in Tables 1
and 2 revealed that some of the newly synthesized aze-
tidinone or thiazolidinone analogues indicated excellent
growth inhibitory profiles. It is worth to mention that
thiazolidinone analogues were displayed better activity
against the mentioned microorganisms that of azetidinone
analogues. The minimum inhibitory concentration (MIC)
profiles of thiazolidinone analogues were also strong than
that of the azetidinone class. It was observed that both the
class of newly synthesized analogues with electro-with-
drawing nitro and electro-withdrawing halo (–Cl, –F)
substituent demonstrated potential antimicrobial properties.
From the bioassay it can be stated that all the final
analogues with electro-donating alkyl (–CH3) substituent
were inactive against all the mentioned bacterial and fungal
strains. However, compounds with unsubstituted amino
1
ited a peak at 760 cm-1. The H NMR spectra of com-
pounds 5a–l showed the signal at 5.70 ppm due to –CH–Cl
on azetidinone ring. Doublets was observed at 6.90 ppm
due to CH–N proton on azetidinone ring, 2.24 ppm due to
the presence of –CH3 group at phenyl ring and aromatic
protons resonated in the range of 6.90–8.08 ppm. In the 1H
NMR spectra of the final compounds, a peak obtained as
doublet of doublet in the range 7.88–7.95 ppm was
assigned due to the C-3 proton of the quinoline ring, as
well as a doublet of triplate was observed at 7.60–7.69 ppm
attributed to the C-6 quinoline proton. In addition, C-1,
C-2, and C-10 proton atoms of the quinoline ring were
appeared to resonate at around 7.49–7.55 and 7.72–7.86 ppm,
123

Med Chem Res
Table 1 In vitro antimicrobial study (MIC lg/mL) of azetidinone analogues (5a–l) MIC
23
Cl
22
13
O
21
20
6
3
10
12
9
8
N
19
5
4
1
2
14
15
N
7
Cl
11
18
17
16
CH3
24
Comp. (100 lg/disc)
R
Zone of inhibition [mm (MIC in lg/mL)]
Gram -ve
Gram ?ve
Fungal species
S. aureus
B. subtilis
E. coli
P. aeruginosa
A. niger
C. albicans
5a
5b
5c
5d
5e
5f
Aniline
\10 (100)
16 (100)
\10 (100)
17 (100)
20 (100)
25 (25)
25 (12.5)
24 (62.5)
25 (25)
21 (50)
23 (25)
23 (50)
30 (B1)
–
\10 (100)
\10 (100)
18 (100)
16 (100)
21 (62.5)
21 (50)
23 (50)
24 (12.5)
23 (12.5)
24 (12.5)
23 (25)
21 (50)
31 (B1)
–
\10 (100)
\10 (100)
14 (100)
15 (100)
22 (100)
22 (62.5)
20 (100)
21 (62.5)
21 (62.5)
22 (50)
23 (25)
24 (25)
32 (B1)
–
\10 (100)
\10 (100)
16 (100)
13 (100)
21 (62.5)
22 (50)
23 (12.5)
20 (50)
22 (25)
23 (25)
22 (50)
21 (50)
33 (B1)
–
\10 (100)
\10 (100)
20 (100)
\10 (100)
22 (50)
26 (50)
24 (50)
19 (100)
25 (62.5)
22 (100)
26 (25)
23 (62.5)
–
\10 (100)
\10 (100)
\10 (100)
19 (100)
20 (100)
19 (100)
19 (100)
18 (100)
20 (62.5)
21 (62.5)
24 (50)
23 (100)
–
2-Methyl aniline
3-Methyl aniline
4-Methyl aniline
2-Nitro aniline
3-Nitro aniline
4-Nitro aniline
2-Chloro aniline
3-Chloro aniline
4-Chloro aniline
4-Fluoro aniline
2-Amino 5-methyl thaizole
5g
5h
5i
5j
5k
5l
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
30 (B3)
–
33 (B1)
–
–
–
–
–
The MIC values were evaluated at concentration range of 3.12–100 lg/mL
Data values in bold letter represents the highest activity
functionality were also to be inactive in all the bioassay
studied. Final azetidinone-based analogues with electron
ortho-nitro (5e) and meta-nitro (5f) aniline substituent
indicated poor activity, but the presence of similar con-
stituents (6e, 6f) in thiazolidinone nucleus demonstrated
excellent activity against Staphylococcus aureus, Esche-
richia coli, and Pseudomonas aeruginosa at 12.5 lg/mL of
MIC, respectively. In addition, the insertion of electro-
withdrawing para-nitro aniline substituent to both of the
nucleus as azetidinone (5g) and thiazolidinone (6g) sys-
tems proved beneficial to display strong activity against
S. aureus and P. aeruginosa (12.5 lg/mL). However,
compound (6g) was also appeared with good inhibitory
efficacy against C. albicans fungi at 25 lg/mL of MIC.
Presence of electron-withdrawing ortho-chloro (5h) and
para-chloro (5j) substituents to the azetidinone ring system
display potential antigrowth activity against gram ?ve
strain B. subtilis at 12.5 lg/mL of MIC, whereas, similar
meta-halo-substituted aniline with thiazolidinone nucleus
demonstrated potential activity against the same strain at
similar concentration level. Compound (6j) with electron-
withdrawing para-chloro aniline-substituted was also effi-
cacious to inhibit B. subtilis at 12.5 lg/mL of MIC along
with similar efficacy against Aspergillus niger fungi.
Hence, it can be stated that all the newer analogues with
chloro functionality were active against gram ?ve strains
as well as fungal strains. Final analogues with strong
electro-negative fluoro substituents either in the form of
azetidinone (5k) or thiazolidinone (6k) class showed
diminished activity against both the type of fungal strains
at the MIC range 12.5–50 lg/mL. However, the MIC
profile exhibited by thiazolidinone class of fluro-based
analogues (6k) was excelled as compared to that of aze-
tidinone class. Final analogues with amino-heterocycles
with sulfur atom functionality showed good efficacy
against gram -ve E. coli strain at 25 lg/mL of MIC. All
the final potent analogues exhibited excellent inhibitory
zones against all the mentioned microorganisms with good
range as compared to that of standard drugs. Again, it will
suffice to mention that inhibitory zones displayed by
123

Med Chem Res
Table 2 In vitro antimicrobial study (MIC lg/mL) of thiazolidinone analogues (6a–l) MIC
11
Cl
22
21
S
20
O
23
12
8
9
N
19
7
N
14
4
13
10
3
2
15
16
5
6
18
17
1
CH3
24
Comp. (100 lg/disc)
R
Zone of inhibition [mm (MIC in lg/mL)]
Gram -ve
Gram ?ve
Fungal species
S. aureus
B. subtilis
E. coli
P. aeruginosa
A. niger
C. albicans
6a
6b
6c
6d
6e
6f
Aniline
17 (100)
\10 (100)
18 (100)
19 (100)
25 (25)
26 (12.5)
26 (12.5)
21 (50)
26 (25)
23 (50)
24 (25)
24 (50)
30 (B1)
–
\10 (100)
\10 (100)
17 (100)
19 (100)
21 (62.5)
22 (50)
23 (50)
23 (12.5)
24 (12.5)
24 (12.5)
23 (12.5)
23 (50)
31 (B1)
–
\10 (100)
\10 (100)
\10 (100)
17 (100)
24 (12.5)
22 (62.5)
21 (62.5)
21 (62.5)
22 (62.5)
23 (50)
23 (25)
24 (25)
32 (B1)
–
13 (100)
\10 (100)
16 (100)
20 (62.5)
25 (12.5)
24 (12.5)
25 (12.5)
21 (25)
23 (25)
24 (25)
24 (25)
22 (50)
33 (B1)
–
14 (100)
\10 (100)
19 (100)
\10 (100)
22 (50)
24 (25)
24 (12.5)
20 (62.5)
24 (50)
25 (12.5)
25 (12.5)
24 (62.5)
–
\10 (100)
\10 (100)
13 (100)
17 (100)
20 (100)
23 (25)
24 (25)
21 (62.5)
20 (100)
22 (50)
24 (25)
23 (100)
–
2-Methyl aniline
3-Methyl aniline
4-Methyl aniline
2-Nitro aniline
3-Nitro aniline
4-Nitro aniline
2-Chloro aniline
3-Chloro aniline
4-Chloro aniline
4-Fluoro aniline
2-Amino 5-methyl thaizole
6g
6h
6i
6j
6k
6l
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
30 (B3)
–
33 (B1)
–
–
–
–
–
The MIC values were evaluated at concentration range of 3.12–100 lg/mL
Data values in bold letter represents the highest activity
thiazolidinone analogues (24–26 mm) were better as
compared to that of azetidinone class (23–26 mm) with
respect to standard drugs (31–33 mm). All the remaining
analogues were displayed good-to-moderate activity with
the MIC range of 50–100 lg/mL (see Figs. 1, 2).
