Med Chem Res
DOI 10.1007/s00044-013-0600-x
ORIGINAL RESEARCH
Synthesis of some novel C-5 and N-3 substituted
2-(2-hydroxyphenylimino)thiazolidin-4-one derivatives
with broad-spectrum antimicrobial activity
N. C. Desai • H. M. Satodiya • K. M. Rajpara •
V. V. Joshi • H. V. Vaghani
Received: 17 February 2013 / Accepted: 24 April 2013
Ó Springer Science+Business Media New York 2013
Abstract In the present article, compounds 5-((substituted-
2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimino)
thiazolidin-4-ones (3a–k), 1-(2-(2-(2-hydroxyphenylimino)-4-
oxothiazolidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-
trione (6) and 1-(2-(5-((substituted-2-chloroquinolin-3-yl)
methylene)-2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-
2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-triones (8a–k) have
been synthesized by substituting C-5 and N-3 position of
parent compound 2-(2-hydroxyphenylimino)thiazolidin-4-
one (1). Structures of the newly synthesized compounds were
assigned on the basis of elemental analyses, IR, 1H NMR,
13
C NMR, and mass spectra. In vitro antimicrobial activity of
target compounds (3a–k, 6 and 8a–k) was investigated
against two Gram-positive, two Gram-negative bacteria and
three fungal strains. Among the tested compounds (3e), (3f),
and (3h) showed very good antifungal activity, while com-
pound (6) showed very good antibacterial activity. Com-
pounds (8e), (8f), and (8h) showed excellent antifungal and
antibacterial activities.
Keywords Thiazolidin-4-one  Quinoline  Barbitone 
SAR  Antimicrobial
Introduction
Previously from our laboratory, we have reported antibac-
terial and antifungal activity of clubbed thiazolidin-4-one,
N. C. Desai (&)  H. M. Satodiya  K. M. Rajpara 
V. V. Joshi  H. V. Vaghani
Division of Medicinal Chemistry, Department of Chemistry,
DST-FIST Sponsored Department, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University,
Bhavnagar 364 002, Gujarat, India
e-mail: dnisheeth@rediffmail.com
MEDICINAL
CHEMISTRY
RESEARCH
quinoline and barbitone ring system. The results of anti-
microbial activity were very much encouraging and
promising (Desai et al., 2013). In continuation to our effort
to improve the antimicrobial activity through continued
broad evaluation, we have done structural variations on
phenyl ring attached to thiazolidinone ring by introducing
hydroxyl group at 2nd position. 4-Thiazolidinone ring
system is very versatile and has featured in a number of
clinically used drugs. It possessed several biological
activities like, antibacterial (Kucukguzel et al., 2002;
Bonde and Gaikwad, 2004), antiinflammatory (Kumar
et al., 2007), antiviral (Barreca et al., 2001), and antitu-
bercular (Babaoglu et al., 2003). Furthermore, successful
introduction of ralitoline as a potent anticonvulsant, etoz-
oline as antihypertensive, and pioglitazone as a hypogly-
cemic agent proved importance of thiazolidinone moiety in
medicinal chemistry. Numerous reports have appeared in
the literature which also highlights antimicrobial activity of
C-5 and N-3 substituted 4-thiazolidinone scaffolds (Omar
et al., 2010; Vicini et al., 2006; Sharma et al., 2006; Desai
et al., 2012a). It has recently been reported that antibac-
terial activity of 4-thiazolidinone may be due to its inhib-
itory effect on bacterial enzyme MurB, which is a
precursor acting during the biosynthesis of peptidoglycan
(Andres et al., 2000).
Quinoline is another heterocyclic moiety which has been
found to possess antimalarial (Peter and Scott, 2005),
antibiotic (Mahamoud et al., 2006; Eswaran et al., 2009),
anticancer (Chen et al., 2005), antihypertensive (Muruga-
nantham et al., 2004), tyrosine kinase PDGF-RTK inhibi-
tion (Maguire et al., 1994), and anti-HIV (Kacprzak, 2005)
properties. Chloroquine, primaquine, mefloquine, and qui-
nine constitute notable examples of the drugs containing
quinoline scaffold which are used for treatment of malaria
(Graves et al., 2002; Amit et al., 2007). Recently
123

antibacterial and antifungal properties of several quinoline
derivatives bearing pyrazoline and pyrimidine have been
reported (Desai et al., 2012b). On the other hand, barbituric
acid derivatives are well known for beneficial activity on
central nervous system, and as anticonvulsant, sedative-
hypnotic and tranquilizer (Holtkamp and Meierkord, 2007).
Moreover, it is also proved that barbitone ring system is
very important for antibacterial activity (Haldar et al.,
2008; Pardasani et al., 2002). In view of the above findings
and in continuation of our research project on the explo-
ration of antimicrobial agents, we have reported synthesis
and antimicrobial activity of C-5 and N-3 substituted
derivative of thiazolidin-4-ones.
Results and discussion
Chemistry
The synthetic pathways to obtain the intermediate and
target compounds are depicted in Scheme 1. 2-(2-Hy-
droxyphenylimino)thiazolidin-4-one (1) was prepared by
previously described method (Desai et al., 2007).
Compound (1) was substituted in two ways; first, it was
reacted with substituted 2-chloroquinoline-3-carbaldehydes
(2a–k) (Ambika and Singh, 2005) in the presence of fused
sodium acetate to give Knoevenagel condensation products
(3a–k). Infrared (IR) spectrum of representative compound
(3a) showed absorption bands at 3,256 and 1,688 cm-1 due
to N–H stretching and carbonyl group of thiazolidinone
ring, respectively. Due to the presence of hydroxyl group
on phenyl ring and chlorine atom on quinoline ring, the
characteristic absorption bands appeared at 3,650 and
760 cm-1, respectively. 1H NMR spectrum showed singlet
at d = 7.81 ppm due to proton of arylidene (thermally
stable Z-isomer) formed between thiazolidinone and quin-
oline ring system. Proton of phenolic –OH exhibited broad
singlet at d = 5.40 ppm. In 13C NMR, signals obtained at
d = 174.1 ppm and d = 143.1 ppm indicated the presence
of carbonyl carbon and carbon of arylidene, respectively.
Mass spectrum of compound (3a) showed molecular ion
peak at m/z = 381 (M?) corresponding to a molecular
formula C19H12ClN3O2S.
Second, compound (1) was reacted with chloroacetyl
chloride using triethylamine as a basic catalyst to afford 3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-4-one
(4). The structure of compound (4) was confirmed by ana-
lytical evidences viz., IR spectrum which showed strong
absorption bands at 1,739 and 761 cm-1 due to carbonyl and
chlorine atom, respectively. Due to hydroxyl group present
on phenyl ring, the absorption band showed at 3,632 cm-1
stretching frequency. The characteristic signal in 1H NMR of
compound (4) displayed singlet at d = 4.08 ppm integrating
123
Med Chem Res
two protons of the methylene group. Protons of the acetyl and
hydroxyl groups appeared as singlets at d = 4.35 ppm and
d = 5.48 ppm, respectively. On the basis of 13C NMR, the
proposed structure was confirmed due to appearance of
signal at d = 171.8 ppm of carbonyl carbon as well as
appearance of signal around d = 30.0 ppm which may be
assigned to methylene carbon of thiazolidinone ring. More-
over, the mass spectrum of compound (4) showed a molec-
ular ion peak at m/z = 284 (M?) corresponding to a
molecular formula C11H9ClN2O3S.
The resulting intermediate (4) possessed good leaving
group i.e., chlorine and active methylene group for dif-
ferent substitutions to be made. Due to the presence of two
active sites in compound (4), it was first reacted with
barbituric acid (5) in the presence of triethylamine for
yielding the 1-(2-(2-(2-hydroxyphenylimino)-4-oxothiaz-
olidin-3-yl)-2-oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-tri-
one (6). IR spectra of compound (6) showed strong
absorption bands at 1725, 1705, and 1680 cm-1, which
confirmed the presence of carbonyl groups and stretching
absorption at 3,283 cm-1 proved the presence of secondary
amines. 1H NMR revealed the appearance of singlets at
d = 3.07 and 4.12 ppm due to the presence of two protons
of methylene group of thiazolidinone and two protons of
the barbitone ring. Proton attached to nitrogen atom in
barbitone ring displayed singlet at d = 9.61 ppm. 13C
NMR confirmed the proposed structure by appearance of
signals at d = 152.0, 165.9, 166.3, 170.2, and 171.6 ppm
due to the presence of five carbonyl carbons. Appearance
of signals around d = 30.1 and 39.7 ppm were assignable
to both methylene groups of the thiazolidinone and barbi-
tone ring. Moreover, the mass spectrum of (6) showed a
molecular ion peak at m/z = 376 (M?) corresponding to a
molecular formula C15H12N4O6S
Treatment of compound (4) with substituted 2-chlor-
oquinoline-3-carbaldehydes (Ambika and Singh, 2005)
(2a–k) in identical conditions provided a set of Knoeve-
nagel condensation products (7a–k). Compound (7a)
showed strong absorption bands at 1,735 and 1,687 cm-1
due to the presence of carbonyl groups in IR spectra.
Absorption bands appeared at 3,640 and 790 cm-1 indi-
cated hydroxyl group and chlorine present in compound
(7a), respectively. In 1H NMR, singlet appeared at
d = 7.82 ppm (thermally stable Z-isomer) due to proton of
arylidene formed in Knoevenagel condensation product.
Looking to the 13C NMR spectra of (7a), carbon of ary-
lidene showed peak at d = 143.3 ppm. The mass spectrum
of (7a) showed a molecular ion peak at m/z = 457 (M?)
corresponding to a molecular formula C21H13Cl2N3O3S.
To achieve targeted compounds (8a–k), intermediate
compounds (7a–k) were reacted with barbituric acid in the
presence of triethylamine and potassium carbonate. The
structures of targeted compounds were proved by spectral
Med Chem Res

