Synthesis and in vitro antimicrobial and anti-tubercular evaluation of some quinoline-based azitidinone and thiazolidinone analogues

Article abstract of DOI:10.1007/s00044-012-0060-8

Keeping the objective to build up a new structural class of potent antimicrobials and antituberculosis agents, a series of potentially active quinoline-based azetidinone and thiazolidinone analogues has been synthesized by a simple and efficient synthetic

Full text of DOI:10.1007/s00044-012-0060-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:635–646
DOI 10.1007/s00044-012-0060-8
ORIGINAL RESEARCH
Synthesis and in vitro antimicrobial and anti-tubercular
evaluation of some quinoline-based azitidinone and thiazolidinone
analogues
•
Bhupendra M. Mistry Smita Jauhari
Received: 18 October 2011 / Accepted: 9 April 2012 / Published online: 22 April 2012
Ó Springer Science+Business Media, LLC 2012
Abstract Keeping the objective to build up a new
structural class of potent antimicrobials and antitubercu-
losis agents, a series of potentially active quinoline-based
azetidinone and thiazolidinone analogues has been syn-
thesized by a simple and efficient synthetic protocol. The
thione nucleus formed from 2-chloroquinoline-3-carbalde-
hyde using sodium sulphide in DMF followed by reaction
with various substituted amine to form the corresponding
Schiff base intermediates. Attempt has been made to derive
final azetidinone and thiazolidinone analogues from Schiff
bases by using chloroacetyl chloride and 2-mercapto acetic
acid, respectively. Newer analogues were characterized by
antituberculosis active compounds prior to their synthesis
according to molecular modeling studies.
Keywords 2-Mercapto-quinoline-3-carbaldehyde Á
Substituted anilines Á Azitidinone Á Thiazolidinone Á
Antimicrobial and antituberculosis activity
Introduction
Over the past few decades, a rapid increase in the oppor-
tunistic microbial infections as well as resistance of
microbial pathogens against current chemotherapeutics has
been observed. To the human civilization, spreading of
such deadly diseases and epidemics is threatening. The rate
of mortality is at more serious stage within the patients
having decreased immunity and patients under organ
transplantation (Vicini et al., 2006; McDonald, 2006).
Despite the numbers of antimicrobial chemotherapeutics
available, the natural occurrence of multidrug resistance in
recent years constitutes a substantial need for developing
new potentially active antimicrobial entities. A potential
approach to overcome the resistance problem is to design
innovative agents with a different mode of action so that no
cross-resistance with the present therapeuticals can occur.
Moreover, the development of drug-resistant strains of
mycobacterium species has contributed to the inefficiency
of the conventional antituberculosis therapy, thus, it is still
necessary to search for new antituberculosis agents. It is
well known that the quinoline ring system is an important
structural unit widely existing in alkaloids, therapeutics and
synthetic analogues with interesting biological activities
(Larsen et al., 1996; Roma et al., 2000; Chen et al., 2001).
Quinoline is a heterocyclic scaffold of paramount impor-
tance to human race. Several quinoline derivatives isolated
1
IR, H NMR, 13C NMR spectroscopy and elemental anal-
yses. 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, Pseudomonas aeruginosa MTCC 741),
two Gram ?ve bacteria (Staphylococcus aureus MTCC 96,
Bacillus subtilis MTCC 430) and two fungal species
(Aspergillus niger MTCC 282, Candida albicans MTCC
183) to develop a novel class of antimicrobial agents and
The final compounds were tested for in vitro antitubercu-
losis activity against Mycobacterium tuberculosis. Strep-
tomycin, Isoniazid, Rifampicin and Ethambutol were used
as standards in this test. These observations provide
some predictions to design further antibacterial and
B. M. Mistry (&) Á S. Jauhari (&)
Department of Applied Chemistry, S.V. National Institute
of Technology, Surat 395 007, Gujarat, India
e-mail: bhupendra.mistry84@gmail.com
S. Jauhari
e-mail: smitajauhari2011@gmail.com
123

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Med Chem Res (2013) 22:635–646
from natural resources or prepared synthetically are sig-
nificant with respect to medicinal chemistry and biomed-
ical use. The quinoline skeleton is often used for the design
of many synthetic compounds with diverse pharmacolog-
ical properties such as, anti-inflammatory (Eswaran et al.,
2009), antimicrobial agents (Donnell et al., 2010), antitu-
berculosis (Mungra et al., 2010), antibacterial (Makawana
et al., 2011), antitumor activity (Rizvi et al., 2011) and
antimalarial (Thomas et al., 2010). Owing to the men-
tioned significance, the synthesis of substituted quinolines
has been a subject of great interest in organic chemistry. In
addition, various fused system of quinolines were studied
for their intercalative DNA binding properties. A literature
survey reveals that the antitumor activity is due to the
intercalation between the base pairs of DNA and inter-
ferences with the normal functioning of enzyme topoiso-
merase II, which is involved in the breaking and releasing
of DNA strands (Gatto et al., 1999). The antitumor drugs
that intercalate DNA are of growing interest in the field of
anticancer derivatives. Generally, they are characterized by
planar chromophore, which is often constituted by three or
four condensed rings, which can intercalate into base pairs.
Results of these various binding studies have been useful
in designing new and promising anticancer agent for
clinical use (Singh et al., 1992). An essential component of
the search for new leads in the drug designing program is
the synthesis of molecules, which are novel yet resemble
known biologically active molecules by virtue of the
presence of some critical structural features. Certain small
heterocyclic molecules act as highly functional scaffolds
and are known pharmacophores of a number of biologi-
cally active and medicinally useful molecules (Silverman,
1992). There are many methods available for fused quin-
olines, the Vilsmeier approach has been recently explored
by Katritzky and others. More recently, synthesis of
functionalized quinoline and their benzo/hetero-fused
analogues have been reported from the reaction of a-ox-
oketene-N,S-acetals with Vilsmeier reagent. It will suffice
to mention here that currently available antimicrobial
drugs such as norfloxacin, ciprofloxacin and ketoconazole
contain 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
quinoline derivatives. In addition, literature survey
revealed that quinoline-based azitidinones (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; Shingade et al., 2011; Desai et al.,
2011; Pawar and Mulwad, 2004; Patel and Patel, 2010;
Pareek et al., 2011), the final analogues, are proved as
promising antimicrobial agents and antituberculosis agents
(Fig. 1).