good inhibitory effect against H37Rv strain at 25 lg/mL of
MIC. Four of the final derivatives (5i, 5g, 6i, and 6g) with
either para-nitro or meta-chloro aniline substituent demon-
strated moderate inhibitory activity at 50 lg/mL of MIC,
while remaining derivatives were found inactive at the MIC
range ranging from 62.5 to 1,000 lg/mL.
Antituberculosis activity
The antimycobacterial biological screening was performed
using Lowenstein–Jensen (L–J) MIC method and it is
worthwhile to note that two derivatives, 5l with 2-amino
5-methyl thaizole moiety to the azetidinone class as well as
6k with electron-withdrawing and strong electro-negative
fluoro substituent within the thiazolidinone class exhibited
good inhibitory potential at 12.5 lg/mL of MIC against
H37Rv strain. The inhibitory potential of the said deriva-
tives was half-fold as compared to standard drugs
(Table 3). In addition, similar fluoro-derivative within the
azetidinone class (5k) as well as derivative 6l with 2-amino 5-
methyl thaizole within the thiazolidinone class appeared with
Experimental
Materials and methods
All the chemicals used in the synthesis were of analytical
grade. The melting points were determined in open capillary
on Veego (Model: VMP-D) electronic apparatus and are
uncorrected. The IR spectra (4,000–400 cm-1) of synthe-
sized compounds were recorded on Shimadzu 8400-S FT-IR
spectrophotometer with KBr pellets. Thin layer chroma-
tography was performed on microscopic glass slides
(2 9 7.5 cm) coated with silica gel-G, using appropriate
123

Med Chem Res
Fig. 1 Schematic diagram for
the synthesis of azetidinone and
thiazolidinone derivatives
DMF-POCl3
80-90 oC
CH3COOH
(CH3COO)2O
NHCOCH3
NH2
1
EtOH
Reflux
CHO
Cl
H2N
R
N
3a-l
2
H
C
N
R
N
Cl
4a-l
1,4 Dioxane
Et3N
ClCOCH2Cl
DMF/ZnCl2
Reflux
Reflux
SHCH2COOH
O
S
Cl
O
N
Cl HC
HC
N
R
N
N
Cl
R
6a-l
5a-l
Fig. 2 [(4a–l), R] Bases
coupled to compound 5a–l and
6a–l
H3C
H2N
5a and 6a
5c and 6c
H2N
5b and 6b
5d and 6d
CH3
H2N
CH3
NO2
H2N
O2N
5e and 6e H2N
5f and 6f
5h and 6h
H2N
H2N
Cl
5g and 6g
5i and 6i
5k and 6k
H2N
H2N
H2N
NO2
Cl
H2N
Cl
5j and 6j
5l and 6l
N
F
H2N
CH3
S
123

Med Chem Res
(Gillespie, 1994). The Mueller–Hinton agar media were
sterilized (autoclaved at 120°C for 30 min), poured at
uniform depth of 5 mm and allowed to solidify. The
microbial suspension (105 CFU/mL) (0.5 McFarland
Nephelometery Standards) was spread over the surface of
media using a sterile cotton swab to ensure even growth of
the organisms. The tested compounds were dissolved in
dimethyl sulfoxide to give solutions of 3.12–100 lg/mL.
Sterile filter paper discs measuring 6.25 mm in diameter
(Whatman no. 1 filter paper), previously soaked in a known
concentration of the respective test compound in dimethyl
sulfoxide were placed on the solidified nutrient agar
medium that had been inoculated with the respective
microorganism and the plates were incubated for 24 h at
(37 1)°C. A control disc impregnated with an equivalent
amount of dimethyl sulfoxide without any sample was also
used and did not produce any inhibition. Ciprofloxacin and
ketoconazole (100 lg/disc) were used as control drugs for
antibacterial and antifungal activities, respectively.
Table 3 In vitro antituberculosis activity
Entry
R
L–J MIC method
MIC
%
(lg/mL) Inhibition
5a
Aniline
500
1,000
500
200
250
100
50
90
91
90
94
92
93
96
97
98
95
98
99
92
90
90
94
93
94
97
95
97
96
99
98
99
99
5b
2-Methyl aniline
3-Methyl aniline
4-Methyl aniline
2-Nitro aniline
3-Nitro aniline
4-Nitro aniline
2-Chloro aniline
3-Chloro aniline
4-Chloro aniline
4-Fluoro aniline
5c
5d
5e
5f
5g
5h
62.5
50
5i
5j
100
25
5k
5l
2-Amino 5-methyl thaizole 12.5
6a
Aniline
250
500
500
250
200
100
50
6b
2-Methyl aniline
3-Methyl aniline
4-Methyl aniline
2-Nitro aniline
3-Nitro aniline
4-Nitro aniline
2-Chloro aniline
3-Chloro aniline
4-Chloro aniline
4-Fluoro aniline
To determine the MIC (Hawkey and Lewis, 1994), agar
streak dilution method was used in which a stock solution of
the synthesized compound (100 lg/mL) in dimethyl sulf-
oxide was prepared and graded quantities of the test com-
pounds were incorporated in a specified quantity of molten
sterile agar, i.e., nutrient agar for evaluation of antibacterial
and Sabouraud dextrose agar for antifungal activity, respec-
tively. The medium containing the test compound was poured
into a Petri dish at a depth of 4–5 mm and allowed to solidify
under aseptic conditions. A suspension of the respective
microorganism of approximately 105 CFU/mL was prepared
and applied to plates with serially diluted compounds with
concentrations in the range of 3.12–100 lg/mL in dimethyl
sulfoxide and incubated at (37 1)°C for 24 h (bacteria) or
48 h (fungi). The lowest concentration of the substance that
preventsthe developmentofvisible growthisconsidered tobe
the MIC value.