Scheme 1 Synthetic route for OH

CHO
the preparation of title N 2 H
R N3
compounds 3a–k, 6 and 8a–k OH
N Cl 1
H S
N (2a-k) 4 O
N 5
O
S (i)
(1) Cl
R N
(3a-k)

(ii) ClCOCH 2Cl

O H O
N
HN NH O
OH O
O Cl N
OH O O N 2
N (5) N3 O
N 1S
S
O
(iii) 4 O
5
(4) (6)

CHO
(iv) R
N Cl
(2a-k)

H O
OH O O N
Cl O
N OH O
N HN NH N
N 2
S O O O N3 O
1
(5) S
CH 4 O
5
(v)
Cl
R N
Cl
R N
(7a-k)
(8a-k)
Reagents and conditions:
(i) Fused sodium acetate, ethanol (99.9%), 8-12 hours, ref lux (ii) Triethylamine, K 2CO 3, anhy. benzene, 7 hours, ref lux
(iii) Toluene, K 2CO3, triethylamine, 5 hours, ref lux (iv) Fused sodium acetate, ethanol (99.9%), 4-8 hours, reflux
(v) Anhy.benzene, K2CO 3, triethylamine, 12-14 hours, ref lux.

data. IR spectra of compound (8a) showed absorption band
in the region of 3,640 cm-1 due to the presence of hydroxyl
group. Carbonyl groups present in targeted compound
showed absorption bands at 1723, 1705 and 1681 cm-1. In
1
H NMR spectra, two protons of methylene group displayed
singlet at d = 3.01 ppm and broad singlet exhibited at
d = 5.36 ppm, which indicated the presence of phenolic
proton. Proton attached to nitrogen in barbitone ring showed
singlet at d = 9.67 ppm. The proton attached to arylidene
linkage showed singlet at d = 7.85 ppm (thermally stable
Z-isomer). All five carbonyl carbons of compound (8a)
showed signals at d = 152.0, 165.7, 16.4, 170.7, and
172.0 ppm as well as carbon of arylidene linkage showed
signal at d = 143.2 ppm. Mass spectra of compound (8a)
showed a molecular ion peak at m/z = 549 (M?) corre-
sponding to a molecular formula C25H16ClN5O6S.
Knoevenagel condensation of thiazolidin-4-one (1) with
2-chlorosubstituted quinoline-3-carbaldehydes (2a–k) at
the nucleophilic C-5 of active methylene was accomplished
using sodium acetate in refluxing ethanol (99.9 %) to
afford compounds (3a–k). In a similar condition, when
compound (4) reacted with 2-chlorosubstituted quinoline-
3-carbaldehydes (2a–k), it furnished compounds (7a–k).
Formation of both products (3a–k and 7a–k) was explained
based on the literature precedence, and the isomeric ratio of
products was presumed to be mainly Z in all cases. It was
reported that the thermodynamically stable Z-isomer pre-
dominated with a ratio of Z:E isomers 10:1 after recrys-
tallization for all arylidene (3a–k and 7a–k). The ratio of
the two geometrical stereoisomers was readily quantified
by 1H NMR as reported in the literature (Ohishi et al.,
1990). The methylene proton of the Z-isomer was more

123
 Med Chem Res

downfield (7.81–7.90 ppm) than that of the E-isomer due to Table 1 Antibacterial activity of compounds 3a–k, 6 and 8a–k
the interaction with the carbonyl group at the 4th position Compound -R Minimum inhibitory concentration (MIC)
(Georgina et al., 2013) of the thiazolidinone moiety. for bacteria in lg/mL ± SD

E. coli P. aeruginosa S. aureus S. pyogenes

Antibacterial activity MTCC 443 MTCC 1688 MTCC 96 MTCC 442

3a -H 500 1,000 500 250

All the newly synthesized compounds (3a–k, 6 and 3b -6-CH3 [1,000 1,000 250 [1,000
8a–k) were evaluated against Gram-positive bacteria 3c -7-CH3 1,000 250 [1,000 500
(Staphylococcus aureus, Staphylococcus pyogenes) and 3d -8-CH3 [1,000 [1,000 250 250
Gram-negative bacteria (Escherichia coli, Pseudomonas 3e -8-CH2CH3 500 500 1,000 1,000
aeruginosa). Individual minimum inhibitory concentration 3f -6-OCH3 [1,000 500 500 250

(MIC, lg/mL) values of tested compounds (3a–k, 6 and 3g -7-OCH3 1,000 [1,000 250 [1,000
3h -8-OCH3 500 250 500 500
8a–k) against the panel of selected bacterial strains are
3i -6-Br 500 1,000 1,000 500
listed in Table 1 along with MIC values of reference
3j -6-Cl [1,000 500 250 250
compound ampicillin. In the series of compounds (3a–k), 3k -7-Cl [1,000 100 500 1,000
C-5 position of 4-thiazolidinone ring has been substituted 6 – 100 50 250 500
with eleven different quinoline derivatives and antibacte- 8a -H 500 250 1,000 1,000
rial activity data of compounds (3a–k) revealed that none 8b -6-CH3 250 500 250 250
of the compounds showed significant activity against 8c -7-CH3 1,000 [1,000 [1,000 500
selected bacterial strains. N-3 position of parent moiety has 8d -8-CH3 100 250 500 500
been substituted with barbitone ring via acetyl linker in 8e -8-CH2CH3 25 50 125 100

compound (6), and it was found that the antibacterial 8f -6-OCH3 25 1,000 100 100
8g -7-OCH3 500 500 250 [1,000
activity increased enormously, and it was found to be
8h -8-OCH3 25 25 125 12.5
active against E. coli and P. aeruginosa.
8i -6-Br 1,000 250 500 250
In the final compounds (8a–k), three motifs like thiazo-
8j -6-Cl [1,000 1,000 250 500
lidinone, quinolone, and barbitone were incorporated in 8k -7-Cl [1,000 500 500 1,000
single molecular framework and results of antibacterial Ampicillin – 250 100 100 100
activity of compounds are reported in Table 1. Results
2 % Dimethyl sulfoxide used as control and its antibacterial activity is nil or zero
revealed that compounds 8e (8-CH2CH3), 8f (6-OCH3), and
8h (8-OCH3) were found to possess excellent activity at
MIC = 25 lg/mL and compound 8d (8-CH3) showed good
activity at MIC = 100 lg/mL against E. coli. Only com- was found to be active against A. niger at MIC = 50 lg/mL
pounds 8h (8-OCH3) and 8e (8-CH2CH3) were found to be and compound 3f (6-OCH3) displayed moderate activity at
active against P. aeruginosa at MIC = 25 and 50 lg/mL, MIC = 100 lg/mL against A. clavatus. Compound 6
respectively. Compound 8f (6-OCH3) was found equipotent exhibited poor activity against all three selected fungal
to ampicillin at MIC = 100 lg/mL against S. aureus. In strains. Compounds 8e (8-CH2CH3) and 8h (8-OCH3)
case of S. pyogenes, compound 8h (8-OCH3) was found to displayed very good activity at MIC = 100 lg/mL against
possess excellent activity at MIC = 12.5 lg/mL, whereas C. albicans. At MIC = 50 lg/mL, compounds 8d (8-CH3)
compounds 8e (8-CH2CH3) and 8f (6-OCH3) were active at and 8e (8-CH2CH3) exhibited very good activity against
MIC = 100 lg/mL. A. niger. Remaining compounds of the series were found to
be inactive against the tested panel of fungi.
Antifungal activity

Antifungal activity of synthesized compounds was Experimental

screened against fungal (Candida albicans, Aspergillus
niger, and Aspergillus clavatus) strains and results were
compared with griseofulvin. The data of the antifungal
activity are reported in Table 2. Results showed that
compounds 3b (6-CH3) and 3d (8-CH3) were found active
at MIC = 250 lg/mL, while compounds 3e (8-CH2CH3),
3f (6-OCH3), and 3h (8-OCH3) showed enhancement in the
activity and displayed excellent activity against C. albicans
at MIC = 100 lg/mL. Only compound 3e (8-CH2CH3)
Melting points were determined on an electrothermal melt-
ing point apparatus and were reported uncorrected. TLC on
silica gel plates (Merck, 60, F254) was used for purity
checking and reaction monitoring. Column chromatography
on silica gel (Merck, 70–230 mesh and 230–400 mesh ASTH
for flash chromatography) was applied when necessary to
isolate and purify the reaction products. The C, H, and N
analyses were carried out on CARLO-ERBA EA1108

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Med Chem Res

Table 2 Antifungal activity of compounds 3a–k, 6 and 8a–k 5-((2-Chloroquinolin-3-yl)methylene)-2-(2-

Compound -R Minimum inhibitory concentration (MIC) for fungal in
hydroxyphenylimino)thiazolidin-4-one (3a)
lg/mL ± SD