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 transfor-
mation into different functionalities. The required acet-
anilide 1 was readily prepared from the reaction of
corresponding anilines 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
carbaldehyde 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, the chloro group in few of the
2-chloro-quinoline 3-carbaldehyde was investigated with
various heteronucleophiles. The replacement of chlorine by
sulphur, sodium sulphide in DMF was found to be an
efficient reagent affording nucleophilic substitution by
sulphur and also providing scope for further reaction and
one pot cyclisation. The substitution was achieved in an
hour at rt to afford thione 3 in quantitative yield. Com-
pound 3 showed prominent peak of thione function group
(–SH) at 2,550–2,600 cm-1. Thus, carbaldehyde group
in quinolines 3 was converted into substituted quinoline
Schiff base derivatives 5a–l in ethanol at refluxed tem-
perature. Schiff base compounds (5a–l) showed most
prominent peak of imine function group (–C=N–) at
1,645 cm-1. The substituted Schiff base derivatives
5a–l were also reaction with chloroacetylchloride in the
presence of triethylamine which act as a catalyst in 1,4
dioxane to undergo cyclization to obtain quinoline azeti-
din-2-one derivatives 6a–l. The IR spectrum of compounds
6a–l which showed sharp peak near 1,736 cm-1 indicates
the presence of ketone (–C=O) functional group of
azetidinone ring. A corresponding peak of C–N–CO was
observed at 1,535 cm-1. Chlorine functional group exhib-
ited a peak at 770 cm-1. The H NMR spectra of com-
1
pounds 6a–l showed the signal at 5.67 parts per million
(ppm) due to –CH–Cl on azetidinone ring. Doublets was
observed at 6.75 ppm due to CH–N proton on azetidinone
ring, singlet was observed at 11.4 ppm due to C–SH proton
on quinoline ring, 1.90 ppm due to the presence of –CH3
group at phenyl ring and aromatic protons resonated in the
1
range of 6.85–8.27 ppm. In the H NMR spectra of the
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Med Chem Res (2013) 22:635–646
637
CHO
Cl
CH3COOH
DMF-POCl3
80-900
(CH3COO)2O
NH2
NHCOCH3
CHO
N
Acetanilide
1
Aniline
2-Chloro-quinoline-3-carbaldehyde
2
H2N
Na2S
EtOH
reflux
R
DMF
N
SH
2-Mercapto-quinoline-3-carbaldehyde
Substituted aromatic amine
3
4a-l
N
CH
R
N
SH
(Z)-3-((phenylimino)methyl)quinoline-2-thiol (Substituted amine)
5a-l
1,4 Dioxane
Et3N
ClCOCH2Cl
SH-CH2-COOH
DMF/ZnCl2
Cl
SH
S
O
O
N
N
N
N
SH
R
R
O
6a-k
Cl
7a-k
O
SH
S
N
N
N
N
N
N
SH
S
S
CH3
CH3
6l
7l
Fig. 1 Schematic diagram for the synthesis of azitidinone and thiazolidinone derivatives. (i) CH3COOH, (CH3COO)2O; (ii) DMF, POCl3,
80–90 °C; (iii) Na2S, DMF (iv) EtOH, reflux; (v-a) 1,4 dioxane, Et3N, ClCOCH2Cl, reflux; (v-b) DMF, ZnCl2, SHCH2COOH, reflux
final compounds a peak obtained as doublet in the range
8.14–8.27 ppm was assigned due to the C-3 proton of the
quinoline ring, as well as a doublet of doublet was observed
at 7.94–8.12 ppm attributed to the C-8 quinoline proton. In
addition, C-5, C-2 and C-10 proton atoms of the quinoline
ring appeared to resonate at around 7.76–7.87 and
7.51–7.68 ppm. 13C NMR spectral assigned signals in the
range between 162.21 and 167.58 due to the presence of
ketone (–C=O) functional group of azetidinone ring,
60.05–61.76 range showed the presence of (–C–Cl) group
of azetidinone ring, 171.14–174.23 ppm range indicates
the presence of (–C–SH) group of quinoline ring,
65.86–68.48 range showed the linkage of azetidinone ring,
while remaining all aromatic carbons resonated in the
range of 120–155.
The same Schiff base derivatives 5a-l were heated with
2-mercapto acetic acid in the presence of anhydrous zinc
chloride which act as a catalyst and solvent DMF undergo
cyclisation to give quinoline thiazolidin-4-one derivatives
7a–l. The IR spectrum of compounds 7a–l which showed
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Med Chem Res (2013) 22:635–646
sharp peak near 1,743 cm-1 indicates the presence of
ketone (–C=O) functional group of thiazolidinone ring.
It also showed corresponding peak of C–N–CO at
1,548 cm-1 and showed peak of C–S–C at 637 cm-1. The
1H NMR spectra of compounds 7a–l showed the signal at
6.45 ppm due to –CH–N on thiazolidinone ring. Doublets
of doublet was observed at 3.85 ppm due to CH–S proton
on thiazolidinone ring, 1.95 ppm due to the presence of
–CH3 group at phenyl ring and aromatic protons resonated
Table 1 List of coupling compounds 6a–l and 7a–l
R (substituted –Ar. amines)
a
b
c
d
e
f
Aniline
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-Floro aniline
2-Amino 5-methyl thaizole
1
in the range of 6.98–8.29 ppm. In the H NMR spectra of
g
h
i
the final compounds a peak obtained as doublet in the range
8.14–8.27 ppm was assigned due to the C-3 proton of the
quinoline ring, as well as a doublet of doublet was observed
at 7.94–8.12 ppm attributed to the C-8 quinoline proton. In
addition, C-5, C-2 and C-10 proton atoms of the quinoline
ring appeared to resonate at around 7.76–7.87 and
7.51–7.68 ppm. 13C NMR spectral assigned signals in the
range between 172.56 and 179.73 due to the presence of
ketone (–C=O) functional group of thiazolidinone ring,
55.45–58.68 range showed the linkage of thiazolidinone
ring, 161.17–167.53 ppm range indicates the presence of
(–C––SH) group of quinoline ring, 34.80–36.59 ppm
indicates the presence of –CH2 group in thiazolidinone
ring, while remaining all aromatic carbons resonated in the
range of 121.53–155.36.
j
k
l
Escherichia coli. Compounds 7f and 7g were found to
contribute promising activity (MIC, 6.25 lg/mL) towards
Gram-negative strain E. coli. Compound 6g appeared with
remarkable activity against Gram-negative Pseudomonas
aeruginosa at 12.5 lg/mL of MIC. Compounds 7i and 7g
appeared with remarkable activity against Gram-negative
P. aeruginosa at 12.5 lg/mL of MIC. All the remaining
final azitidinone and thiazolidinone derivatives exerted
good to moderate activity profile at MIC level ranging from
25 to 100 lg/mL, whereas, some derivatives were found to
display weak at a higher concentration of 200–500 lg/mL.
The antifungal bioassay results summarized in Table 2
revealed that final azetidinone derivatives 6f, 6g and 6k
displayed antigrowth activity (MIC, 12.5 lg/mL) against
Aspergillus niger. The antifungal bioassay results summa-
rized in Table 3 revealed that final thiazolidinone deriva-
tives 7k and 7j displayed antigrowth activity (MIC,
12.5 lg/mL; 26 mm of zone of inhibition) against A. niger.
Compound 6k appeared to inhibit Candida albicans at
25 lg/mL. Compound 7k appeared to inhibit C. albicans at
12.5 lg/mL. Compound 7j indicated half fold activity
(25 lg/mL) than the most active analogues tested towards
C. albicans. All the remaining final azitidinone and thia-
zolidinone derivatives were found to demonstrate good to
moderate activity profile at MIC level ranging from 25 to
100 lg/mL, whereas, some final derivatives were found
to display weak activity at a higher concentration of
200–500 lg/mL (Table 4).