6c
6d
6e
6f
6g
6h
100
50
6i
6j
62.5
12.5
6k
6l
2-Amino 5-methyl thaizole 25
3.12
6.25
Ethambutol
Pyrazinamide
mobile phase system and spots were visualized under UV
radiation. Nuclear magnetic resonance spectra were recor-
ded on Varian 400 MHz model spectrometer using dimeth-
ylsulfoxide (DMSO) as a solvent and TMS as internal
standard (Chemical shifts in d ppm). The mass spectra were
recorded on JOEL SX-102 model and were performed at
CDRI, Lucknow. Elemental analyses (C, H, N) were per-
formed using a Heraeus Carlo Erba 1180 CHN analyzer
(Hanau, Germany). All the novel compounds gave C, H, and
N analyses within 0.2 % points from the theoretical values.
Methods for in vitro antituberculosis evaluations of the
newer analogues
In vitro antituberculosis activity assay was carried
out using L–J MIC method against Mycobacterium
tuberculosis H37Rv and the results are expressed in terms
of MIC (Isenberg, 1992). Stock solutions of primary 1,000,
500, 250 lg/mL, and secondary 200, 100, 62.5, 50, 25,
12.5, 6.25, 3.25 lg/mL dilutions of each test compound in
DMSO were added in the liquid L–J medium and then
media were sterilized by inspissation method. A culture of
M. tuberculosis H37Rv growing on L–J medium was har-
vested in 0.85 % saline in bijou bottles. These tubes were
then incubated at (37 1)°C for 24 h followed by
streaking of M. tuberculosis H37Rv (5 9 104 bacilli per
tube). These tubes were then incubated at (37 1)°C.
Methods for in vitro antimicrobial evaluations of the
newer analogues
The synthesized azetidinone and thiazolidinone derivatives
(5a–l and 6a–l) were examined for antimicrobial activity
against several bacteria (S. aureus MTCC 96, B. subtilis
MTCC 430, E. coli MTCC 739, P. aeruginosa MTCC 741)
and fungi (A. niger MTCC 282, Candida albicans MTCC
183) species using the paper disc diffusion technique
123

Med Chem Res
Growth of bacilli was seen after 12, 22, and finally 28 days
of incubation. Tubes having the compounds were com-
pared with control tubes where medium alone was incu-
bated with M. tuberculosis H37Rv. The concentration at
which no development of colonies occurred or \20 colo-
nies was taken as MIC concentration of test compound.
The standard strain M. tuberculosis H37Rv was tested with
known drugs ethambutol and pyrazinamide.
760 (C–Cl). 1H NMR (400 MHz, DMSO-d6) d 5.70
(d, J = 6.5 Hz, 1H, CH–Cl at azetidinone ring), 6.90
(d, J = 6.6 Hz, 1H, CH–N at azetidinone ring), 7.20–7.35 (m,
5H, Ar–H), 7.52 (m, J = 1.6 Hz, 1H, C-1 proton of quino-
line), 7.64 (dt, J = 7.5, 1.7 Hz, 1H, C-6 proton of quinoline),
7.77–7.80 (m, 2H, C-2, and C-10 proton of quinoline), 7.94
(dd, J = 8.0, 1.5 Hz, 1H, C-3 proton of quinoline). 13C NMR
(400 MHz, DMSO-d6) d 61.78 (1C, C-21, C–Cl of b-lactam
ring), 67.37 (1C, C-12, –Ar–azetidinone ring linkage),
146.78–119.22 (14C, Ar–C), 149.51 (1C, C-8, C–Cl of
quinoline ring), 165.57 (1C, C-20, C=O). EMI–MS (m/z):
344.74 (M?). Anal. Calcd. for C18H12Cl2N2O: C, 62.99; H,
3.52; N, 8.16. Found: C, 62.90; H, 3.61; N, 8.21.
General procedure for the synthesis of 2-chloro-
quinoline 3-carbaldehyde (2)
To a solution of 1 (15 g, 0.05 mol) in dry DMF (24.5 mL,
0.15 mol) at 0–5°C with stirring POCl3 (204.1 mL,
0.6 mol) was added dropwise and the mixture stirred at
80–90°C for time ranging between 4 and 15 h. The mixture
was poured into crushed ice, stirred for 5 min and the
resulting solid filtered, washed well with water, and dried.
The compounds were purified by recrystallization from
either ethyl acetate or acetonitrile. Yield: 85 %, m.p. 146–
149°C (dec.). IR (KBr) cm-1: 1,680–1,696 cm-1 (–CHO).
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-o-tolyl-azetidin-
2-one (5b)
Yield: 75 %. m.p. 261–263°C (DMF). IR (KBr) cm-1
:
1,734 (C=O of b-lactam ring), 1,580 (C=C), 1,533 (C–N),
770 (C–Cl). 1H NMR (400 MHz, DMSO-d6) d 2.13 (s, 3H,
Ar–CH3), 5.75 (d, J = 6.7 Hz, 1H, CH–Cl at azetidinone
ring), 6.91 (d, J = 6.4 Hz, 1H, CH–N at azetidinone ring),
7.01–7.35 (m, 4H, Ar–H), 7.53 (m, J = 1.4 Hz, 1H, C-1
proton of quinoline), 7.64 (dt, J = 7.7, 1.5 Hz, 1H, C-6
proton of quinoline), 7.76–7.83 (m, 2H, C-2, and C-10
proton of quinoline), 7.93 (dd, J = 8.1, 1.7 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
22.59 (1C, C-26, C–CH3), 62.43 (1C, C-21, C–Cl of
b-lactam ring), 67.93 (1C, C-12, –Ar.–azetidinone ring
linkage), 145.81–120.45 (14C, Ar–C), 147.56 (1C, C-8,
C–Cl of quinoline ring), 166.17 (1C, C-20, C=O). EMI–MS
(m/z): 358.86 (M?). Anal. Calcd. for C19H14Cl2N2O: C,
63.88; H, 3.95; N, 7.84. Found: C, 63.94; H, 3.90; N, 7.93.
General procedure for the synthesis of (2-chloro-
quinoline-3-yl-methylene)-phenyl-substituted amine
(4a–l)
2-Chloro-quinoline 3-carbaldehyde (0.01 mol) 2, substi-
tuted aromatic amine 3a–l (0.01 mol) were taken in ethanol
with catalytic amount of conc. H2SO4 (2 mL) and heated to
refluxed for 6–7 h. After conclusion of the reaction (TLC),
the reaction mixture was poured onto crushed ice; the solid
mass thus separated out was filtered, washed with water,
and dried to give desired compounds 4a–l. The compounds
were purified by recrystallization from ethanol.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-m-tolyl-azetidin-
2-one (5c)
General procedure for preparation of compounds (5a–l)
A mixture of (2-chloro-quinoline-3-yl-methylene)-phenyl-
substituted amine 4a–l (0.01 mol) and triethylamine
(0.02 mol) was dissolved in 1,4-dioxane (50 mL). To this
well-stirred cooled solution, chloroacetylchloride (0.02 mol)
was added dropwise during 30 min. The reaction mixture was
then stirred for further 1 h and refluxing for 10 h. the trieth-
ylamine hydrochloride salt formed was filtered to separate the
salt. The filtrate was concentrated to half of its initial volume
and then poured onto crushed ice. The product obtained was
filtered, washed with water, and recrystallized from DMF.