C. albicans A. niger A. clavatus Yield: 68 %; m.p.: 178–180 °C; IR (KBr) vmax/cm-1: 3650
MTCC 227 MTCC 282 MTCC 1323 (OH, phenolic), 3256 (N–H), 3040 (C–H, aromatic), 1688
3a -H [1,000 500 250 (C=O), 1601 (C=N), 1585 (C=C), 760 (C–Cl); 1H NMR
3b -6-CH3 250 250 500 (300 MHz, DMSO-d6, d, ppm): 5.40 (brs, 1H, –OH), 6.95
3c -7-CH3 [1,000 1,000 [1,000 (d, J = 7.0 Hz, 1H, Ar–H), 7.09 (t, J = 7.8 Hz, 2H, Ar–H),
3d -8-CH3 250 125 250 7.20 (d, J = 7.6 Hz, 1H, Ar–H), 7.63 (t, J = 7.7 Hz, 2H,
3e -8-CH2CH3 100 50 500 Ar–H), 7.81 (s, 1H, arylidene –CH–), 7.91 (d, J = 8.0 Hz,
3f -6-OCH3 100 125 100 1H, Ar–H), 8.01 (d, J = 7.0 Hz, 1H, Ar–H), 8.60 (s, 1H,
3g -7-OCH3 1,000 250 500 Ar–H), 9.46 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-
3h -8-OCH3 100 250 1,000
d6, d, ppm): 122.0 (1C, thiazolidinone-C5), 143.1 (1C,
3i -6-Br 1,000 500 250
arylidene-C), 149.3 (1C, C–Cl), 151.5 (1C, C–OH), 158.3
3j -6-Cl [1,000 1,000 500
3k -7-Cl 500 500 1,000
(1C, thiazolidinone-C2), 174.1 (1C, C=O), 115.0–147.0
6 – [1,000 250 500
(13C, Ar–C); LCMS (m/z): 381 (M?); Anal. Calcd. for
8a -H 500 500 1,000 C19H12ClN3O2S: C-59.76, H-3.17, N-11.00; Found:
8b -6-CH3 1,000 1,000 250 C-59.87, H-3.30, N-10.92 %.
8c -7-CH3 [1,000 125 500
8d -8-CH3 500 50 1,000 5-((2-Chloro-6-methylquinolin-3-yl)methylene)-2-(2-
8e -8-CH2CH3 100 50 1,000 hydroxyphenylimino)thiazolidin-4-one (3b)
8f -6-OCH3 500 250 500
8g -7-OCH3 1,000 250 250
Yield: 61 %; m.p.: 214–216 °C; IR (KBr) vmax/cm-1: 3657
8h -8-OCH3 100 500 500
(OH, phenolic), 3250 (N–H), 3049 (C–H, aromatic), 1680
8i -6-Br [1,000 1,000 500
(C=O), 1600 (C=N), 1587 (C=C), 761 (C–Cl); 1H NMR
8j -6-Cl [1,000 250 1,000
8k -7-Cl 500 250 250
(300 MHz, DMSO-d6, d, ppm): 2.37 (s, 3H, –CH3), 5.33
Griseofulvin – 500 100 100 (brs, 1H, –OH), 6.70 (d, J = 6.7 Hz, 1H, Ar–H), 7.01 (t,
J = 8.0 Hz, 2H, Ar–H), 7.08 (d, J = 7.5 Hz, 1H, Ar–H),
2 % Dimethyl sulfoxide used as control and its fungal activity is nil or zero
7.50 (d, J = 7.3 Hz, 1H, Ar–H) 7.70 (s, 1H, Ar–H), 7.83
(s, 1H, arylidene –CH–), 7.90 (d, J = 8.0 Hz, 1H, Ar–H),
8.70 (s, 1H, Ar–H), 9.41 (s, 1H, N–H); 13C NMR
elemental analyzer, and the results are within ±0.6 % of the (100 MHz, DMSO-d6, d, ppm): 21.7 (1C, CH3), 122.1 (1C,
theoretical values. IR spectra were recorded on a FT-IR thiazolidinone-C5), 143.1 (1C, arylidene-C), 148.1 (1C, C–
Perkin-Elmer spectrometer in KBr. 1H NMR spectra were Cl), 151.0 (1C, C–OH), 158.1 (1C, thiazolidinone-C2),
recorded on Varian Gemini 300 MHz and 13C NMR spectra 174.2 (1C, C=O), 115.1–144.8 (13C, Ar–C); LCMS (m/z):
on Varian Mercury-400, 100 MHz in DMSO-d6 as a sol- 395 (M?); Anal. Calcd. for C20H14ClN3O2S: C-60.68,
vent and tetramethylsilane (TMS) as an internal standard. H-3.56, N-10.61; Found: C-60.55, H-3.72, N-10.74 %.
Mass spectra were scanned on a LCMS 2010 spectrometer.
Anhydrous reactions were carried out in oven-dried glass- 5-((2-Chloro-7-methylquinolin-3-yl)methylene)-2-(2-
ware in a nitrogen atmosphere. hydroxyphenylimino)thiazolidin-4-one (3c)

General procedure for preparation of 5-((substituted-2-
chloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-ones (3a–k)
A mixture of the 2-(2-hydroxyphenylimino)thiazolidin-4-
one (1) (0.01 mol), substituted 2-chloroquinoline-3-car-
baldehydes (2a–k) (0.01 mol) and fused sodium acetate
(0.02 mol) was taken in 10 mL of ethanol (99.9 %) and
refluxed for 8–12 h. The reaction mixture was then poured
into 25 mL of cold water and precipitate obtained was
filtered, washed with cold ethanol and crystallized from
chloroform:methanol (1:1) to get compounds (3a–k).
Yield: 71 %; m.p.: 214–216 °C; IR (KBr) vmax/cm-1: 3650
(OH, phenolic), 3247 (N–H), 3054 (C–H, aromatic), 1685
(C=O), 1591 (C=N), 1568 (C=C), 758 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.48 (s, 3H, –CH3), 5.27
(brs, 1H, –OH), 6.90 (d, J = 6.2 Hz, 1H, Ar–H), 7.05 (t,
J = 8.1 Hz, 2H, Ar–H), 7.21 (d, J = 7.5 Hz, 1H, Ar–H),
7.60 (d, J = 7.4 Hz, 1H, Ar–H), 7.65 (s, 1H, Ar–H), 7.80
(s, 1H, arylidene –CH–), 8.00 (d, J = 7.6 Hz, 1H, Ar–H),
8.71 (s, 1H, Ar–H), 9.38 (s, 1H, N–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 21.0 (1C, CH3), 122.0 (1C,
thiazolidinone-C5), 143.0 (1C, arylidene-C), 149.0 (1C,
C–Cl), 151.2 (1C, C–OH), 158.0 (1C, thiazolidinone-C2),