Antimicrobial activity
The antimicrobial bioassay results summarized in Tables 1
and 2 revealed that some of the newly synthesized azitid-
inone or thiazolidinone analogues indicated excellent
growth inhibitory profiles. It is worth to mention that
thiazolidinone analogues displayed better activity against
the mentioned microorganisms than that of azitidinone
analogues. The minimum inhibitory concentration (MIC)
profiles of thiazolidinone analogues were also strong than
that of azitidinone class. It was observed that both the class
of newly synthesized analogues with electro withdrawing
nitro and electro withdrawing halo (–Cl, –F) substituent
demonstrated potential antimicrobial properties. Final
azetidinone compounds 6j, 6h and 6k showed excellent
activity against Gram-positive strain Staphylococcus aur-
eus at 6.25 lg/mL of MIC. Final thiazolidinone compound
7k showed excellent activity (MIC, 3.12 lg/mL, 25 mm of
zone of inhibition) against Gram-positive strain S. aureus.
Final azetidinone analogues 6j, 6k and 6l displayed strong
inhibitory action at 6.25 lg/mL, 25 mm of zone of inhi-
bition against Gram-positive Bacillus subtilis. Final thia-
zolidinone analogues 7i and 7j displayed strong inhibitory
action at 3.12 lg/mL, 25 mm of zone of inhibition against
Gram-positive B. subtilis. Compounds 6g, 6k and 6l was
found to contribute promising activity (MIC, 12.5 lg/mL,
25 mm of zone of inhibition) towards Gram-negative strain
Antituberculosis activity
In vitro tuberculosis activities of compounds 6a–l and
7a–l were assessed against Mycobacterium tuberculosis
H37Rv. The results indicated that both azetidinone and
thiazolidinone analogues were active against mycobacteria.
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Med Chem Res (2013) 22:635–646
639
Table 2 In vitro antimicrobial study (MIC lg/mL) of azetidinone analogues 6a–l MIC
Compd no.
(100 lg/disc)
R
Gram negative
Gram positive
Fungal species
C. albicans
\10 (100) \10 (100)
S. aureus B. subtilis E. coli
P. aeruginosa A. niger
6a
Aniline
17 (100)
17 (100)
\10 (100) \10 (100)
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-Floro aniline
21 (62.5) \10 (100) \10 (100) 19 (100)
18 (100)
19 (100)
17 (100)
23 (25)
24 (12.5)
24 (12.5)
20 (62.5)
25 (50)
25 (25)
25 (12.5)
22 (50)
–
20 (100)
18 (100)
15 (100)
21 (62.5)
20 (100)
20 (100)
19 (100)
21 (62.5)
22 (100)
24 (25)
24 (62.5)
–
6c
19 (100)
18 (100)
18 (100)
19 (100)
17 (100)
18 (100)
21 (62.5)
22 (50)
25 (12.5)
23 (50)
22 (62.5)
24 (25)
24 (12.5)
24 (12.5)
32 (B1)
–
\10 (100)
18 (100)
24 (25)
23 (50)
24 (12.5)
22 (50)
23 (62.5)
24 (25)
23 (25)
22 (100)
33 (B1)
–
6d
6e
22 (62.5) 22 (62.5)
6f
22 (50)
24 (50)
22 (50)
24 (25)
6g
6h
24 (6.25) 25 (12.5)
24 (12.5) 25 (12.5)
26 (6.25) 25 (6.25)
26 (6.25) 25 (6.25)
6i
6j
6k
6l
2-Amino 5-methyl thaizole 24 (25)
22 (6.25)
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
30 (B1)
31 (B1)
–
–
–
–
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
Table 3 In vitro antimicrobial study (MIC lg/mL) of thiazolidinone analogues 7a–l MIC
Compd no. (100 lg/disc)
R
Gram negative
Gram positive
Fungal species
S. aureus B. subtilis E. coli
P. aeruginosa A. niger
C. albicans
7a
Aniline
19 (100)
20 (100)
17 (100)
15 (100)
16 (100)
15 (100)
19 (100)
19 (100)
17 (100)
14 (1,000)
18 (100)
19 (100)
16 (100)
16 (100)
20 (100)
17 (100)
23 (50)
23 (25)
25 (25)
15 (100)
17 (100)
19 (100)
15 (100)
22 (100)
20 (100)
18 (100)
7b
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-Floro aniline
7c
21 (62.5) 19 (100)
20 (100) 20 (100)
22 (62.5) 23 (62.5)
22 (50) 22 (50)
7d
7e
23 (62.5) 23 (25)
24 (6.25) 23 (25)
23 (6.25) 24 (12.5)
23 (12.5) 23 (62.5)
7f
7g
23 (12.5) 23 (50)
23 (6.25) 25 (12.5)
24 (6.25) 25 (3.12)
25 (6.25) 25 (3.12)
25 (3.12) 25 (6.25)
7h
21 (62.5) 22 (62.5)
25 (50) 22 (50)
7i
22 (50)
23 (25)
25 (12.5)
7j
24 (25)
25 (12.5) 24 (25)
26 (12.5) 26 (12.5)
23 (62.5) 24 (62.5)
7k
24 (12.5) 24 (50)
24 (12.5) 23 (62.5)
7l
2-Amino 5-methyl thaizole 24 (12.5) 23 (25)
Ciprofloxacin (100 lg/disc)
Ketoconazole (100 lg/disc)
DMSO
30 (B1)
31 (B1)
32 (B1)
33 (B1)
–
–
–
–
–
–
–
–
–
–
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
Preliminary antituberculosis screening results using BAC-
TEC MGIT method revealed that final azetidinone
analogues 6j and 6k as well as thiazolidinone analogues
7g, 7j, 7k and 7l analogues displayed highest inhibition
at a constant concentration level (62.5 lg/mL) against
M. tuberculosis H37Rv.
Experimental
Materials and methods
All the chemicals used in the synthesis were of analytical
grade. The melting points were determined in open capillary
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Med Chem Res (2013) 22:635–646
analyses (C, H, N) were performed using a Heraeus Carlo
Erba 1180 CHN analyzer (Hanau, Germany).
Table 4 Antituberculosis activity of azetidinone and thiazolidinone
analogues
Compounds
R
MIC (lg/mL)
M. Tuberculosis
(H37Rv)
Methods of in vitro evaluation of antimicrobial
and antitubercular activity
6a
Aniline
1,000
500
500
250
500
250
250
125
125
62.5
62.5
125
1,000
500
500
250
250
125
62.5
125
125
62.5
62.5
62.5
40
Synthesized quinoline derivatives 6a–l and 7a–l were
examined for antimicrobial activity against several bacteria
(Staphylococcus aureus MTCC 96, Bacillus subtilis MTCC
430, Escherichia coli MTCC 739, Pseudomonas aerugin-
osa MTCC 741) and fungi (Aspergillus niger MTCC 282,
Candida albicans MTCC 183) using agar streak dilution
method (Hawkey and Lewis, 1994) as well as against
M. tuberculosis H37Rv strain using BACTEC MGIT
method (Anargyros et al., 1990). Ciprofloxacin and keto-
conazole (100 lg/disc) were used as control drugs for
antibacterial and antifungal activity, respectively, and
assayed for MICs at the concentration levels 1000, 500,
250, 125 and 62.5 lg/mL in this study.