Yield: 70 %. m.p. 255–257°C (DMF). IR (KBr) cm-1
:
1,736 (C=O of b-lactam ring), 1,585 (C=C), 1,529 (C–N),
773 (C–Cl). 1H NMR (400 MHz, DMSO-d6) d 2.25 (s, 3H,
Ar–CH3), 5.71 (d, J = 6.6 Hz, 1H, CH–Cl at azetidinone
ring), 6.89 (d, J = 6.5 Hz, 1H, CH–N at azetidinone ring),
7.05–7.39 (m, 4H, Ar–H), 7.50 (m, J = 1.7 Hz, 1H, C-1
proton of quinoline), 7.61 (dt, J = 7.6, 1.7 Hz, 1H, C-6
proton of quinoline), 7.73–7.81 (m, 2H, C-2, and C-10
proton of quinoline), 7.91 (dd, J = 7.9, 1.6 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
24.87 (1C, C-26, C–CH3), 61.37 (1C, C-21, C–Cl of
b-lactam ring), 69.70 (1C, C-12, –Ar.–azetidinone ring
linkage), 146.91–114.56 (14C, –Ar–C), 149.29 (1C, C-8,
C–Cl of quinoline ring), 164.95 (1C, C-20, C=O). EMI–MS
(m/z): 358.73 (M?). Anal. Calcd. for C19H14Cl2N2O: C,
63.88; H, 3.95; N, 7.84. Found: C, 63.80; H, 3.87; N, 7.91.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-phenyl-azetidin-
2-one (5a)
Yield: 77 %. m.p. 240–243°C (DMF). IR (KBr) cm-1
1,731 (C=O of b-lactam ring), 1,589 (C=C), 1,531 (C–N),
:
123

Med Chem Res
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-p-tolyl-azetidin-
2-one (5d)
C-21, C–Cl of b-lactam ring), 68.90 (1C, C-12,
–Ar.–azetidinone ring linkage), 150.62–112.09 (13C, Ar–C),
147.21 (1C, C-8, C–Cl of quinoline ring), 149.93 (1C, C-13,
C–NO2), 163.78 (1C, C-20, C=O). EMI–MS (m/z): 389.63
(M?). Anal. Calcd. for C18H11Cl2N3O3: C, 55.69; H, 2.86; N,
10.82. Found: C, 55.65; H, 2.81; N, 10.85.
Yield: 73 %. m.p. 263–264°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam ring), 1,571 (C=C), 1,527 (C–N),
767 (C–Cl). 1H NMR (400 MHz, DMSO-d6) d 2.35 (s, 3H,
Ar–CH3), 5.77 (d, J = 6.8 Hz, 1H, CH–Cl at azetidinone
ring), 6.90 (d, J = 6.4 Hz, 1H, CH–N at azetidinone ring),
6.85–7.15 (m, 4H, Ar–H), 7.52 (m, J = 1.6 Hz, 1H, C-1
proton of quinoline), 7.63 (dt, J = 7.8, 1.6 Hz, 1H, C-6
proton of quinoline), 7.75–7.83 (m, 2H, C-2, and C-10
proton of quinoline), 7.94 (dd, J = 8.2, 1.4 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
25.41 (1C, C-26, C–CH3), 62.65 (1C, C-21, C–Cl of
b-lactam ring), 69.98 (1C, C-12, –Ar.–azetidinone ring
linkage), 147.75–127.32 (14C, Ar–C), 149.29 (1C, C-8,
C–Cl of quinoline ring), 165.33 (1C, C-20, C=O). EMI–MS
(m/z): 358.79 (M?).Anal. Calcd. for C19H14Cl2N2O: C,
63.88; H, 3.95; N, 7.84. Found: C, 63.84; H, 3.91; N, 7.86.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-(4-nitro-phenyl)-
azetidin-2-one (5g)
Yield: 67 %. m.p. 262–264°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam ring), 1,591 (C=C), 1,536 (C–N),
1
762 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.70 (d,
J = 6.5 Hz, 1H, CH–Cl at azetidinone ring), 7.09 (d,
J = 6.7 Hz, 1H, CH–N at azetidinone ring), 6.95–8.09 (m,
4H, Ar–H), 7.54 (m, J = 1.7 Hz, 1H, C-1 proton of quin-
oline), 7.65 (dt, J = 7.5, 1.5 Hz, 1H, C-6 proton of quin-
oline), 7.75–7.81 (m, 2H, C-2, and C-10 proton of
quinoline), 7.93 (dd, J = 8.1, 1.5 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 60.29 (1C,
C-21, C–Cl of b-lactam ring), 68.37 (1C, C-12,
–Ar.–azetidinone ring linkage), 149.41–122.62 (13C, Ar–C),
145.95 (1C, C-13, C–NO2), 148.29 (1C, C-8, C–Cl of quin-
oline ring), 162.98 (1C, C-20, C=O). EMI–MS (m/z): 389.79
(M?). Anal. Calcd. for C18H11Cl2N3O3: C, 55.69; H, 2.86; N,
10.82. Found: C, 55.73; H, 2.94; N, 10.73.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-(2-nitro-phenyl)-
azetidin-2-one (5e)
Yield: 68 %. m.p. 270–271°C (DMF). IR (KBr) cm-1
:
1,737 (C=O of b-lactam ring), 1,577 (C=C), 1,538 (C–N),
1
769 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.67 (d,
J = 6.6 Hz, 1H, CH–Cl at azetidinone ring), 7.09 (d,
J = 6.7 Hz, 1H, CH–N at azetidinone ring), 7.37–8.31 (m,
4H, Ar–H), 7.54 (m, J = 1.8 Hz, 1H, C-1 proton of quin-
oline), 7.66 (dt, J = 7.5, 1.4 Hz, 1H, C-6 proton of quin-
oline), 7.73–7.81 (m, 2H, C-2, and C-10 proton of
quinoline), 7.94 (dd, J = 8.0, 1.5 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 60.59 (1C,
C-21, C–Cl of b-lactam ring), 69.56 (1C, C-12,
–Ar.–azetidinone ring linkage), 147.09–121.31 (13C,
Ar–C), 145.01 (1C, C-8, C–Cl of quinoline ring), 148.27 (1C,
C-13, C–NO2), 166.58 (1C, C-20, C=O). EMI–MS (m/z):
389.56 (M?). Anal. Calcd. for C18H11Cl2N3O3: C, 55.69; H,
2.86; N, 10.82. Found: C, 55.73; H, 2.84; N, 10.85.