123

174.0 (1C, C=O), 115.0–146.7 (13C, Ar–C); LCMS (m/z):
395 (M?); Anal. Calcd. for C20H14ClN3O2S: C-60.68,
H-3.56, N-10.61; Found: C-60.52, H-3.69, N-10.70 %.
5-((2-Chloro-8-methylquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3d)
Yield: 65 %; m.p.: 185–187 °C; IR (KBr) vmax/cm-1: 3643
(OH, phenolic), 3253 (N–H), 3050 (C–H, aromatic), 1670
(C=O), 1590 (C=N), 1560 (C=C), 753 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 2.57 (s, 3H, –CH3), 5.40
(brs, 1H, –OH), 6.93 (d, J = 6.7 Hz, 1H, Ar–H), 7.10 (t,
J = 7.8 Hz, 2H, Ar–H), 7.16 (d, J = 7.0 Hz, 1H, Ar–H),
7.65 (t, J = 8.1 Hz, 1H, Ar–H), 7.74 (d, J = 8.2 Hz, 1H,
Ar–H), 7.87 (s, 1H, arylidene –CH–), 8.05 (d, J = 7.5 Hz,
1H, Ar–H), 8.64 (s, 1H, Ar–H), 9.45 (s, 1H, N–H); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 20.2 (1C, CH3),
122.3 (1C, thiazolidinone-C5), 143.3 (1C, arylidene-C),
148.9 (1C, C–Cl), 151.0 (1C, C–OH), 158.1 (1C, thiazo-
lidinone-C2), 174.6 (1C, C=O), 115.6–155.2 (13C, Ar–C);
LCMS (m/z): 395 (M?); Anal. Calcd. for C20H14ClN3O2S:
C-60.68, H-3.56, N-10.61; Found: C-60.56, H-3.42,
N-10.73 %.
5-((2-Chloro-8-ethylquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3e)
Yield: 60 %; m.p.: 201–203 °C; IR (KBr) vmax/cm-1: 3637
(OH, phenolic), 3260 (N–H), 3046 (C–H, aromatic), 2870
(C–H, aliphatic), 1677 (C=O), 1601 (C=N), 1579 (C=C),
765 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 1.79
(t, J = 5.0 Hz, 3H, –CH3), 3.01 (q, J = 4.1 Hz, 2H,
–CH3), 5.40 (brs, 1H, –OH), 6.80 (d, J = 6.1 Hz, 1H, Ar–
H), 7.19 (t, J = 7.0 Hz, 2H, Ar–H), 7.31 (d, J = 7.3 Hz,
1H, Ar–H), 7.68 (t, J = 7.9 Hz, 1H, Ar–H), 7.80 (d,
J = 8.2 Hz, 1H, Ar–H), 7.89 (s, 1H, arylidene –CH–), 7.98
(d, J = 7.8 Hz, 1H, Ar–H), 8.68 (s, 1H, Ar–H), 9.37 (s, 1H,
N–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 14.1 (1C,
CH3), 23.9 (1C, CH2), 122.0 (1C, thiazolidinone-C5), 143.0
(1C, arylidene-C), 148.8 (1C, C–Cl), 151.1 (1C, C–OH),
158.3 (1C, thiazolidinone-C2), 174.3 (1C, C=O),
115.1–155.0 (13C, Ar–C); LCMS (m/z): 410 (M?); Anal.
Calcd. for C21H16ClN3O2S: C-61.53, H-3.93, N-10.25;
Found: C-61.41, H-4.05, N-10.09 %.
5-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3f)
Yield: 69 %; m.p.: 248–250 °C; IR (KBr) vmax/cm-1: 3631
(OH, phenolic), 3265 (N–H), 3052 (C–H, aromatic), 2820
(–OCH3), 1670 (C=O), 1616 (C=N), 1580 (C=C), 769 (C–
Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.91 (s, 3H,
123
Med Chem Res
–OCH3), 5.46 (brs, 1H, –OH), 6.91 (d, J = 6.9 Hz, 1H,
Ar–H), 7.00 (t, J = 7.5 Hz, 2H, Ar–H), 7.16 (s, 1H, Ar–H),
7.31 (d, J = 7.8 Hz, 1H, Ar–H), 7.51 (d, J = 7.3 Hz, 1H,
Ar–H), 7.80 (d, J = 8.2 Hz, 1H, Ar–H), 7.88 (s, 1H, ary-
lidene –CH–), 8.71 (s, 1H, Ar–H), 9.30 (s, 1H, N–H); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 55.1 (1C, OCH3),
122.4 (1C, thiazolidinone-C5), 143.3 (1C, arylidene-C),
147.0 (1C, C–Cl), 151.2 (1C, C–OH), 158.3 (1C, thiazo-
lidinone-C2), 174.5 (1C, C=O), 115.3–157.0 (13C, Ar–C);
LCMS (m/z): 411 (M?); Anal. Calcd. for C20H14ClN3O3S:
C-58.32, H-3.43, N-10.20; Found: C-58.47, H-3.35,
N-10.11 %.
5-((2-Chloro-7-methoxyquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3g)
Yield: 72 %; m.p.: 192–194 °C; IR (KBr) vmax/cm-1: 3643
(OH, phenolic), 3250 (N–H), 3049 (C–H, aromatic), 2829
(–OCH3), 1675 (C=O), 1620 (C=N), 1578 (C=C), 755 (C–
Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.90 (s, 3H,
–OCH3), 5.33 (brs, 1H, –OH), 6.85 (d, J = 6.8 Hz, 1H,
Ar–H), 7.19 (t, J = 7.9 Hz, 2H, Ar–H), 7.20 (s, 1H, Ar–H),
7.25 (d, J = 7.3 Hz, 1H, Ar–H), 7.42 (s, 1H, Ar–H), 7.85
(s, 1H, arylidene –CH–), 8.00 (d, J = 7.5 Hz, 1H, Ar–H),
8.80 (s, 1H, Ar–H), 9.37 (s, 1H, N–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 56.1 (1C, OCH3), 122.1
(1C, thiazolidinone-C5), 143.1 (1C, arylidene-C), 149.8
(1C, C–Cl), 151.5 (1C, C–OH), 158.1 (1C, thiazolidinone-
C2), 174.0 (1C, C=O), 115.3–148.0 (13C, Ar–C); LCMS
(m/z): 411 (M?); Anal. Calcd. for C20H14ClN3O3S:
C-58.32, H-3.43, N-10.20; Found: C-58.43, H-3.29,
N-10.06 %.
5-((2-Chloro-8-methoxyquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3h)
Yield: 62 %; m.p.: 218–220 °C; IR (KBr) vmax/cm-1: 3648
(OH, phenolic), 3255 (N–H), 3037 (C–H, aromatic), 2821
(–OCH3), 1683 (C=O), 1618 (C=N), 1583 (C=C), 764 (C–
Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.72 (s, 3H,
–OCH3), 5.42 (brs, 1H, –OH), 6.79 (d, J = 7.0 Hz, 1H,
Ar–H), 7.11 (t, J = 7.8 Hz, 2H, Ar–H), 7.26 (s, 1H, Ar–H),
7.45 (d, J = 7.1 Hz, 1H, Ar–H), 7.65 (d, J = 7.5 Hz, 1H,
Ar–H), 7.81 (t, J = 8.2 Hz, 1H, Ar–H), 7.90 (s, 1H, ary-
lidene –CH–), 8.74 (s, 1H, Ar–H), 9.29 (s, 1H, N–H); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 55.8 (1C, OCH3),
122.0 (1C, thiazolidinone-C5), 143.0 (1C, arylidene-C),
148.1 (1C, C–Cl), 151.7 (1C, C–OH), 158.0 (1C, thiazo-
lidinone-C2), 174.3 (1C, C=O), 115.6–156.0 (13C, Ar–C);
LCMS (m/z): 411 (M?); Anal. Calcd. for C20H14ClN3O3S:
C-58.32, H-3.43, N-10.20; Found: C-58.45, H-3.31,
N-10.29 %.
Med Chem Res
5-((6-Bromo-2-chloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3i)
Yield: 57 %; m.p.: 192–194 °C; IR (KBr) vmax/cm-1: 3654
(OH, phenolic), 3260 (N–H), 3029 (C–H, aromatic), 1687
(C=O), 1625 (C=N), 1580 (C=C), 771 (C–Cl), 620 (C–Br);
1
H NMR (300 MHz, DMSO-d6, d, ppm): 5.41 (brs, 1H,
–OH), 6.72 (d, J = 7.2 Hz, 1H, Ar–H), 7.18 (t, J = 7.8 Hz,
2H, Ar–H), 7.25 (s, 1H, Ar–H), 7.87 (s, 1H, arylidene
–CH–), 8.09 (d, J = 7.5 Hz, 1H, Ar–H), 8.30 (d,
J = 8.01 Hz, 1H, Ar–H), 8.42 (s, 1H, Ar–H), 8.68 (s, 1H,
Ar–H), 9.32 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 121.5 (1C, C–Br), 122.7 (1C, thiazolidinone-
C5), 143.1 (1C, arylidene-C), 149.5 (1C, C–Cl), 151.2 (1C,
C–OH), 158.1 (1C, thiazolidinone-C2), 174.3 (1C, C=O),
115.6–156.0 (12C, Ar–C); LCMS (m/z): 460 (M?); Anal.
Calcd. for C19H11BrClN3O2S: C-49.53, H-2.41, N-9.12;
Found: C-49.60, H-2.28, N-8.97 %.
5-((2,6-Dichloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3j)
Yield: 72 %; m.p.: 256–258 °C; IR (KBr) vmax/cm-1: 3650
(OH, phenolic), 3268 (N–H), 3037 (C–H, aromatic), 1690
(C=O), 1625 (C=N), 1588 (C=C), 760 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 5.46 (brs, 1H, –OH), 6.70
(d, J = 7.2 Hz, 1H, Ar–H), 7.15 (t, J = 7.6 Hz, 2H, Ar–
H), 7.32 (s, 1H, Ar–H), 7.83 (s, 1H, arylidene –CH–), 8.00
(d, J = 7.7 Hz, 1H, Ar–H), 8.32 (d, J = 7.9 Hz, 1H, Ar–
H), 8.51 (s, 1H, Ar–H), 8.68 (s, 1H, Ar–H), 9.30 (s, 1H,
N–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 122.1
(1C, thiazolidinone-C5), 132.0 (1C, C–Cl), 143.8 (1C,
arylidene-C), 149.5 (1C, C–Cl), 151.0 (1C, C–OH), 158.6
(1C, thiazolidinone-C2), 174.0 (1C, C=O), 115.0–147.0
(12C, Ar–C); LCMS (m/z): 416 (M?); Anal. Calcd. for
C19H11Cl2N3O2S: C-54.82, H-2.66, N-10.09; Found:
C-54.69, H-2.73, N-10.22 %.
5-((2,7-Dichloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (3k)
Yield: 55 %; m.p.: 285–287 °C; IR (KBr) vmax/cm-1: 3650
(OH, phenolic), 3261 (N–H), 3033 (C–H, aromatic), 1687
(C=O), 1625 (C=N), 1590 (C=C), 768 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 5.38 (brs, 1H, –OH), 6.70
(d, J = 7.2 Hz, 1H, Ar–H), 7.12 (t, J = 7.0 Hz, 2H, Ar–
H), 7.29 (s, 1H, Ar–H), 7.71 (d, J = 7.1 Hz, 1H, Ar–H),
7.82 (s, 1H, arylidene –CH–), 7.99 (s, 1H, Ar–H), 8.42 (d,
J = 7.1 Hz, 1H, Ar–H), 8.70 (s, 1H, Ar–H), 9.41 (s, 1H,
N–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 122.5
(1C, thiazolidinone-C5), 136.9 (1C, C–Cl), 143.3 (1C,
arylidene-C), 150.1 (1C, C–Cl), 151.6 (1C, C–OH), 158.3
(1C, thiazolidinone-C2), 174.2(1C, C=O), 115.1–147.5
(12C, Ar–C); LCMS (m/z): 416 (M?); Anal. Calcd. for
C19H11Cl2N3O2S: C-54.82, H-2.66, N-10.09; Found:
C-54.70, H-2.80, N-10.28 %.
Procedure for preparation of 3-(2-chloroacetyl)-2-(2-
hydroxyphenylimino)thiazolidin-4-one (4)
A solution of 2-(2-hydroxyphenylimino)thiazolidin-4-one
(1) (0.01 mol) in 10 mL anhydrous benzene was cooled to
0–5 °C. Chloroacetyl chloride (0.01 mol) was added with
vigorous stirring, followed by addition of triethylamine
(1 mL) and potassium carbonate (0.01 mol). The reaction
mixture was then refluxed for 7 h. At the end of the reac-
tion, solvent was removed in vacuum. An oily product was
obtained which was dissolved in a minimum quantity of
methanol to obtain precipitate which was filtered off, dried
and crystallized from ethanol.
Yield: 72 %; m.p.: 160–162 °C; IR (KBr) vmax/cm-1:
3632 (OH, phenolic), 3049 (C–H, aromatic), 2868 (C–H,
aliphatic), 1739, 1691 (C=O), 1580 (C=N), 761 (C–Cl); 1H
NMR (300 MHz, DMSO-d6, d, ppm): 4.08 (s, 2H, CH2-
thiazolidine ring), 4.35 (s, 2H, COCH2), 5.48 (brs, 1H,
–OH), 6.80 (d, J = 6.9 Hz, 1H, Ar–H), 7.03 (t, J = 8.1 Hz,
1H, Ar–H), 7.21 (d, J = 7.2 Hz, 1H, Ar–H), 7.38 (t,
J = 8.4 Hz, 1H, Ar–H); 13C NMR (100 MHz, DMSO-d6,
d, ppm): 30.0 (1C, thiazolidinone-C5), 39.3 (1C, acetyl-
CH2), 151.5 (1C, C–OH), 158.3 (1C, thiazolidinone-C2),
165.4 (1C, acetyl-C=O), 171.8 (1C, thiazolidinone-C=O),
115.5–137.0 (5C, Ar–C); LCMS (m/z): 284 (M?); Anal.
Calcd. for C11H9ClN2O3S: C-46.40, H-3.19, N-9.84;
Found: C-46.34, H-3.24, N-9.89 %.
Procedure for preparation of 1-(2-(2-(2-
hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (6)
To a mixture of barbituric acid (5) (0.01 mol) in 20 mL of
toluene and 3-(2-chloroacetyl)-2-(2-hydroxyphenylimi-
no)thiazolidin-4-one (4) (0.01 mol), triethylamine (0.5 mL)
and potassium carbonate (0.01 mol) were added. The
mixture was refluxed for 5 h with constant stirring. The
solvent was removed in vacuum. The residue obtained was
treated with ice-cold water (20 mL), filtered, dried and
crystallized from chloroform.
Yield: 67 %; m.p.:198–200 °C; IR (KBr) vmax/cm-1:
3621 (OH, phenolic), 3283 (N–H), 3052 (C–H, aromatic),
2870 (C–H, aliphatic), 1725, 1705, 1680 (C=O), 1565
(C=N); 1H NMR (300 MHz, DMSO-d6, d, ppm): 3.07 (s,
2H, CH2-barbitone ring), 4.12 (s, 2H, CH2-thiazolidine
ring), 4.39 (s, 2H, COCH2), 5.51 (brs, 1H, –OH), 6.92 (d,
J = 7.1 Hz, 1H, Ar–H), 7.08 (t, J = 8.1 Hz, 1H, Ar–H),
7.20 (d, J = 7.4 Hz, 1H, Ar–H), 7.41 (t, J = 8.0 Hz, 1H,
Ar–H), 9.61 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-d6,
123