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-Floro aniline
2-Amino 5-methyl thaizole
Aniline
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
7a
7b
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-Floro aniline
2-Amino 5-methyl thaizole
7c
General procedure for the synthesis of 2-chloro-
7d
quinoline 3-carbaldehyde (2)
7e
7f
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 was stirred at
80–90 °C for time ranging between 4 and 15 h. The mix-
ture was poured into crushed ice, stirred for 5 min and the
resultant was solid filtered, washed well with water and
dried. The compounds were purified by recrystallisation
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).
7g
7h
7i
7j
7k
7l
Rifampicin
Isoniazid
0.2
Data values in bold letter represents the highest activity
Synthesis of 2-mercapto-quinoline-3-carbaldehyde (3)
on Veego electronic apparatus VMP-D (Veego Instrument
Corporation, Mumbai, India) and are uncorrected. The IR
spectra (4,000–400 cm-1) of synthesized compounds were
recorded on Shimadzu 8400-S FT-IR spectrophotometer
(Shimadzu India Pvt. Ltd., Mumbai, India) using KBr pel-
lets. Thin layer chromatography was performed on micro-
scopic glass slides (2 9 7.5 cm) coated with silica gel-G,
using appropriate mobile phase system and spots were
To a solution of 2 (0.01 mol) in dry DMF (50 mL), sodium
sulphide (0.015 mol) was added and stirred for 1–2 h at rt.
On completion of the reaction (monitored by TLC), the
reaction mixture was poured into crushed ice and made
acidic with acetic acid. The product was filtered off,
washed well with water, dried to give desired compounds
3. The compounds were purified by recrystallisation from
DMF. Yield 83 %, m.p. 283–285 °C (dec.). IR (KBr)
1
visualized under UV radiation. H NMR and 13C NMR
cm-1
:
1,687–1,693 cm-1 (–CHO), 2,575–2,595 cm-1
spectra were recorded on a Varian 400 MHz model spec-
trometer (Varian India Pvt. Ltd., Mumbai, India) using
(–SH) (Raghavendra et al., 2008; Halehatty et al., 2009).
1
DMSO as a solvent and TMS as internal standard with H
resonant frequency of 400 MHz and 13C resonant frequency
General procedure for the Synthesis of (Z)-3-
((phenylimino)methyl)quinoline-2-thiol (substituted
amine) 5a–l
1
of 400 MHz. The H NMR and 13C NMR chemical shifts
were reported as ppm downfield from TMS (Me4Si) and
CFCl3 and were performed at centre for excellence, Vapi,
India. The splitting patterns are designated as follows:
s—singlet, d—doublet and m—multiplet. Elemental
2-Mercapto-quinoline-3-carbaldehyde
(0.01 mol)
3,
substituted aromatic amine 4a–l (0.01 mol) were taken in
123

Med Chem Res (2013) 22:635–646
641
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
5a–l. The compounds were purified by recrystallisation
from ethanol.
linkage), 61.23 (1C, C-21, C–Cl), 22.42 (1C, C-24, –C–
CH3). Anal. calcd for C19H15ClN2OS: C, 64.31; H, 4.26; N,
7.89. Found: C, 64.42; H, 4.35; N, 7.93.
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-m-tolylazetidin-2-
one (6c)
Yield: 70 %. m.p. 253–255 °C (DMF). IR (KBr) cm-1
2583 (S–H), 1733 (C=O), 1587 (C=C), 1533 (C–N), 767
:
General procedure for preparation of compounds 6a–l
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.5 (s, 1H,
A mixture of (Z)-3-((phenylimino)methyl)quinoline-2-thiol
(substituted amine) 5a–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
triethylamine 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 ethanol.
–SH), 8.25 (d, J = 1.5 Hz, 1H, H3, quinoline), 8.13 (dd,
J = 7.8, 1.4 Hz, 1H, H8, quinoline), 7.83 (dd, J = 7.3,
1.6 Hz, 1H, H5, quinoline), 7.66–7.52 (m, 2H, quinoline),
7.47–7.21 (m, 4H, Ar–H), 6.60 (d, J = 6.7 Hz, 1H, CH–N
at azitidinone ring), 5.91 (d, J = 6.7 Hz, 1H), 1.92 (s, 3H,
Ar–CH3). 13C NMR (400 MHz, DMSO-d6) d 174.27 (1C,
C-8, C–SH), 166.14 (1C, C-20, C=O), 156.41–120.11
(14C, Ar–C), 67.89 (1C, C-12, –Ar.–Azetidinone ring
linkage), 62.74 (1C, C-21, C–Cl), 23.45 (1C, C-24, –C–
CH3). Anal. calcd for C19H15ClN2OS: C, 64.31; H, 4.26; N,
7.89. Found: C, 64.37; H, 4.33; N, 7.87.
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-phenylazetidin-2-
one (6a)
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-p-tolylazetidin-2-
one (6d)
Yield: 79 %. m.p. 220–223 °C (DMF). IR (KBr) cm-1
2585 (S–H), 1731 (C=O), 1589 (C=C), 1531 (C–N), 760
:
Yield: 70 %. m.p. 253–255 °C (DMF). IR (KBr) cm-1
2575 (S–H), 1729 (C=O), 1575 (C=C), 1529 (C–N), 763
:
1
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.4 (s, 1H,
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.3 (s, 1H,
–SH), 8.17 (d, J = 1.4 Hz, 1H, H3, quinoline), 8.05 (dd,
J = 7.9, 1.6 Hz, 1H, H8, quinoline), 7.78 (dd, J = 7.3,
1.9 Hz, 1H, H5, quinoline), 7.63–7.52 (m, 2H, quinoline),
7.42–7.20 (m, 5H, Ar–H), 6.51 (d, J = 6.7 Hz, 1H, CH–N
at azitidinone ring), 5.88 (d, J = 6.7 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.15 (1C, C-8, C–SH), 163.97