3-Chloro-1-(2-chloro-phenyl)-4-(2-chloro-quinoline-3-yl)-
azetidin-2-one (5h)
Yield: 73 %. m.p. 280–281°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam ring), 1,592 (C=C), 1,533 (C–N),
1
777 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.73 (d,
J = 6.4 Hz, 1H, CH–Cl at azetidinone ring), 6.80 (d,
J = 6.5 Hz, 1H, CH–N at azetidinone ring), 7.10–7.87 (m,
4H, Ar–H), 7.52 (m, J = 1.4 Hz, 1H, C-1 proton of quin-
oline), 7.68 (dt, J = 7.2, 1.7 Hz, 1H, C-6 proton of quin-
oline), 7.73–7.82 (m, 2H, C-2, and C-10 proton of
quinoline), 7.91 (dd, J = 8.0, 1.6 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 60.29
(1C, C-21, C–Cl of b-lactam ring), 68.37 (1C, C-12,
–Ar.–azetidinone ring linkage), 149.41–122.62 (14C,
Ar–C), 148.29 (1C, C-8, C–Cl of quinoline ring), 165.98
(1C, C-20, C=O). EMI–MS (m/z): 378.89 (M?). Anal.
Calcd. for C18H11Cl3N2O: C, 57.25; H, 2.94; N, 7.42.
Found: C, 57.33; H, 2.89; N, 7.49.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-(3-nitro-phenyl)-
azetidin-2-one (5f)
Yield: 65 %. m.p. 275–277°C (DMF). IR (KBr) cm-1
:
1,733 (C=O of b-lactam ring), 1,580 (C=C), 1,533 (C–N),
1
773 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.63 (d,
J = 6.3 Hz, 1H, CH–Cl at azetidinone ring), 7.03 (d,
J = 6.5 Hz, 1H, CH–N at azetidinone ring), 7.53–8.20 (m,
4H, Ar–H), 7.51 (m, J = 1.6 Hz, 1H, C-1 proton of quin-
oline), 7.62 (dt, J = 7.2, 1.2 Hz, 1H, C-6 proton of quin-
oline), 7.73–7.79 (m, 2H, C-2, and C-10 proton of
quinoline), 7.90 (dd, J = 7.8, 1.6 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 61.12 (1C,
3-Chloro-1-(3-chloro-phenyl)-4-(2-chloro-quinoline-3-yl)-
azetidin-2-one (5i)
Yield: 68 %. m.p. 269–270°C (DMF). IR (KBr) cm-1
:
1,733 (C=O of b-lactam ring), 1,595 (C=C), 1,540 (C–N),
1
766 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.68 (d,
123

Med Chem Res
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-(5-methyl-thiazol-
2-yl)-azetidin-2-one (5l)
J = 6.1 Hz, 1H, CH–Cl at azetidinone ring), 6.94 (d,
J = 6.3 Hz, 1H, CH–N at azetidinone ring), 7.04–7.69 (m,
4H, Ar–H), 7.55 (m, J = 1.3 Hz, 1H, C-1 proton of quin-
oline), 7.64 (dt, J = 7.4, 1.5 Hz, 1H, C-6 proton of quin-
oline), 7.74–7.81 (m, 2H, C-2, and C-10 proton of
quinoline), 7.89 (dd, J = 7.8, 1.4 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 60.98 (1C,
C-21, C–Cl of b-lactam ring), 68.01 (1C, C-12,
–Ar.–azetidinone ring linkage), 146.23–117.95 (14C,
Ar–C), 148.56 (1C, C-8, C–Cl of quinoline ring), 162.71
(1C, C-20, C=O of b-lactam ring). EMI–MS (m/z): 378.80
(M?).Anal. Calcd. for C18H11Cl3N2O: C, 57.25; H, 2.94;
N, 7.42. Found: C, 57.20; H, 2.92; N, 7.48.
Yield: 59 %. m.p. 295–296°C (DMF). IR (KBr) cm-1
:
1,731 (C=O of b-lactam ring), 1,539 (C–N), 762 (C–Cl),
1
650 (C–S-C). H NMR (400 MHz, DMSO-d6) d 2.41 (s,
3H, Ar–CH3 at thaizole ring), 5.73 (d, J = 6.7 Hz, 1H,
CH–Cl at azetidinone ring), 6.96 (d, J = 6.5 Hz, 1H,
CH–N at azetidinone ring), 7.21 (d, 1H, Ar–H at thaizole
ring), 7.52 (m, J = 1.7 Hz, 1H, C-1 proton of quinoline),
7.69 (dt, J = 7.7, 1.5 Hz, 1H, C-6 proton of quinoline),
7.75–7.83 (m, 2H, C-2, and C-10 proton of quinoline), 7.93
(dd, J = 8.0, 1.6 Hz, 1H, C-3 proton of quinoline). 13C
NMR (400 MHz, DMSO-d6) d 14.77 (1C, C–CH3 in sulfur
heterocycle), 60.21 (1C, C-15, C–Cl of b-lactam ring),
64.56 (1C, C-12, –Ar.–azetidinone ring linkage), 122.81–
145.96 (10C, Ar–C), 147.88 (1C, C-8, C–Cl of quinoline
ring), 158.07 (1C, C-20, -N–C at azetidinone-heterocyclic
coupling ring), 159.26 (1C, C-14, C=O). EMI–MS (m/z):
365.59 (M?). Anal. Calcd. for C16H11Cl2N3OS: C, 52.76;
H, 3.04; N, 11.54. Found: C, 52.82; H, 3.10; N, 11.49.
3-Chloro-1-(4-chloro-phenyl)-4-(2-chloro-quinoline-3-yl)-
azetidin-2-one (5j)
Yield: 73 %. m.p. 253–254°C (DMF). IR (KBr) cm-1
:
1,733 (C=O of b-lactam ring), 1,576 (C=C), 1,539 (C–N),
1
770 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.71 (d,
J = 6.3 Hz, 1H, CH–Cl at azetidinone ring), 6.91 (d,
J = 6.5 Hz, 1H, CH–N at azetidinone ring), 7.32 (m, 4H,
Ar–H), 7.53 (m, J = 1.6 Hz, 1H, C-1 proton of quinoline),
7.61 (dt, J = 7.7, 1.6 Hz, 1H, C-6 proton of quinoline),
7.71–7.79 (m, 2H, C-2, and C-10 proton of quinoline), 7.87
(dd, J = 8.1, 1.7 Hz, 1H, C-3 proton of quinoline). 13C
NMR (400 MHz, DMSO-d6) d 60.59 (1C, C-21, C–Cl of
b-lactam ring), 68.35 (1C, C-12, –Ar.–azetidinone ring
linkage), 145.31–119.91 (14C, Ar–C), 148.78 (1C, C-8,
C–Cl of quinoline ring), 163.11 (1C, C-20, C=O). EMI–MS
(m/z): 378.92 (M?).Anal. Calcd. for C18H11Cl3N2O: C,
57.25; H, 2.94; N, 7.42. Found: C, 57.21; H, 2.86; N, 7.38.
General procedure for preparation of compounds (6a–l)
A mixture of (2-chloro-quinoline-3-yl-methylene)-phenyl-
substituted amine 4a–l (0.01 mol) and catalytic amount of
zinc chloride (0.05 g) in DMF was taken in Dean stark
apparatus and to it thioglycolic acid (0.02 mol) in DMF
was added slowly. The reaction mass was refluxed for 12 h
the DMF was distilled off to get the solid mixture. This was
then treated with an excess of 10 % sodium bicarbonate
solution to remove excess of thioglycolic acid. The product
obtained was filtered, washed several times with water, and
recrystallized from DMF.