d, ppm): 30.1 (1C, thiazolidinone-C5), 39.7 (1C, barbitone-
CH2), 46.0 (1C, acetyl-CH2), 151.5 (1C, C–OH), 158.7 (1C,
thiazolidinone-C2), 152.0–171.6 (5C, C=O), 115.5–137.1
(5C, Ar–C); LCMS (m/z): 376 (M?); Anal. Calcd. for
C15H12N4O6S: C-47.87, H-3.21, N-14.89; Found: C-47.90,
H-3.16, N-14.96 %.
General procedure for preparation of 3-(2-
chloroacetyl)-5-((substituted-2-chloroquinolin-3-
yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-
ones (7a–k)
A mixture of the 3-(2-chloroacetyl)-2-(2-hydroxyphenyli-
mino)thiazolidin-4-one (4) (0.01 mol), substituted 2-chlor-
oquinoline-3-carbaldehydes (2a–k) (0.01 mol) and fused
sodium acetate (0.02 mol) was taken in 25 mL of ethanol
(99.9 %) and refluxed for 4–8 h. The mixture was then
poured into 100 mL of water and kept overnight. The pre-
cipitate obtained was filtered, washed with water, and
crystallized from chloroform to give compounds (7a–k).
3-(2-Chloroacetyl)-5-((2-chloroquinolin-3-yl)methylene)-
2-(2-hydroxyphenylimino)thiazolidin-4-one (7a)
Yield: 59 %; m.p.: 210–212 °C; IR (KBr) vmax/cm-1: 3640
(OH, phenolic), 3051 (C–H, aromatic), 2922, 2870 (C–H,
aliphatic), 1735, 1687 (C=O), 1578 (C=N), 1510 (C=C),
790 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 4.21
(s, 2H, COCH2), 5.41 (brs, 1H, –OH), 6.90 (d, J = 6.7 Hz,
1H, Ar–H), 7.06 (t, J = 8.0 Hz, 2H, Ar–H), 7.18 (d,
J = 7.5 Hz, 1H, Ar–H), 7.60 (t, J = 7.6 Hz, 2H, Ar–H),
7.82 (s, 1H, arylidene –CH–), 7.82 (d, J = 8.1 Hz, 1H, Ar–
H), 8.10 (d, J = 7.2 Hz, 1H, Ar–H), 8.70 (s, 1H, Ar–H);
13
C NMR (100 MHz, DMSO-d6, d, ppm): 39.1 (1C,
acetyl-CH2), 122.0 (1C, thiazolidinone-C5), 143.3 (1C,
arylidene-C), 149.3 (1C, C–Cl), 151.8 (1C, C–OH), 158.1
(1C, thiazolidinone-C2), 165.7 (1C, acetyl-C=O), 172.0
(1C, thiazolidinone-C=O), 115.0–147.0 (13C, Ar–C);
LCMS (m/z): 457 (M?); Anal. Calcd. for C21H13Cl2N3O3S:
C-55.03, H-2.86, N-9.17; Found: C-55.98, H-2.91,
N-9.21 %.
5-((2-Chloro-6-methylquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7b)
Yield: 64 %; m.p.: 264–266 °C; IR (KBr) vmax/cm-1: 3648
(OH, phenolic), 3054 (C–H, aromatic), 2917, 2870 (C–H,
aliphatic), 1741, 1690 (C=O), 1575 (C=N), 1509 (C=C),
776 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.39
(s, 3H, –CH3), 4.24 (s, 2H, COCH2), 5.35 (brs, 1H, –OH),
6.97 (d, J = 6.5 Hz, 1H, Ar–H), 7.03 (t, J = 8.2 Hz, 2H,
Ar–H), 7.15 (d, J = 7.7 Hz, 1H, Ar–H), 7.51 (d,
123
Med Chem Res
J = 7.0 Hz, 1H, Ar–H) 7.68 (s, 1H, Ar–H), 7.87 (s, 1H,
arylidene –CH–), 7.89 (d, J = 8.1 Hz, 1H, Ar–H), 8.68 (s,
1H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 21.3
(1C, CH3), 40.2 (1C, acetyl-CH2), 122.1 (1C, thiazolidi-
none-C5), 143.1 (1C, arylidene-C), 148.0 (1C, C–Cl), 151.1
(1C, C–OH), 158.0 (1C, thiazolidinone-C2), 165.1 (1C,
acetyl-C=O), 172.3 (1C, thiazolidinone-C=O), 115.2–144.8
(13C, Ar–C); LCMS (m/z): 471 (M?); Anal. Calcd. for
C22H15Cl2N3O3S: C-55.94, H-3.20, N-8.90; Found:
C-55.87, H-3.16, N-8.93 %.
5-((2-Chloro-7-methylquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7c)
Yield: 59 %; m.p.: 236–238 °C; IR (KBr) vmax/cm-1: 3651
(OH, phenolic), 3043 (C–H, aromatic), 2920, 2873 (C–H,
aliphatic), 1745, 1687 (C=O), 1571 (C=N), 1509 (C=C),
786 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.42
(s, 3H, –CH3), 4.25 (s, 2H, COCH2), 5.27 (brs, 1H, –OH),
6.91 (d, J = 6.3 Hz, 1H, Ar–H), 7.08 (t, J = 8.1 Hz, 2H,
Ar–H), 7.20 (d, J = 7.5 Hz, 1H, Ar–H), 7.57 (d,
J = 7.2 Hz, 1H, Ar–H), 7.64 (s, 1H, Ar–H), 7.85 (s, 1H,
arylidene –CH–), 8.01 (d, J = 7.6 Hz, 1H, Ar–H), 8.65 (s,
1H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 21.0
(1C, CH3), 39.5 (1C, acetyl-CH2), 122.1 (1C, thiazolidi-
none-C5), 143.5 (1C, arylidene-C), 149.0 (1C, C–Cl), 151.4
(1C, C–OH), 158.3 (1C, thiazolidinone-C2), 165.0 (1C,
acetyl-C=O), 172.1 (1C, thiazolidinone-C=O), 115.0–146.3
(13C, Ar–C); LCMS (m/z): 471 (M?); Anal. Calcd. for
C22H15Cl2N3O3S: C-55.94, H-3.20, N-8.90; Found:
C-55.98, H-3.23, N-8.83 %.
5-((2-Chloro-8-methylquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino) thiazolidin-
4-one (7d)
Yield: 67 %; m.p.: 270–272 °C; IR (KBr) vmax/cm-1: 3654
(OH, phenolic), 3037 (C–H, aromatic), 2922, 2871 (C–H,
aliphatic), 1745, 1685 (C=O), 1571 (C=N), 1514 (C=C), 779
(C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 2.49 (s, 3H,
–CH3), 4.19 (s, 2H, COCH2), 5.35 (brs, 1H, –OH), 6.99 (d,
J = 6.8 Hz, 1H, Ar–H), 7.14 (t, J = 7.8 Hz, 2H, Ar–H), 7.13
(d, J = 7.4 Hz, 1H, Ar–H), 7.62 (t, J = 8.2 Hz, 1H, Ar–H),
7.74 (d, J = 8.0 Hz, 1H, Ar–H), 7.83 (s, 1H, arylidene –CH–),
7.95 (d, J = 7.9 Hz, 1H, Ar–H), 8.60 (s, 1H, Ar–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 17.1 (1C, CH3), 40.3 (1C,
acetyl-CH2), 122.1 (1C, thiazolidinone-C5), 143.8 (1C, ary-
lidene-C), 148.5 (1C, C–Cl), 151.6 (1C, C–OH), 158.1 (1C,
thiazolidinone-C2), 165.4 (1C, acetyl-C=O), 172.5 (1C, thia-
zolidinone-C=O), 116.0–154.0 (13C, Ar–C); LCMS (m/z):
471 (M?); Anal. Calcd. for C22H15Cl2N3O3S: C-55.94,
H-3.20, N-8.90; Found: C-55.87, H-3.17, N-8.97 %.