(1C, C-20, C=O), 154.15–119.20 (14C, Ar–C), 67.95 (1C,
C-12, –Ar.–Azetidinone ring linkage), 60.19 (1C, C-21, C–
Cl). Anal. calcd for C18H13ClN2OS: C, 63.43; H, 3.84; N,
8.22. Found: C, 63.55; H, 3.93; N, 8.34.
–SH), 8.21 (d, J = 1.5 Hz, 1H, H3, quinoline), 8.07 (dd,
J = 7.6, 1.4 Hz, 1H, H8, quinoline), 7.81 (dd, J = 7.2,
1.4 Hz, 1H, H5, quinoline), 7.61–7.49 (m, 2H, quinoline),
7.41–7.19 (m, 4H, Ar–H), 6.55 (d, J = 6.6 Hz, 1H, CH–N
at azitidinone ring), 5.81 (d, J = 6.7 Hz, 1H), 1.95 (s, 3H,
Ar–CH3). 13C NMR (400 MHz, DMSO-d6) d 173.39 (1C,
C-8, C–SH), 163.69 (1C, C-20, C=O), 154.66–127.32
(14C, Ar–C), 67.83 (1C, C-12, –Ar.–Azetidinone ring
linkage), 61.72 (1C, C-21, C–Cl), 21.20 (1C, C-24, –C–
CH3). Anal. calcd for C19H15ClN2OS: C, 64.31; H, 4.26; N,
7.89. Found: C, 64.25; H, 4.34; N, 7.84.
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-o-tolylazetidin-2-
one (6b)
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-(2-
nitrophenyl)azetidin-2-one (6e)
Yield: 73 %. m.p. 245–248 °C (DMF). IR (KBr) cm-1
2581 (S–H), 1738 (C=O), 1585 (C=C), 1537 (C–N), 770
:
Yield: 68 %. m.p. 270–271 °C (DMF). IR (KBr) cm-1
2581 (S–H), 1737 (C=O), 1570 (C=C), 1538 (C–N), 769
:
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.7 (s, 1H,
1
–SH), 8.20 (d, J = 1.6 Hz, 1H, H3, quinoline), 8.11 (dd,
J = 7.7, 1.4 Hz, 1H, H8, quinoline), 7.80 (dd, J = 7.5,
1.7 Hz, 1H, H5, quinoline), 7.65–7.53 (m, 2H, quinoline),
7.44–7.19 (m, 4H, Ar–H), 6.57 (d, J = 6.6 Hz, 1H, CH–N
at azitidinone ring), 5.90 (d, J = 6.5 Hz, 1H), 1.90 (s, 3H,
Ar–CH3). 13C NMR (400 MHz, DMSO-d6) d 171.18 (1C,
C-8, C–SH), 165.67 (1C, C-20, C=O), 155.24–118.31
(14C, Ar–C), 66.68 (1C, C-12, –Ar.–Azetidinone ring
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.8 (s, 1H,
–SH), 8.17 (d, J = 1.3 Hz, 1H, H3, quinoline), 7.95 (dd,
J = 7.8, 1.5 Hz, 1H, H8, quinoline), 7.79 (dd, J = 7.4,
1.6 Hz, 1H, H5, quinoline), 7.67–7.51 (m, 2H, quinoline),
7.43–7.20 (m, 4H, Ar–H), 6.67 (d, J = 6.7 Hz, 1H, CH–N
at azitidinone ring), 5.85 (d, J = 6.7 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.67 (1C, C-8, C–SH), 166.28
(1C, C-20, C=O), 154.70–121.15 (13C, Ar–C), 145.35 (1C,
123

642
Med Chem Res (2013) 22:635–646
C-13, C–NO2), 69.45 (1C, C-12, –Ar.–Azetidinone ring
linkage), 60.35 (1C, C-21, C–Cl). Anal. calcd for
C18H12ClN3O3S: C, 56.03; H, 3.13; N, 10.89. Found: C,
56.15; H, 3.08; N, 10.94.
(1C, C-20, C=O), 154.89–123.46 (14C, Ar–C), 68.25 (1C,
C-12, –Ar.–Azetidinone ring linkage), 60.22 (1C, C-21,
C–Cl). Anal. calcd for C18H12Cl2N2OS: C, 57.61; H, 3.22;
N, 7.46. Found: C, 57.70; H, 3.30; N, 7.51.
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-(3-
nitrophenyl)azetidin-2-one (6f)
3-Chloro-1-(3-chlorophenyl)-4-(2-mercaptoquinolin-3-
yl)azetidin-2-one (6i)
Yield: 63 %. m.p. 260–262 °C (DMF). IR (KBr) cm-1
2585 (S–H), 1733 (C=O), 1580 (C=C), 1533 (C–N), 773
:
Yield: 70 %. m.p. 255–257 °C (DMF). IR (KBr) cm-1
2580 (S–H), 1733 (C=O), 1595 (C=C), 1540 (C–N), 766
:
1
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.6 (s, 1H,
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.1 (s, 1H,
–SH), 8.21 (d, J = 1.4 Hz, 1H, H3, quinoline), 7.99 (dd,
J = 7.6, 1.6 Hz, 1H, H8, quinoline), 7.81 (dd, J = 7.5,
1.7 Hz, 1H, H5, quinoline), 7.68–7.49 (m, 2H, quinoline),
7.41–7.22 (m, 4H, Ar–H), 6.70 (d, J = 6.7 Hz, 1H, CH–N
at azitidinone ring), 5.88 (d, J = 6.7 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.51 (1C, C-8, C–SH), 163.95
(1C, C-20, C=O), 150.62–110.15 (13C, Ar–C), 149.75 (1C,
C-13, C–NO2), 67.75 (1C, C-12, –Ar.–Azetidinone ring
linkage), 60.75 (1C, C-21, C–Cl of b-lactum ring), Anal.
calcd for C18H12ClN3O3S: C, 56.03; H, 3.13; N, 10.89.
Found: C, 56.12; H, 3.18; N, 10.83.
–SH), 8.21 (d, J = 1.3 Hz, 1H, H3, quinoline), 8.03 (dd,
J = 7.9, 1.6 Hz, 1H, H8, quinoline), 7.79 (dd, J = 8.0,
1.2 Hz, 1H, H5, quinoline), 7.63–7.51 (m, 2H, quinoline),
7.39–7.20 (m, 4H, Ar–H), 6.65 (d, J = 6.6 Hz, 1H, CH–N
at azitidinone ring), 5.83 (d, J = 6.3 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.37 (1C, C-8, C–SH), 163.75
(1C, C-20, C=O), 154.23–117.95 (14C, Ar–C), 67.95 (1C,
C-12, –Ar.–Azetidinone ring linkage), 60.45 (1C, C-21, C–
Cl). Anal. calcd for C18H12Cl2N2OS: C, 57.61; H, 3.22; N,
7.46. Found: C, 57.57; H, 3.18; N, 7.55.
3-Chloro-1-(4-chlorophenyl)-4-(2-mercaptoquinolin-3-
yl)azetidin-2-one (6j)
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-(4-
nitrophenyl)azetidin-2-one (6g)
Yield: 73 %. m.p. 253–254 °C (DMF). IR (KBr) cm-1
2583 (S–H), 1735 (C=O), 1576 (C=C), 1539 (C–N), 770
:
Yield: 69 %. m.p. 270–272 °C (DMF). IR (KBr) cm-1
2583 (S–H), 1738 (C=O), 1591 (C=C), 1536 (C–N), 762
:
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.4 (s, 1H,
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.7 (s, 1H,
–SH), 8.25 (d, J = 1.5 Hz, 1H, H3, quinoline), 8.11 (dd,
J = 8.3, 1.7 Hz, 1H, H8, quinoline), 7.82 (dd, J = 8.0,
1.4 Hz, 1H, H5, quinoline), 7.65–7.49 (m, 2H, quinoline),
7.40–7.18 (m, 4H, Ar–H), 6.70 (d, J = 6.7 Hz, 1H, CH–N
at azitidinone ring), 5.88 (d, J = 6.5 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.31 (1C, C-8, C–SH), 163.95
(1C, C-20, C=O), 154.38–118.90 (14C, Ar–C), 67.75 (1C,
C-12, –Ar.–Azetidinone ring linkage), 60.55 (1C, C-21,
C–Cl). Anal. calcd for C18H12Cl2N2OS: C, 57.61; H, 3.22;
N, 7.46. Found: C, 57.68; H, 3.15; N, 7.38.