3-Chloro-4-(2-chloro-quinoline-3-yl)-1-(4-fluoro-phenyl)-
azetidin-2-one (5k)
2-(2-Chloro-quinoline-3-yl)-3-phenyl-thiazolidin-4-one
(6a)
Yield: 66 %. m.p. 290–292°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam ring), 1,593 (C=C), 1,541 (C–N),
773 (C–Cl). H NMR (400 MHz, DMSO-d6) d 5.75 (d,
Yield: 63 %. m.p. 245–247°C (DMF). IR (KBr) cm-1
:
1
1,734 (C=O of b-lactam), 1,588 (C=C), 1,536 (C–N), 761
(C–Cl), 621 (C–S-C). H NMR (400 MHz, DMSO-d6) d
J = 6.5 Hz, 1H, CH–Cl at azetidinone ring), 6.93 (d,
J = 6.6 Hz, 1H, CH–N at azetidinone ring), 7.11–7.29 (m,
4H, Ar–H), 7.54 (m, J = 1.5 Hz, 1H, C-1 proton of quin-
oline), 7.63 (dt, J = 7.9, 1.7 Hz, 1H, C-6 proton of quin-
oline), 7.73–7.80 (m, 2H, C-2, and C-10 proton of
quinoline), 7.90 (dd, J = 8.3, 1.5 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 60.59
(1C, C-21, C–Cl of b-lactam ring), 68.35 (1C, C-12,
–Ar.–azetidinone ring linkage), 145.31–119.91 (14C,
Ar–C), 148.78 (1C, C-8, C–Cl of quinoline ring), 163.11
(1C, C-20, C=O). EMI–MS (m/z): 362.71 (M?). Anal.
Calcd. for C18H11Cl2FN2O: C, 59.85; H, 3.07; N, 7.76.
Found: C, 59.81; H, 3.12; N, 7.80.
1
3.93 (dd, J = 12.3 Hz, 2H, CH–S at thiazolidinone ring),
6.49 (s, J = 6.5 Hz, 1H, CH–N at thiazolidinone ring),
7.17–7.39 (m, 5H, Ar–H), 7.48 (m, J = 1.6 Hz, 1H, C-1
proton of quinoline), 7.63 (dt, J = 7.6, 1.5 Hz, 1H, C-6
proton of quinoline), 7.73–7.79 (m, 2H, C-2, and C-10
proton of quinoline), 7.89 (dd, J = 7.8, 1.6 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
36.92 (1C, C-22, S–C at thiazolidinone ring), 57.87 (1C, C-
12, –Ar.–thiazolidinone ring linkage), 148.23–125.34
(14C, Ar–C), 150.88 (1C, C-8, C–Cl at quinoline ring),
172.35 (1C, C-20, C=O). EMI–MS (m/z): 342.15 (M?).
123

Med Chem Res
Anal. Calcd. for C18H13ClN2OS: C, 63.43; H, 3.84; N,
8.22. Found: C, 63.40; H, 3.89; N, 8.28.
thiazolidinone ring), 7.01–7.37 (m, 4H, Ar–H), 7.44 (m,
J = 1.8 Hz, 1H, C-1 proton of quinoline), 7.64 (dt,
J = 7.5, 1.5 Hz, 1H, C-6 proton of quinoline), 7.74–7.81
(m, 2H, C-2, and C-10 proton of quinoline), 7.91 (dd,
J = 8.0, 1.5 Hz, 1H, C-3 proton of quinoline). 13C NMR
(400 MHz, DMSO-d6) d 21.89 (1C, C-24, C–CH3), 36.77
(1C, C-22, S–C at thiazolidinone ring), 58.05 (1C, C-12,
–Ar.–thiazolidinone ring linkage), 148.89–123.31 (14C,
Ar–C), 151.21 (1C, C-8, C–Cl at quinoline ring), 173.09
(1C, C-20, C=O). EMI–MS (m/z): 356.19 (M?). Anal.
Calcd. for C19H15ClN2OS: C, 64.31; H, 4.26; N, 7.89.
Found: C, 64.25; H, 4.21; N, 7.95.
2-(2-Chloro-quinoline-3-yl)-3-o-tolyl-thiazolidin-4-one
(6b)
Yield: 67 %. m.p. 265–266°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam), 1,596 (C=C), 1,536 (C–N), 767
1
(C–Cl), 625 (C–S-C). H NMR (400 MHz, DMSO-d6) d
2.15 (s, 3H, Ar–CH3), 3.95 (dd, J = 12.5 Hz, 2H, CH–S at
thiazolidinone ring), 6.47 (s, J = 6.6 Hz, 1H, CH–N at
thiazolidinone ring), 7.01–7.31 (m, 4H, Ar–H), 7.45 (m,
J = 1.7 Hz, 1H, C-1 proton of quinoline), 7.65 (dt,
J = 7.8, 1.6 Hz, 1H, C-6 proton of quinoline), 7.73–7.79
(m, 2H, C-2, and C-10 proton of quinoline), 7.94 (dd,
J = 8.0, 1.5 Hz, 1H, C-3 proton of quinoline). 13C NMR
(400 MHz, DMSO-d6) d 18.21 (1C, C-24, C–CH3), 36.11
(1C, C-22, S–C at thiazolidinone ring), 58.67 (1C, C-12,
–Ar.–thiazolidinone ring linkage), 147.61–124.88 (14C,
Ar–C), 151.65 (1C, C-8, C–Cl at quinoline ring), 173.53
(1C, C-20, C=O). EMI–MS (m/z): 356.23 (M?). Anal.
Calcd. for C19H15ClN2OS: C, 64.31; H, 4.26; N, 7.89.
Found: C, 64.36; H, 4.31; N, 7.85.
2-(2-Chloro-quinoline-3-yl)-3-(2-nitro-phenyl)-thiazolidin-
4-one (6e)
Yield: 78 %. m.p. 257–258°C (DMF). IR (KBr) cm-1
:
1,741 (C=O of b-lactam), 1,576 (C=C), 1,539 (C–N), 774
1
(C–Cl), 621 (C–S-C). H NMR (400 MHz, DMSO-d6) d
3.88 (dd, J = 11.9 Hz, 2H, CH–S at thiazolidinone ring),
6.47 (s, J = 6.8 Hz, 1H, CH–N at thiazolidinone ring),
7.43–8.35 (m, 4H, Ar–H), 7.49 (m, J = 1.4 Hz, 1H, C-1
proton of quinoline), 7.68 (dt, J = 7.7, 1.3 Hz, 1H, C-6
proton of quinoline), 7.78–7.86 (m, 2H, C-2, and C-10
proton of quinoline), 7.88 (dd, J = 7.9, 1.4 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
35.23 (1C, C-22, S–C at thiazolidinone ring), 58.26 (1C,
C-12, –Ar.–thiazolidinone ring linkage), 148.26–124.85
(13C, Ar–C), 145.03 (1C, C-13, C–NO2), 150.96 (1C, C-8,
C–Cl at quinoline ring), 174.02 (1C, C-20, C=O). EMI–MS
(m/z): 387.09 (M?). Anal. Calcd. for C18H12ClN3O3S: C,
56.03; H, 3.13; N, 10.89. Found: C, 56.07; H, 3.10; N, 10.93.