Med Chem Res
5-((2-Chloro-8-ethylquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7e)
Yield: 70 %; m.p.: 245–247 °C; IR (KBr) vmax/cm-1: 3660
(OH, phenolic), 3035 (C–H, aromatic), 2920, 2865 (C–H,
aliphatic), 1739, 1683 (C=O), 1575 (C=N), 1521 (C=C),
772 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 1.70
(t, J = 5.6 Hz, 3H, –CH3), 3.10 (q, J = 4.3 Hz, 2H,
–CH3), 4.21 (s, 2H, COCH2), 5.42 (brs, 1H, –OH), 6.89 (d,
J = 6.2 Hz, 1H, Ar–H), 7.11 (t, J = 7.1 Hz, 2H, Ar–H),
7.21 (d, J = 7.9 Hz, 1H, Ar–H), 7.65 (t, J = 7.9 Hz, 1H,
Ar–H), 7.78 (d, J = 8.1 Hz, 1H, Ar–H), 7.87 (s, 1H, ary-
lidene –CH–), 7.97 (d, J = 7.8 Hz, 1H, Ar–H), 8.68 (s, 1H,
Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 14.3
(1C, CH3), 23.5 (1C, CH2), 39.1 (1C, acetyl-CH2), 122.1
(1C, thiazolidinone-C5), 143.2 (1C, arylidene-C), 148.5
(1C, C–Cl), 151.3 (1C, C–OH), 158.1 (1C, thiazolidinone-
C2), 165.3 (1C, acetyl-C=O), 172.1 (1C, thiazolidinone-
C=O), 115.5–154.7 (13C, Ar–C); LCMS (m/z): 485 (M?);
Anal. Calcd. for C23H17Cl2N3O3S: C-56.80, H-3.52,
N-8.64; Found: C-56.75, H-3.61, N-8.67 %.
5-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7f)
Yield: 61 %; m.p.: 287–289 °C; IR (KBr) vmax/cm-1: 3664
(OH, phenolic), 3041 (C–H, aromatic), 2929, 2871 (C–H,
aliphatic), 2815 (–OCH3), 1737, 1683 (C=O), 1571 (C=N),
1530 (C=C), 778 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.80 (s, 3H, –OCH3), 4.29 (s, 2H, COCH2), 5.40
(brs, 1H, –OH), 6.90 (d, J = 6.8 Hz, 1H, Ar–H), 7.01 (t,
J = 7.4 Hz, 2H, Ar–H), 7.11 (s, 1H, Ar–H), 7.24 (d,
J = 7.8 Hz, 1H, Ar–H), 7.39 (d, J = 7.5 Hz, 1H, Ar–H),
7.79 (d, J = 8.1 Hz, 1H, Ar–H), 7.85 (s, 1H, arylidene
–CH–), 8.68 (s, 1H, Ar–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 39.5 (1C, acetyl-CH2), 55.6 (1C, OCH3),
122.0 (1C, thiazolidinone-C5), 143.3 (1C, arylidene-C),
147.0 (1C, C–Cl), 151.5 (1C, C–OH), 158.0 (1C, thiazo-
lidinone-C2), 165.1 (1C, acetyl-C=O), 172.3 (1C, thiazo-
lidinone-C=O), 105.7–157.0 (13C, Ar–C); LCMS (m/z):
487 (M?); Anal. Calcd. for C22H15Cl2N3O4S: C-54.11,
H-3.10, N-8.60; Found: C-54.09, H-3.12, N-8.68 %.
5-((2-Chloro-7-methoxyquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7g)
Yield: 57 %; m.p.: 265–267 °C; IR (KBr) vmax/cm-1: 3671
(OH, phenolic), 3037 (C–H, aromatic), 2931, 2870 (C–H,
aliphatic), 2817 (–OCH3), 1740, 1678 (C=O), 1570 (C=N),
1531 (C=C), 770 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.81 (s, 3H, –OCH3), 4.33 (s, 2H, COCH2), 5.31
(brs, 1H, –OH), 6.91 (d, J = 6.7 Hz, 1H, Ar–H), 7.11 (t,
J = 7.8 Hz, 2H, Ar–H), 7.19 (s, 1H, Ar–H), 7.25 (d,
J = 7.1 Hz, 1H, Ar–H), 7.37 (s, 1H, Ar–H), 7.86 (s, 1H,
arylidene –CH–), 7.99 (d, J = 7.5 Hz, 1H, Ar–H), 8.71 (s,
1H, Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 40.0
(1C, acetyl-CH2), 55.9 (1C, OCH3), 122.0 (1C, thiazolid-
inone-C5), 143.2 (1C, arylidene-C), 149.5 (1C, C–Cl),
151.2 (1C, C–OH), 158.3 (1C, thiazolidinone-C2), 165.7
(1C, acetyl-C=O), 172.3 (1C, thiazolidinone-C=O),
105.0–148.3 (13C, Ar–C); LCMS (m/z): 487 (M?); Anal.
Calcd. for C22H15Cl2N3O4S: C-54.11, H-3.10, N-8.60;
Found: C-54.18, H-3.03, N-8.56 %.
5-((2-Chloro-8-methoxyquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7h)
Yield: 65 %; m.p.: 271–273 °C; IR (KBr) vmax/cm-1: 3676
(OH, phenolic), 3033 (C–H, aromatic), 2931, 2875 (C–H,
aliphatic), 2824 (–OCH3), 1741, 1670 (C=O), 1571 (C=N),
1536 (C=C), 771 (C–Cl); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 3.85 (s, 3H, –OCH3), 4.36 (s, 2H, COCH2), 5.24
(brs, 1H, –OH), 6.87 (d, J = 7.0 Hz, 1H, Ar–H), 7.08 (t,
J = 7.8 Hz, 2H, Ar–H), 7.15 (s, 1H, Ar–H), 7.39 (d,
J = 7.1 Hz, 1H, Ar–H), 7.67 (d, J = 7.5 Hz, 1H, Ar–H),
7.72 (t, J = 8.2 Hz, 1H, Ar–H), 7.84 (s, 1H, arylidene
–CH–), 8.71 (s, 1H, Ar–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 39.8 (1C, acetyl-CH2), 56.0 (1C, OCH3),
122.0 (1C, thiazolidinone-C5), 143.5 (1C, arylidene-C),
148.4 (1C, C–Cl), 151.5 (1C, C–OH), 158.3 (1C, thiazo-
lidinone-C2), 165.3 (1C, acetyl-C=O), 172.7 (1C, thiazo-
lidinone-C=O), 108.0–155.1 (13C, Ar–C); LCMS (m/z):
487 (M?); Anal. Calcd. for C22H15Cl2N3O4S: C-54.11,
H-3.10, N-8.60; Found: C-54.20, H-3.16, N-8.63 %.
5-((6-Bromo-2-chloroquinolin-3-yl)methylene)-3-(2-
chloroacetyl)-2-(2-hydroxyphenylimino)thiazolidin-
4-one (7i)
Yield: 67 %; m.p.: 268–270 °C; IR (KBr) vmax/cm-1: 3670
(OH, phenolic), 3033 (C–H, aromatic), 2937, 2881 (C–H,
aliphatic), 1744, 1676 (C=O), 1564 (C=N), 1540 (C=C),
770 (C–Cl), 617 (C–Br); 1H NMR (300 MHz, DMSO-d6,
d, ppm): 4.31 (s, 2H, COCH2), 5.33 (brs, 1H, –OH), 6.80
(d, J = 7.2 Hz, 1H, Ar–H), 7.11 (t, J = 7.6 Hz, 2H, Ar–
H), 7.17 (s, 1H, Ar–H), 7.85 (s, 1H, arylidene –CH–), 8.01
(d, J = 7.9 Hz, 1H, Ar–H), 8.27 (d, J = 8.0 Hz, 1H, Ar–
H), 8.36 (s, 1H, Ar–H), 8.70 (s, 1H, Ar–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 39.1 (1C, acetyl-CH2),
121.5 (1C, C–Br), 122.0 (1C, thiazolidinone-C5), 143.2
(1C, arylidene-C), 149.5 (1C, C–Cl), 151.5 (1C, C–OH),
158.3 (1C, thiazolidinone-C2), 165.7 (1C, acetyl-C=O),
123