–SH), 8.19 (d, J = 1.5 Hz, 1H, H3, quinoline), 7.97 (dd,
J = 7.7, 1.5 Hz, 1H, H8, quinoline), 7.77 (dd, J = 7.4,
1.6 Hz, 1H, H5, quinoline), 7.66–7.52 (m, 2H, quinoline),
7.40–7.23 (m, 4H, Ar–H), 6.66 (d, J = 6.6 Hz, 1H, CH–N
at azitidinone ring), 5.84 (d, J = 6.6 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.35 (1C, C-8, C–SH), 163.75
(1C, C-20, C=O), 154.41–124.62 (13C, Ar–C), 145.15 (1C,
C-13, C–NO2), 67.58 (1C, C-12, –Ar.–Azetidinone ring
linkage), 60.55 (1C, C-21, C–Cl). Anal. calcd for
C18H12ClN3O3S: C, 56.03; H, 3.13; N, 10.89. Found: C,
55.09; H, 3.18; N, 10.95.
3-Chloro-1-(4-fluorophenyl)-4-(2-mercaptoquinolin-3-
yl)azetidin-2-one (6k)
3-Chloro-1-(2-chlorophenyl)-4-(2-mercaptoquinolin-3-
yl)azetidin-2-one (6h)
Yield: 71 %. m.p. 266–268 °C (DMF). IR (KBr) cm-1
2589 (S–H), 1738 (C=O), 1593 (C=C), 1541 (C–N), 773
:
Yield: 73 %. m.p. 280–281 °C (DMF). IR (KBr) cm-1
2577 (S–H), 1738 (C=O), 1592 (C=C), 1533 (C–N), 777
:
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.4 (s, 1H,
1
–SH), 8.26 (d, J = 1.4 Hz, 1H, H3, quinoline), 8.12 (dd,
J = 8.2, 1.7 Hz, 1H, H8, quinoline), 7.83 (dd, J = 8.0,
1.3 Hz, 1H, H5, quinoline), 7.63–7.50 (m, 2H, quinoline),
7.41–7.21 (m, 4H, Ar–H), 6.68 (d, J = 6.6 Hz, 1H, CH–N
at azitidinone ring), 5.90 (d, J = 6.8 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.35 (1C, C-8, C–SH), 163.89
(1C, C-20, C=O), 154.30–115.75 (14C, Ar–C), 68.05 (1C,
C-12, –Ar.–Azetidinone ring linkage), 60.75 (1C, C-21,
1
(C–Cl). H NMR (400 MHz, DMSO-d6): d 11.5 (s, 1H,
–SH), 8.25 (d, J = 1.5 Hz, 1H, H3, quinoline), 8.06 (dd,
J = 8.1, 1.2 Hz, 1H, H8, quinoline), 7.81 (dd, J = 7.9,
1.4 Hz, 1H, H5, quinoline), 7.68–7.50 (m, 2H, quinoline),
7.42–7.18 (m, 4H, Ar–H), 6.68 (d, J = 6.8 Hz, 1H, CH–N
at azitidinone ring), 5.89 (d, J = 6.4 Hz, 1H). 13C NMR
(400 MHz, DMSO-d6) d 173.45 (1C, C-8, C–SH), 166.30
123

Med Chem Res (2013) 22:635–646
643
2-(2-Mercaptoquinolin-3-yl)-3-o-tolylthiazolidin-4-one
(7b)
C–Cl). Anal. calcd for C18H12ClFN2OS: C, 60.25; H, 3.37;
N, 7.81. Found: C, 60.37; H, 3.45; N, 7.85.
Yield: 71 %. m.p. 263–265 °C (DMF). IR (KBr) cm-1
:
3-Chloro-4-(2-mercaptoquinolin-3-yl)-1-(5-methylthiazol-
2-yl)azetidin-2-one (6l)
2583 (S–H), 1739 (C=O of b-lactum), 1594 (C=C), 1537
(C–N), 763 (C–Cl), 627 (C–S–C). H NMR (400 MHz,
1
DMSO-d6): d 11.4 (s, 1H, –SH), 8.24 (d, J = 1.4 Hz, 1H,
H3, quinoline), 8.05 (dd, J = 8.0, 1.5 Hz, 1H, H8, quino-
line), 7.82 (dd, J = 7.8, 1.6 Hz, 1H, H5, quinoline),
7.65–7.52 (m, 2H, quinoline), 7.41–7.19 (m, 4H, Ar–H),
6.48 (d, J = 6.6 Hz, 1H, CH–N at thiazolidinone ring),
3.89 (dd, J = 12.3 Hz, 2H, CH–S at thiazolidinone ring),
1.91 (s, 3H, Ar–CH3). 13C NMR (400 MHz, DMSO-d6) d
172.56 (1C, C-8, C–SH), 165.30 (1C, C-20, C=O),
153.91–123.46 (14C, Ar–C), 58.25 (1C, C-12, –Ar.–Aze-
tidinone ring linkage), 35.47 (1C, C-22, –S–C at thiazo-
lidinone ring), 18.14 (1C, C-24, –C–CH3). Anal. calcd for
C19H16N2OS2: C, 64.74; H, 4.58; N, 7.95. Found: C, 64.80;
H, 4.63; N, 7.87.
Yield: 58 %. m.p. 291–293 °C (DMF). IR (KBr) cm-1
2585 (S–H), 1731 (C=O), 1539 (C–N), 762 (C–Cl), 650
:
1
(C–S–C). H NMR (400 MHz, DMSO-d6): d 11.8 (s, 1H,
–SH), 8.23 (d, J = 1.5 Hz, 1H, H3, quinoline), 8.11 (dd,
J = 8.1, 1.5 Hz, 1H, H8, quinoline), 7.79 (dd, J = 8.1,
1.3 Hz, 1H, H5, quinoline), 7.61–7.52 (m, 2H, quinoline),
7.20 (d, 1H, Ar–H at thaizole ring), 6.63 (d, J = 6.5 Hz,
1H, CH–N at azitidinone ring), 5.88 (d, J = 6.8 Hz, 1H),
2.02 (s, 3H, Ar–CH3). 13C NMR (400 MHz, DMSO-d6) d
173.55 (1C, C-8, C–SH), 160.12 (1C, C-14, C=O), 157.85
(1C, C-20, –N–C at azetidinone-heterocyclic coupling
ring), 154.15–126.75 (10C, Ar–C), 64.25 (1C, C-12, –Ar.–
Azetidinone ring linkage), 59.50 (1C, C-15, C–Cl),14.45
(1C, C–CH3). Anal. calcd for C16H12ClN3OS2: C, 53.11;
H, 3.34; N, 11.61. Found: C, 53.08; H, 3.41; N, 11.57.
2-(2-Mercaptoquinolin-3-yl)-3-m-tolylthiazolidin-4-one
(7c)
Yield: 66 %. m.p. 245–247 °C (DMF). IR (KBr) cm-1
2578 (S–H), 1731 (C=O), 1582 (C=C), 1533 (C–N), 769
:
General procedure for preparation of compounds 7a–l
1
A mixture of (Z)-3-((phenylimino)methyl)quinoline-2-thiol
(substituted amine) 5a–l (0.01 mol) and catalytic amount
of zinc chloride (0.05 gm) 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 bicar-
bonate solution to remove excess of thioglycolic acid. The
product obtained was filtered, washed several times with
water and recrystallized from ethanol.