2-(2-Chloro-quinoline-3-yl)-3-m-tolyl-thiazolidin-4-one
(6c)
Yield: 63 %. m.p. 259–260°C (DMF). IR (KBr) cm-1
:
1,739 (C=O of b-lactam), 1,581 (C=C), 1,538 (C–N), 769
1
(C–Cl), 631 (C–S-C). H NMR (400 MHz, DMSO-d6) d
2.30 (s, 3H, Ar–CH3), 3.95 (dd, J = 12.4 Hz, 2H, CH–S at
thiazolidinone ring), 6.41 (s, J = 6.4 Hz, 1H, CH–N at
thiazolidinone ring), 7.05–7.37 (m, 4H, Ar–H), 7.47 (m,
J = 1.5 Hz, 1H, C-1 proton of quinoline), 7.69 (dt,
J = 7.6, 1.7 Hz, 1H, C-6 proton of quinoline), 7.77–7.86
(m, 2H, C-2, and C-10 proton of quinoline), 7.95 (dd,
J = 8.1, 1.7 Hz, 1H, C-3 proton of quinoline). 13C NMR
(400 MHz, DMSO-d6) d 22.25 (1C, C-24, C–CH3), 36.55
(1C, C-22, S–C at thiazolidinone ring), 58.86 (1C, C-12,
–Ar.–thiazolidinone ring linkage), 148.23–121.56 (14C,
Ar–C), 150.77 (1C, C-8, C–Cl at quinoline ring), 172.83
(1C, C-20, C=O). EMI–MS (m/z): 356.34 (M?). Anal.
Calcd. for C19H15ClN2OS: C, 64.31; H, 4.26; N, 7.89.
Found: C, 64.37; H, 4.21; N, 7.92.
2-(2-Chloro-quinoline-3-yl)-3-(3-nitro-phenyl)-thiazolidin-
4-one (6f)
Yield: 57 %. m.p. 283–285°C (DMF). IR (KBr) cm-1
:
1,739 (C=O of b-lactam), 1,579 (C=C), 1,537 (C–N), 776
1
(C–Cl), 619 (C–S-C). H NMR (400 MHz, DMSO-d6) d
3.87 (dd, J = 12.2 Hz, 2H, CH–S at thiazolidinone ring),
6.43 (s, J = 6.6 Hz, 1H, CH–N at thiazolidinone ring),
7.51–8.20 (m, 4H, Ar–H), 7.46 (m, J = 1.7 Hz, 1H, C-1
proton of quinoline), 7.66 (dt, J = 7.5, 1.6 Hz, 1H, C-6
proton of quinoline), 7.73–7.81 (m, 2H, C-2, and C-10
proton of quinoline), 7.86 (dd, J = 8.1, 1.5 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
35.89 (1C, C-22, S–C at thiazolidinone ring), 56.93 (1C, C-
12, –Ar.–thiazolidinone ring linkage), 149.81–119.57
(13C, Ar–C), 148.03 (1C, C-18, C–NO2), 151.08 (1C, C-8,
C–Cl at quinoline ring), 173.63 (1C, C-20, C=O). EMI–MS
(m/z): 387.13 (M?). Anal. Calcd. for C18H12ClN3O3S: C,
56.03; H, 3.13; N, 10.89. Found: C, 56.01; H, 3.19; N,
10.83.
2-(2-Chloro-quinoline-3-yl)-3-p-tolyl-thiazolidin-4-one
(6d)
Yield: 67 %. m.p. 269–271°C (DMF). IR (KBr) cm-1
:
1,736 (C=O of b-lactam), 1,579 (C=C), 1,532 (C–N), 773
1
(C–Cl), 629 (C–S-C). H NMR (400 MHz, DMSO-d6) d
2.37 (s, 3H, Ar–CH3), 3.93 (dd, J = 12.6 Hz, 2H, CH–S at
thiazolidinone ring), 6.47 (s, J = 6.7 Hz, 1H, CH–N at
123

Med Chem Res
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
37.55 (1C, C-22, S–C at thiazolidinone ring), 57.97 (1C,
C-12, –Ar.–thiazolidinone ring linkage), 148.11–124.63
(1C, 14C, Ar–C), 149.68 (1C, C-8, C–Cl at quinoline ring),
174.03 (1C, C-20, C=O). EMI–MS (m/z): 376.59 (M?).
Anal. Calcd. for C18H12Cl2N2OS: C,57.61; H, 3.22; N,
7.46. Found: C, 57.69; H, 3.25; N, 7.50.
2-(2-Chloro-quinoline-3-yl)-3-(4-nitro-phenyl)-thiazolidin-
4-one (6g)
Yield: 59 %; m.p. 249–250°C (DMF). IR (KBr) cm-1
1,740 (C=O of b-lactam), 1,575 (C=C), 1,538 (C–N), 780
:
1
(C–Cl), 627 (C–S-C). H NMR (400 MHz, DMSO-d6) d
3.91 (dd, J = 12.0 Hz, 2H, CH–S at thiazolidinone ring),
6.46 (s, J = 6.7 Hz, 1H, CH–N at thiazolidinone ring),
6.91–8.11 (m, 4H, Ar–H), 7.48 (m, J = 1.5 Hz, 1H, C-1
proton of quinoline), 7.68 (dt, J = 7.4, 1.8 Hz, 1H, C-6
proton of quinoline), 7.75–7.82 (m, 2H, C-2, and C-10
proton of quinoline), 7.90 (dd, J = 7.9, 1.7 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
35.49 (1C, C-22, S–C at thiazolidinone ring), 58.15 (1C, C-
12, –Ar.–thiazolidinone ring linkage), 148.75–121.07
(13C, Ar–C), 144.86 (1C, C-17, –C–NO2), 151.23 (1C,
C-8, C–Cl at quinoline ring), 174.11 (1C, C-20, C=O).
EMI–MS (m/z): 387.18 (M?).Anal. Calcd. for C18H12ClN3O3S:
C, 56.03; H, 3.13; N, 10.89. Found: C, 56.09; H, 3.15; N,
10.85.
3-(4-Chloro-phenyl)-2-(2-chloro-quinoline-3-yl)-
thiazolidin-4-one (6j)
Yield: 65 %. m.p. 260–261°C (DMF). IR (KBr) cm-1
:
1,739 (C=O of b-lactam), 1,593 (C=C), 1,535 (C–N), 773
1
(C–Cl), 628 (C–S–C). H NMR (400 MHz, DMSO-d6) d
3.92 (dd, J = 12.3 Hz, 2H, CH–S at thiazolidinone ring),
6.44 (s, J = 6.5 Hz, 1H, CH–N at thiazolidinone ring),
7.38 (m, 4H, Ar–H), 7.52 (m, J = 1.5 Hz, 1H, C-1 proton
of quinoline), 7.63 (dt, J = 7.7, 1.6 Hz, 1H, C-6 proton of
quinoline), 7.75–7.83 (m, 2H, C-2, and C-10 proton of
quinoline), 7.90 (dd, J = 8.1, 1.7 Hz, 1H, C-3 proton of
quinoline). 13C NMR (400 MHz, DMSO-d6) d 37.09
(1C, C-22, S–C at thiazolidinone ring), 57.35 (1C, C-12,
–Ar.–thiazolidinone ring linkage), 149.37–125.88 (14C,
Ar–C), 150.07 (1C, C-8, C–Cl at quinoline ring), 174.58
(1C, C-20, C=O). EMI–MS (m/z): 376.57 (M?). Anal.