172.7 (1C, thiazolidinone-C=O), 115.5–147.5 (12C, Ar–
C); LCMS (m/z): 487 (M?); Anal. Calcd. for C21H12
BrCl2N3O3S: C-46.95, H-2.25, N-7.82; Found: C-47.01,
H-2.36, N-7.79 %.
3-(2-Chloroacetyl)-5-((2,6-dichloroquinolin-3-
yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-one
(7j)
Yield: 71 %; m.p.: 240–242 °C; IR (KBr) vmax/cm-1: 3676
(OH, phenolic), 3039 (C–H, aromatic), 2937, 2874 (C–H,
aliphatic), 1748, 1680 (C=O), 1564 (C=N), 1540 (C=C),
781 (C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 4.42
(s, 2H, COCH2), 5.31 (brs, 1H, –OH), 6.75 (d, J = 7.3 Hz,
1H, Ar–H), 7.12 (t, J = 7.6 Hz, 2H, Ar–H), 7.20 (s, 1H,
Ar–H), 7.87 (s, 1H, arylidene –CH–), 8.00 (d, J = 7.5 Hz,
1H, Ar–H), 8.20 (d, J = 8.3 Hz, 1H, Ar–H), 8.35 (s, 1H,
Ar–H), 8.77 (s, 1H, Ar–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 39.2 (1C, acetyl-CH2), 122.3 (1C, thiazolidi-
none-C5), 132.0 (1C, C–Cl), 143.1 (1C, arylidene-C), 149.4
(1C, C–Cl), 151.8 (1C, C–OH), 158.1 (1C, thiazolidinone-
C2), 165.2 (1C, acetyl-C=O), 172.5 (1C, thiazolidinone-
C=O), 115.5–144.5 (12C, Ar–C); LCMS (m/z): 493.0
(M?); Anal. Calcd. for C21H12Cl3N3O3S: C-51.19, H-2.45,
N-8.53; Found: C-51.21, H-2.33, N-8.57 %.
3-(2-Chloroacetyl)-5-((2,7-dichloroquinolin-3-
yl)methylene)-2-(2-hydroxyphenylimino)thiazolidin-4-one
(7k)
Yield: 62 %; m.p.: 288–290 °C; IR (KBr) vmax/cm-1: 3670
(OH, phenolic), 3041 (C–H, aromatic), 2937, 2870 (C–H,
aliphatic), 1750, 1678 (C=O), 1560 (C=N), 1537 (C=C), 780
(C–Cl); 1H NMR (300 MHz, DMSO-d6, d, ppm): 4.40 (s, 2H,
COCH2), 5.30 (brs, 1H, –OH), 6.73 (d, J = 7.3 Hz, 1H, Ar–
H), 7.16 (t, J = 7.6 Hz, 2H, Ar–H), 7.23 (s, 1H, Ar–H), 7.64
(d, J = 7.3 Hz, 1H, Ar–H), 7.87 (s, 1H, arylidene –CH–), 7.90
(s, 1H, Ar–H), 8.20 (d, J = 7.1 Hz, 1H, Ar–H), 8.77 (s, 1H,
Ar–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 39.3 (1C,
acetyl-CH2), 122.1 (1C, thiazolidinone-C5), 136.0 (1C, C–Cl),
143.0 (1C, arylidene-C), 150.0 (1C, C–Cl), 151.3 (1C, C–
OH), 158.0 (1C, thiazolidinone-C2), 165.7 (1C, acetyl-C=O),
172.1 (1C, thiazolidinone-C=O), 115.5–147.8 (12C, Ar–C);
LCMS (m/z): 493.0 (M?); Anal. Calcd. for C21H12Cl3N3O3S:
C-51.19, H-2.45, N-8.53; Found: C-51.25, H-2.36, N-8.55 %.
General procedure for preparation of 1-(2-(5-
((substituted-2-chloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-triones (8a–k)
To a mixture of barbituric acid (5) (0.01 mol) in 20 mL of
anhydrous benzene and 3-(2-chloroacetyl)-5-((substituted-
123
Med Chem Res
2-chloroquinolin-3-yl)methylene)-2-(2-hydroxyphenylimi-
no)thiazolidin-4-ones (7a–k) (0.01 mol), triethylamine
(0.5 mL) and potassium carbonate (0.01 mol) were added.
The mixture was refluxed for 12–14 h with constant stir-
ring. The solvent was removed in vacuum. The residue
obtained was treated with methanol (20 mL), filtered, dried
and crystallized from chloroform.
1-(2-(-5-((2-Chloroquinolin-3-yl)methylene)-2-(2-
hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8a)
Yield: 55 %; m.p.: 226–228 °C; IR (KBr) vmax/cm-1: 3640
(OH, phenolic), 3285 (N–H), 3048 (C–H, aromatic), 2923,
2875 (C–H, aliphatic), 1723, 1705, 1681 (C=O), 1579
(C=N), 1509 (C=C), 762 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 3.01 (s, 2H, CH2-barbitone ring), 4.45
(s, 2H, COCH2), 5.36 (brs, 1H, –OH), 6.97 (d, J = 7.1 Hz,
1H, Ar–H), 7.10 (t, J = 8.1 Hz, 2H, Ar–H), 7.23 (d,
J = 7.6 Hz, 1H, Ar–H), 7.63 (t, J = 7.6 Hz, 2H, Ar–H),
7.85 (s, 1H, arylidene –CH–), 7.91 (d, J = 8.1 Hz, 1H, Ar–
H), 8.08 (d, J = 7.6 Hz, 1H, Ar–H), 8.65 (s, 1H, Ar–H),
9.67 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 39.0 (1C, barbitone-CH2), 46.3 (1C, acetyl-CH2),
122.3 (1C, thiazolidinone-C5), 143.3 (1C, arylidene-C),
149.3 (1C, C–Cl), 151.2 (1C, C–OH), 158.1 (1C, thiazo-
lidinone-C2), 115.0–147.0 (13C, Ar–C), 152.0–172.0 (5C,
C=O); LCMS (m/z): 549 (M?); Anal. Calcd. for
C25H16ClN5O6S: C-54.60, H-2.93, N-12.73; Found:
C-54.63, H-3.01, N-12.66 %.
1-(2-(-5-((2-Chloro-6-methylquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8b)
Yield: 66 %; m.p.: 278–280 °C; IR (KBr) vmax/cm-1: 3648
(OH, phenolic), 3282 (N–H), 3050 (C–H, aromatic), 2920,
2877 (C–H, aliphatic), 1720, 1705, 1685 (C=O), 1572
(C=N), 1500 (C=C), 771 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.41 (s, 3H, –CH3), 3.05 (s, 2H, CH2-
barbitone ring), 4.25 (s, 2H, COCH2), 5.31 (brs, 1H, –OH),
6.89 (d, J = 6.8 Hz, 1H, Ar–H), 7.00 (t, J = 8.1 Hz, 2H,
Ar–H), 7.11 (d, J = 7.9 Hz, 1H, Ar–H), 7.57 (d,
J = 7.3 Hz, 1H, Ar–H) 7.68 (s, 1H, Ar–H), 7.81 (s, 1H,
arylidene –CH–), 7.91 (d, J = 8.2 Hz, 1H, Ar–H), 8.70 (s,
1H, Ar–H), 9.71 (s, 1H, N–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.3 (1C, CH3), 39.0 (1C, barbitone-
CH2), 46.5 (1C, acetyl-CH2), 122.2 (1C, thiazolidinone-
C5), 143.2 (1C, arylidene-C), 148.1 (1C, C–Cl), 151.3 (1C,
C–OH), 158.4 (1C, thiazolidinone-C2), 115.5–144.0 (13C,
Ar–C), 152.0–172.5 (5C, C=O); LCMS (m/z): 563 (M?);
Anal. Calcd. for C26H18ClN5O6S: C-55.37, H-3.22,
N-12.42; Found: C-55.41, H-3.25, N-12.33 %.
Med Chem Res
1-(2-(-5-((2-Chloro-7-methylquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8c)
Yield: 72 %; m.p.: 265–267 °C; IR (KBr) vmax/cm-1: 3638
(OH, phenolic), 3286 (N–H), 3050 (C–H, aromatic), 2922,
2879 (C–H, aliphatic), 1716, 1708, 1685 (C=O), 1571
(C=N), 1511 (C=C), 770 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.51 (s, 3H, –CH3), 3.07 (s, 2H, CH2-
barbitone ring), 4.26 (s, 2H, COCH2), 5.30 (brs, 1H, –OH),
6.92 (d, J = 6.7 Hz, 1H, Ar–H), 7.03 (t, J = 8.1 Hz, 2H,
Ar–H), 7.12 (d, J = 7.5 Hz, 1H, Ar–H), 7.61 (d,
J = 7.6 Hz, 1H, Ar–H), 7.69 (s, 1H, Ar–H), 7.84 (s, 1H,
arylidene –CH–), 8.00 (d, J = 8.3 Hz, 1H, Ar–H), 8.63 (s,
1H, Ar–H), 9.78 (s, 1H, N–H); 13C NMR (100 MHz,
DMSO-d6, d, ppm): 21.0 (1C, CH3), 39.3 (1C, barbitone-
CH2), 46.0 (1C, acetyl-CH2), 122.3 (1C, thiazolidinone-
C5), 143.1 (1C, arylidene-C), 149.0 (1C, C–Cl), 151.8 (1C,
C–OH), 158.4 (1C, thiazolidinone-C2), 115.5–146.7 (13C,
Ar–C), 152.2–172.0 (5C, C=O); LCMS (m/z): 563 (M?);
Anal. Calcd. for C26H18ClN5O6S: C-55.37, H-3.22,
N-12.42; Found: C-55.39, H-3.14, N-12.51 %.
1-(2-(-5-((2-Chloro-8-methylquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8d)
Yield: 66 %; m.p.: 280–282 °C; IR (KBr) vmax/cm-1: 3641
(OH, phenolic), 3280 (N–H), 3048 (C–H, aromatic), 2914,
2879 (C–H, aliphatic), 1711, 1708, 1690 (C=O), 1564
(C=N), 1510 (C=C), 770 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 2.53 (s, 3H, –CH3), 3.07 (s, 2H, CH2-
barbitone ring), 4.31 (s, 2H, COCH2), 5.31 (brs, 1H, –OH),
6.90 (d, J = 6.9 Hz, 1H, Ar–H), 7.00 (t, J = 8.1 Hz, 2H,
Ar–H), 7.18 (d, J = 7.6 Hz, 1H, Ar–H), 7.61 (t,
J = 8.2 Hz, 1H, Ar–H), 7.79 (d, J = 7.5 Hz, 1H, Ar–H),
7.83 (s, 1H, arylidene –CH–), 7.93 (d, J = 8.3 Hz, 1H, Ar–
H), 8.61 (s, 1H, Ar–H), 9.70 (s, 1H, N–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 17.1 (1C, CH3), 39.0 (1C,
barbitone-CH2), 45.9 (1C, acetyl-CH2), 122.0 (1C, thiazo-
lidinone-C5), 143.1 (1C, arylidene-C), 148.5 (1C, C–Cl),
151.5 (1C, C–OH), 158.2 (1C, thiazolidinone-C2),
115.5–155.0 (13C, Ar–C), 151.7–172.0 (5C, C=O); LCMS
(m/z): 563 (M?); Anal. Calcd. for C26H18ClN5O6S:
C-55.37, H-3.22, N-12.42; Found: C-55.45, H-3.29,
N-12.35 %.
1-(2-(-5-((2-Chloro-8-ethylquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8e)
Yield: 52 %; m.p.: 241–243 °C; IR (KBr) vmax/cm-1: 3648
(OH, phenolic), 3278 (N–H), 3050 (C–H, aromatic), 2916,
2879 (C–H, aliphatic), 1729, 1705, 1694 (C=O), 1566
(C=N), 1518 (C=C), 770 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 1.78 (t, J = 5.9 Hz, 3H, –CH3), 2.62
(q, J = 4.1 Hz, 2H, –CH3), 3.07 (s, 2H, CH2-barbitone
ring), 4.41 (s, 2H, COCH2), 5.37 (brs, 1H, –OH), 6.92 (d,
J = 6.9 Hz, 1H, Ar–H), 7.07 (t, J = 7.8 Hz, 2H, Ar–H),
7.16 (d, J = 7.5 Hz, 1H, Ar–H), 7.65 (t, J = 8.0 Hz, 1H,
Ar–H), 7.71 (d, J = 7.5 Hz, 1H, Ar–H), 7.80 (s, 1H, ary-
lidene –CH–), 7.90 (d, J = 7.6 Hz, 1H, Ar–H), 8.64 (s, 1H,
Ar–H), 9.68 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-
d6, d, ppm): 14.3 (1C, CH3), 23.5 (1C, CH2), 39.1 (1C,
barbitone-CH2), 46.3 (1C, acetyl-CH2), 122.0 (1C, thiazo-
lidinone-C5), 143.3 (1C, arylidene-C), 148.4 (1C, C–Cl),
151.2 (1C, C–OH), 158.1 (1C, thiazolidinone-C2),
115.0–155.0 (13C, Ar–C), 151.5–172.6 (5C, C=O); LCMS
(m/z): 577 (M?); Anal. Calcd. for C27H20ClN5O6S:
C-56.11, H-3.49, N-12.12; Found: C-56.01, H-3.45,
N-12.19 %.
1-(2-(-5-((2-Chloro-6-methoxyquinolin-3-yl)methylene)-
2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8f)
Yield: 68 %; m.p.: 238–240 °C; IR (KBr) vmax/cm-1: 3645
(OH, phenolic), 3284 (N–H), 3034 (C–H, aromatic), 2910,
2875 (C–H, aliphatic), 2815 (–OCH3), 1712, 1708, 1694
(C=O), 1560 (C=N), 1518 (C=C), 765 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.07 (s, 2H, CH2-barbitone
ring), 3.80 (s, 3H, –OCH3), 4.38 (s, 2H, COCH2), 5.35 (brs,
1H, –OH), 6.95 (d, J = 7.0 Hz, 1H, Ar–H), 7.05 (t,
J = 8.1 Hz, 2H, Ar–H), 7.16 (d, J = 7.8 Hz, 1H, Ar–H),
7.20 (s, 1H, Ar–H), 7.38 (d, J = 7.6 Hz, 1H, Ar–H),7.72
(d, J = 8.5 Hz, 1H, Ar–H), 7.83 (s, 1H, arylidene –CH–),
8.63 (s, 1H, Ar–H), 9.73 (s, 1H, N–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 39.0 (1C, barbitone-CH2),
46.2 (1C, acetyl-CH2), 55.9 (1C, OCH3), 122.0 (1C, thia-
zolidinone-C5), 143.6 (1C, arylidene-C), 147.0 (1C, C–Cl),
151.2 (1C, C–OH), 158.1 (1C, thiazolidinone-C2),
115.0–157.0 (13C, Ar–C), 152.0–172.0 (5C, C=O); LCMS
(m/z): 563 (M?); Anal. Calcd. for C26H18ClN5O7S:
C-53.84, H-3.13, N-12.08; Found: C-53.87, H-3.04,
N-12.14 %.
1-(2-(-5-((2-Chloro-7-methoxyquinolin-3-yl)methylene)-
2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8g)
Yield: 72 %; m.p.: 258–260 °C; IR (KBr) vmax/cm-1: 3651
(OH, phenolic), 3280 (N–H), 3031 (C–H, aromatic), 2908,
2851 (C–H, aliphatic), 2812 (–OCH3), 1718, 1700, 1686
(C=O), 1566 (C=N), 1519 (C=C), 769 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.15 (s, 2H, CH2-barbitone
ring), 3.78 (s, 3H, –OCH3), 4.31 (s, 2H, COCH2), 5.41 (brs,
123