(C–Cl), 633 (C–S–C). H NMR (400 MHz, DMSO-d6): d
11.1 (s, 1H, –SH), 8.19 (d, J = 1.3 Hz, 1H, H3, quinoline),
8.02 (dd, J = 8.1, 1.4 Hz, 1H, H8, quinoline), 7.84 (dd,
J = 7.9, 1.5 Hz, 1H, H5, quinoline), 7.62–7.49 (m, 2H,
quinoline), 7.43–7.20 (m, 4H, Ar–H), 6.52 (d, J = 6.6 Hz,
1H, CH–N at thiazolidinone ring), 3.83 (dd, J = 12.0 Hz,
2H, CH–S at thiazolidinone ring), 1.95 (s, 3H, Ar–CH3).
13C NMR (400 MHz, DMSO-d6) d 174.21 (1C, C-8,
C–SH), 161.87 (1C, C-20, C=O), 153.89–120.85 (14C,
Ar–C), 56.45 (1C, C-12, –Ar.–Azetidinone ring linkage),
33.74 (1C, C-22, –S–C at thiazolidinone ring), 19.25 (1C,
C-24, –C–CH3).Anal. calcd for C19H16N2OS2: C, 64.74; H,
4.58; N, 7.95. Found: C, 64.79; H, 4.65; N, 7.90.
2-(2-Mercaptoquinolin-3-yl)-3-phenylthiazolidin-4-one
(7a)
Yield: 75 %. m.p. 271–272 °C (DMF). IR (KBr) cm-1
2578 (S–H), 1735 (C=O), 1586 (C=C), 1534 (C–N), 759
:
2-(2-Mercaptoquinolin-3-yl)-3-p-tolylthiazolidin-4-one
(7d)
1
(C–Cl), 624 (C–S–C). H NMR (400 MHz, DMSO-d6): d
Yield: 67 %. m.p. 269–271 °C (DMF). IR (KBr) cm-1
2588 (S–H), 1736 (C=O), 1578 (C=C), 1537 (C–N), 772
:
10.9 (s, 1H, –SH), 8.16 (d, J = 1.5 Hz, 1H, H3, quinoline),
8.03 (dd, J = 7.9, 1.6 Hz, 1H, H8, quinoline), 7.76 (dd,
J = 7.4, 1.7 Hz, 1H, H5, quinoline), 7.61–7.51 (m, 2H,
quinoline), 7.40–7.21 (m, 5H, Ar–H), 6.42 (d, J = 6.6 Hz,
1H, CH–N at thiazolidinone ring), 3.85 (dd, J = 12.2 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 174.35 (1C, C-20, C=O), 163.88 (1C, C-8,
C–SH), 151.23–125.34 (14C, Ar–C), 57.87 (1C, C-12, –Ar.
- thiazolidinone ring linkage), 36.92 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H14N2OS2: C,
63.88; H, 4.17; N, 8.28. Found: C, 63.75; H, 4.25; N, 8.34.
1
(C–Cl), 629 (C–S–C). H NMR (400 MHz, DMSO-d6): d
11.5 (s, 1H, –SH), 8.26 (d, J = 1.5 Hz, 1H, H3, quinoline),
8.07 (dd, J = 8.3, 1.6 Hz, 1H, H8, quinoline), 7.86 (dd,
J = 7.8, 1.6 Hz, 1H, H5, quinoline), 7.61–7.51 (m, 2H,
quinoline), 7.41–7.19 (m, 4H, Ar–H), 6.49 (d, J = 6.7 Hz,
1H, CH–N at thiazolidinone ring), 3.88 (dd, J = 12.2 Hz,
2H, CH-S at thiazolidinone ring), 1.90 (s, 3H, Ar–CH3).
13C NMR (400 MHz, DMSO-d6) d 172.56 (1C, C-8, C–
SH), 161.87 (1C, C-20, C=O), 151.89–122.85 (14C, Ar–C),
123

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Med Chem Res (2013) 22:635–646
57.45 (1C, C-12, –Ar.–Azetidinone ring linkage), 34.73
(1C, C-22, –S–C at thiazolidinone ring), 20.18 (1C, C-24,
–C–CH3). Anal. calcd for C19H16N2OS2: C, 64.74; H, 4.58;
N, 7.95. Found: C, 64.81; H, 4.66; N, 7.85.
DMSO-d6) d 174.57 (1C, C-8, C–SH), 164.53 (1C, C-20,
C=O), 148.22–119.58 (14C, Ar–C), 58.84 (1C, C-12,
–Ar.–Azetidinone ring linkage), 35.74 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13N3O3S2: C,
56.38; H, 3.42; N, 10.96. Found: C, 56.43; H, 3.51; N, 10.85.
2-(2-Mercaptoquinolin-3-yl)-3-(2-nitrophenyl)thiazolidin-
4-one (7e)
3-(2-Chlorophenyl)-2-(2-mercaptoquinolin-3-
yl)thiazolidin-4-one (7h)
Yield: 65 %. m.p. 257–258 °C (DMF). IR (KBr) cm-1
2588 (S–H), 1740 (C=O), 1573 (C=C), 1539 (C–N), 778
:
Yield: 59 %. m.p. 263–265 °C (DMF). IR (KBr) cm-1
2587 (S–H), 1736 (C=O), 1591 (C=C), 1536 (C–N), 773
:
1
(C–Cl), 620 (C–S–C). H NMR (400 MHz, DMSO-d6): d
1
11.7 (s, 1H, –SH), 8.23 (d, J = 1.4 Hz, 1H, H3, quinoline),
7.91 (dd, J = 8.0, 1.7 Hz, 1H, H8, quinoline), 7.83 (dd,
J = 7.9, 1.6 Hz, 1H, H5, quinoline), 7.63–7.54 (m, 2H,
quinoline), 7.45–7.22 (m, 4H, Ar–H), 6.51 (d, J = 6.7 Hz,
1H, CH–N at thiazolidinone ring), 3.94 (dd, J = 12.4 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 177.31 (1C, C-8, C–SH), 164.82 (1C, C-20,
C=O), 151.65–120.78 (14C, Ar–C), 59.46 (1C, C-12,
–Ar.–Azetidinone ring linkage), 36.57 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13N3O3S2: C,
56.38; H, 3.42; N, 10.96. Found: C, 56.45; H, 3.49; N, 10.88.
(C–Cl), 630 (C–S–C). H NMR (400 MHz, DMSO-d6): d
12.1 (s, 1H, –SH), 8.15 (d, J = 1.4 Hz, 1H, H3, quinoline),
8.11 (dd, J = 8.2, 1.7 Hz, 1H, H8, quinoline), 7.85 (dd,
J = 7.7, 1.8 Hz, 1H, H5, quinoline), 7.61–7.55 (m, 2H,
quinoline), 7.43–7.22 (m, 4H, Ar–H), 6.49 (d, J = 6.7 Hz,
1H, CH–N at thiazolidinone ring), 3.89 (dd, J = 11.9 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 172.75 (1C, C-8, C–SH), 162.27 (1C, C-20,
C=O), 150.22–120.58 (14C, Ar–C), 57.26 (1C, C-12,
–Ar.–Azetidinone ring linkage), 34.72 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13ClN2OS2: C,
57.98; H, 3.51; N, 7.51. Found: C, 57.90; H, 3.59; N, 7.41.