Calcd. for C18H12Cl2N2OS: C, 57.61; H, 3.22; N, 7.46.
Found: C, 57.65; H, 3.26; N, 7.48.
3-(2-Chloro-phenyl)-2-(2-chloro-quinoline-3-yl)-
thiazolidin-4-one (6h)
Yield: 60 %. m.p. 287–289°C (DMF). IR (KBr) cm-1
:
1,741 (C=O of b-lactam), 1,591 (C=C), 1,536 (C–N), 770
1
(C–Cl), 630 (C–S-C). H NMR (400 MHz, DMSO-d6) d
3.91 (dd, J = 12.1 Hz, 2H, CH–S at thiazolidinone ring),
6.43 (s, J = 6.5 Hz, 1H, CH–N at thiazolidinone ring),
7.15–7.69 (m, 4H, Ar–H), 7.51 (m, J = 1.8 Hz, 1H, C-1
proton of quinoline), 7.63 (dt, J = 7.6, 1.6 Hz, 1H, C-6
proton of quinoline), 7.76–7.81 (m, 2H, C-2, and C-10
proton of quinoline), 7.89 (dd, J = 8.0, 1.6 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
36.51 (1C, C-22, S–C at thiazolidinone ring), 59.66 (1C, C-
12, –Ar.–thiazolidinone ring linkage), 149.43–125.57
(14C, Ar–C), 150.88 (1C, C-8, C–Cl at quinoline ring),
175.66 (1C, C-20, C=O). EMI–MS (m/z): 376.73 (M?).
Anal. Calcd. for C18H12Cl2N2OS: C, 57.61; H, 3.22; N,
7.46. Found: C, 57.56; H, 3.20; N, 7.41.
2-(2-Chloro-quinoline-3-yl)-3-(4-fluoro-phenyl)-
thiazolidin-4-one (6k)
Yield: 59 %. m.p. 295–297°C (DMF). IR (KBr) cm-1
:
1,738 (C=O of b-lactam), 1,589 (C=C), 1,536 (C–N), 765
1
(C–Cl), 617 (C–S-C); H NMR (400 MHz, DMSO-d6) d
3.93 (dd, J = 12.4 Hz, 2H, CH–S at thiazolidinone ring),
6.45 (s, J = 6.8 Hz, 1H, CH–N at thiazolidinone ring),
7.10–7.31 (m, 4H, Ar–H), 7.55 (m, J = 1.7 Hz, 1H, C-1
proton of quinoline), 7.67 (dt, J = 7.8, 1.7 Hz, 1H, C-6
proton of quinoline), 7.73–7.82 (m, 2H, C-2, and C-10
proton of quinoline), 7.93 (dd, J = 8.3, 1.5 Hz, 1H, C-3
proton of quinoline). 13C NMR (400 MHz, DMSO-d6) d
36.67 (1C, C-22, S–C at thiazolidinone ring), 57.06 (1C, C-
12, –Ar.–thiazolidinone ring linkage), 148.07–115.57
(14C, Ar–C), 150.67 (1C, C-8, C–Cl at quinoline ring),
173.79 (1C, C-20, C=O). EMI–MS (m/z): 360.08 (M?).
Anal. Calcd. for C18H12Cl2FN2OS: C, 60.25; H, 3.37; N,
7.81; Found: C, 60.20; H, 3.39; N, 7.84.
3-(3-Chloro-phenyl)-2-(2-chloro-quinoline-3-yl)-
thiazolidin-4-one (6i)
Yield: 62 %. m.p. 286–288°C (DMF). IR (KBr) cm-1
:
1,743 (C=O of b-lactam), 1,587 (C=C), 1,538(C–N), 777
1
(C–Cl), 632 (C–S-C). H NMR (400 MHz, DMSO-d6) d
3.90 (dd, J = 11.9 Hz, 2H, CH–S at thiazolidinone ring),
6.43 (s, J = 6.4 Hz, 1H, CH–N at thiazolidinone ring),
7.05–7.51 (m, 4H, Ar–H), 7.49 (m, J = 1.6 Hz, 1H, C-1
proton of quinoline), 7.61 (dt, J = 7.4, 1.4 Hz, 1H, C-6
proton of quinoline), 7.74–7.79 (m, 2H, C-2, and C-10
proton of quinoline), 7.87 (dd, J = 7.8, 1.5 Hz, 1H, C-3
20-(2-Chloro-quinoline-3-yl)-5-methyl-[2,
30]bithiazolyl-40-one (6l)
Yield: 55 %. m.p. 296–298°C (DMF). IR (KBr) cm-1
1,737 (C=O of b-lactam), 1,583 (C=C), 1,535 (C–N), 770
:
123

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1
naturally occurring quinolines. Int
35(1):30–38
J
Antimicrob Agents
(C–Cl), 629 (C–S-C). H NMR (400 MHz, DMSO-d6) d
2.39 (s, 3H, Ar–CH3 at thaizole ring), 3.89 (dd,
J = 12.2 Hz, 2H, CH–S at thiazolidinone ring), 6.48 (s,
J = 6.5 Hz, 1H, CH–N at thiazolidinone ring), 7.49 (m,
J = 1.8 Hz, 1H, C-1 proton of quinoline), 7.63 (dt,
J = 7.7, 1.5 Hz, 1H, C-6 proton of quinoline), 7.75–7.81
(m, 2H, C-2, and C-10 proton of quinoline), 7.86 (dd,
J = 8.0, 1.7 Hz, 1H, C-3 proton of quinoline). 7.21 (s, 1H,
CH-C at thaizole ring). 13C NMR (400 MHz, DMSO-d6) d
15.23 (1C, C-23, C–CH3 in heterocycles ring), 35.02 (1C,
C-21, S–C at thiazolidinone ring), 57.08 (1C, C-12, -Ar at
thiazolidinone-heterocyclic coupling ring), 148.69–124.33
(10C, Ar–C), 151.38 (1C, C-8, C–Cl at quinoline ring),
156.65 (1C, C-20, C–N) 178.37 (1C, C-14, C=O). EMI–MS
(m/z): 363.11 (M?). Anal. Calcd. for C16H12ClN3OS2: C,
53.11; H, 3.34; N, 11.61. Found: C, 53.16; H, 3.37; N, 11.59.
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Conclusion
In this study various quinoline-based azetidinone and
thiazolidinone analogues were synthesized and screened in
vitro against various microorganisms as well as against
mycobacteria. Briefly, high potency has been observed
with the final scaffolds in the form of azetidinones and
thiazolidinones bearing various amines containing halo-
gen(s) such as chloro or fluoro and nitro functional groups.
The final results indicated that quinoline-based thiazolidi-
nones are more efficacious antimicrobial agents compared
to quinoline-based azetidinones analogues. Hence, there is
enough scope for further study in developing such com-
pounds as a good lead activity.
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Acknowledgments The authors are thankful to Applied Chemistry
Department of S. V. National Institute of Technology, Surat for the
scholarship, encouragement and facilities. The authors wish to offer
their deep gratitude to Centre of Excellence, Vapi, India for carrying
1
out H NMR and 13C NMR analysis.
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