2-(2-Mercaptoquinolin-3-yl)-3-(3-nitrophenyl)thiazolidin-
4-one (7f)
3-(3-Chlorophenyl)-2-(2-mercaptoquinolin-3-
yl)thiazolidin-4-one (7i)
Yield: 60 %. m.p. 275–277 °C (DMF). IR (KBr) cm-1
2593 (S–H), 1737 (C=O), 1579 (C=C), 1537 (C–N), 774
:
Yield: 55 %. m.p. 286–288 °C (DMF). IR (KBr) cm-1
2575 (S–H), 1739 (C=O), 1587 (C=C), 1538 (C–N), 780
:
1
(C–Cl), 619 (C–S–C). H NMR (400 MHz, DMSO-d6): d
1
11.9 (s, 1H, –SH), 8.27 (d, J = 1.3 Hz, 1H, H3, quinoline),
7.84 (dd, J = 7.9, 1.6 Hz, 1H, H8, quinoline), 7.82 (dd,
J = 7.8, 1.5 Hz, 1H, H5, quinoline), 7.62–7.51 (m, 2H,
quinoline), 7.43–7.19 (m, 4H, Ar–H), 6.60 (d, J = 6.5 Hz,
1H, CH–N at thiazolidinone ring), 3.91 (dd, J = 12.1 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 175.16 (1C, C-8, C–SH), 162.95 (1C, C-20,
C=O), 149.62–115.19 (14C, Ar–C), 57.85 (1C, C-12,
–Ar.–Azetidinone ring linkage), 34.78 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13N3O3S2: C,
56.38; H, 3.42; N, 10.96. Found: C, 56.30; H, 3.35; N, 10.91.
(C–Cl), 626 (C–S–C). H NMR (400 MHz, DMSO-d6): d
12.3 (s, 1H, –SH), 8.20 (d, J = 1.5 Hz, 1H, H3, quinoline),
8.13 (dd, J = 8.0, 1.6 Hz, 1H, H8, quinoline), 7.87 (dd,
J = 7.8, 1.6 Hz, 1H, H5, quinoline), 7.64–7.53 (m, 2H,
quinoline), 7.41–7.20 (m, 4H, Ar–H), 6.46 (d, J = 6.7 Hz,
1H, CH–N at thiazolidinone ring), 3.85 (dd, J = 11.9 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 170.85 (1C, C-8, C–SH), 160.45 (1C, C-20,
C=O), 152.47–119.68 (14C, Ar–C), 56.87 (1C, C-12,
–Ar.–Azetidinone ring linkage), 35.78 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13ClN2OS2: C,
57.98; H, 3.51; N, 7.51. Found: C, 57.93; H, 3.45; N, 7.58.
2-(2-Mercaptoquinolin-3-yl)-3-(4-nitrophenyl)thiazolidin-
4-one (7g)
3-(4-Chlorophenyl)-2-(2-mercaptoquinolin-3-
yl)thiazolidin-4-one (7j)
Yield: 63 %; m.p. 249–251 °C (DMF). IR (KBr) cm-1
2593 (S–H), 1740 (C=O), 1575 (C=C), 1538 (C–N), 780
:
Yield: 60 %. m.p. 260–262 °C (DMF). IR (KBr) cm-1
2575 (S–H), 1733 (C=O), 1593 (C=C), 1536 (C–N), 773
:
1
(C–Cl), 627 (C–S–C). H NMR (400 MHz, DMSO-d6): d
1
11.6 (s, 1H, –SH), 8.20 (d, J = 1.5 Hz, 1H, H3, quinoline),
7.90 (dd, J = 7.9, 1.7 Hz, 1H, H8, quinoline), 7.80 (dd,
J = 7.9, 1.6 Hz, 1H, H5, quinoline), 7.63–7.54 (m, 2H,
quinoline), 7.41–7.20 (m, 4H, Ar–H), 6.58 (d, J = 6.6 Hz,
1H, CH–N at thiazolidinone ring), 3.93 (dd, J = 12.3 Hz,
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
(C–Cl), 629 (C–S–C). H NMR (400 MHz, DMSO-d6): d
11.9 (s, 1H, –SH), 8.15 (d, J = 1.6 Hz, 1H, H3, quinoline),
8.07 (dd, J = 8.2, 1.5 Hz, 1H, H8, quinoline), 7.79 (dd,
J = 7.6, 1.4 Hz, 1H, H5, quinoline), 7.62–7.54 (m, 2H,
quinoline), 7.43–7.19 (m, 4H, Ar–H), 6.49 (d, J = 6.8 Hz,
1H, CH–N at thiazolidinone ring), 3.89 (dd, J = 11.7 Hz,
123

Med Chem Res (2013) 22:635–646
645
2H, CH–S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 173.24 (1C, C-8, C–SH), 162.28 (1C, C-20,
C=O), 150.47–122.68 (14C, Ar–C), 58.48 (1C, C-12,
–Ar.–Azetidinone ring linkage), 36.75 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13ClN2OS2: C,
57.98; H, 3.51; N, 7.51. Found: C, 57.92; H, 3.55; N, 7.47.
The presence of substituted amines is also an instrumental
in contributing the net biological activity. In brief, high
potency has been observed with the final scaffolds in the
form of azetidinones and thiazolidinones bearing various
amines containing halogen(s) such as chloro or fluoro and
nitro functional groups. The final results indicated that
quinoline-based thiazolidinones are more efficious antimi-
crobial agents compared to quinoline-based azetidinones
analogues. Hence, there is enough scope for further study
in developing such compounds as a good lead activity.
Overall conclusion placed for synthesized compounds is
that most of the compounds shown moderate to promising
activity as compared to standard drug against all repre-
sentative panel of bacterial and fungal strains.
3-(4-Fluorophenyl)-2-(2-mercaptoquinolin-3-
yl)thiazolidin-4-one (7k)
Yield: 59 %. m.p. 274–277 °C (DMF). IR (KBr) cm-1
2575 (S–H), 1738 (C=O), 1589 (C=C), 1536 (C–N), 765
:
1
(C–Cl), 617 (C–S–C); H NMR (400 MHz, DMSO-d6): d
12.2 (s, 1H, –SH), 8.19 (d, J = 1.7 Hz, 1H, H3, quinoline),
8.13 (dd, J = 8.3, 1.4 Hz, 1H, H8, quinoline), 7.83 (dd,
J = 7.7, 1.5 Hz, 1H, H5, quinoline), 7.64–7.52 (m, 2H,
quinoline), 7.42–7.21 (m, 4H, Ar–H), 6.51 (d, J = 6.6 Hz,
1H, CH–N at thiazolidinone ring), 3.91 (dd, J = 11.9 Hz,
2H, CH-S at thiazolidinone ring). 13C NMR (400 MHz,
DMSO-d6) d 172.92 (1C, C-8, C–SH), 161.37 (1C, C-20,
C=O), 151.74–121.46 (14C, Ar–C), 57.88 (1C, C-12,
–Ar.–Azetidinone ring linkage), 36.22 (1C, C-22, –S–C at
thiazolidinone ring). Anal. calcd for C18H13FN2OS2: C,
60.65; H, 3.68; N, 7.86; Found: C, 60.73; H, 3.74; N, 7.77.
Acknowledgments The authors are thankful to Applied Chemistry
Department of S. V. National Institute of Technology, Surat for
encouragement and facilities. The authors wish to offer their deep
gratitude to Centre of Excellence, Vapi, India for carrying out 1H
NMR and 13C NMR analysis.
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