1H, –OH), 6.97 (d, J = 7.1 Hz, 1H, Ar–H), 7.05 (t,
J = 7.6 Hz, 2H, Ar–H), 7.14 (d, J = 7.5 Hz, 1H, Ar–H),
7.28 (d, J = 7.3 Hz, 1H, Ar–H), 7.37 (s, 1H, Ar–H), 7.87
(s, 1H, arylidene –CH–), 7.99 (d, J = 8.0 Hz, 1H, Ar–H),
8.68 (s, 1H, Ar–H), 9.69 (s, 1H, N–H); 13C NMR
(100 MHz, DMSO-d6, d, ppm): 39.1 (1C, barbitone-CH2),
46.0 (1C, acetyl-CH2), 55.7 (1C, OCH3), 122.1 (1C, thia-
zolidinone-C5), 143.2 (1C, arylidene-C), 149.0 (1C, C–Cl),
151.5 (1C, C–OH), 158.3 (1C, thiazolidinone-C2),
105.0–148.1 (13C, Ar–C), 152.1–171.8 (5C, C=O); LCMS
(m/z): 563 (M?); Anal. Calcd. for C26H18ClN5O7S:
C-53.84, H-3.13, N-12.08; Found: C-53.81, H-3.09,
N-12.16 %.
1-(2-(-5-((2-Chloro-8-methoxyquinolin-3-yl)methylene)-
2-(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8h)
Yield: 63 %; m.p.: 233–235 °C; IR (KBr) vmax/cm-1: 3647
(OH, phenolic), 3276 (N–H), 3030 (C–H, aromatic), 2910,
2859 (C–H, aliphatic), 2810 (–OCH3), 1724, 1703, 1686
(C=O), 1575 (C=N), 1505 (C=C), 761 (C–Cl); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.13 (s, 2H, CH2-barbitone
ring), 3.74 (s, 3H, –OCH3), 4.36 (s, 2H, COCH2), 5.37 (brs,
1H, -OH), 6.91 (d, J = 7.0 Hz, 1H, Ar–H), 7.08 (t,
J = 7.4 Hz, 2H, Ar–H), 7.19 (d, J = 7.5 Hz, 1H, Ar–H),
7.51 (d, J = 7.5 Hz, 1H, Ar–H), 7.67 (d, J = 7.8 Hz, 1H,
Ar–H), 7.71 (t, J = 7.9 Hz, 2H, Ar–H), 7.81 (s, 1H, ary-
lidene –CH–), 8.66 (s, 1H, Ar–H), 9.70 (s, 1H, N–H); 13C
NMR (100 MHz, DMSO-d6, d, ppm): 39.2 (1C, barbitone-
CH2), 46.0 (1C, acetyl-CH2), 55.3 (1C, OCH3), 122.3 (1C,
thiazolidinone-C5), 143.3 (1C, arylidene-C), 148.5 (1C, C–
Cl), 151.1 (1C, C–OH), 158.3 (1C, thiazolidinone-C2),
108.0–155.0 (13C, Ar–C), 151.0–172.0 (5C, C=O); LCMS
(m/z): 563 (M?); Anal. Calcd. for C26H18ClN5O7S:
C-53.84, H-3.13, N-12.08; Found: C-53.80, H-3.19,
N-12.15 %.
1-(2-(-5-((6-Bromo-2-chloroquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8i)
Yield: 55 %; m.p.: 252–254 °C; IR (KBr) vmax/cm-1: 3649
(OH, phenolic), 3281 (N–H), 3035 (C–H, aromatic), 2910,
2875 (C–H, aliphatic), 1712, 1708, 1690 (C=O), 1565
(C=N), 1510 (C=C), 765 (C–Cl), 617 (C–Br); 1H NMR
(300 MHz, DMSO-d6, d, ppm): 3.00 (s, 2H, CH2-barbitone
ring), 4.38 (s, 2H, COCH2), 5.38 (brs, 1H, -OH), 6.91 (d,
J = 7.2 Hz, 1H, Ar–H), 7.11 (t, J = 8.1 Hz, 2H, Ar–H),
7.10 (d, J = 7.5 Hz, 1H, Ar–H), 7.80 (s, 1H, arylidene
–CH–), 8.06 (d, J = 7.9 Hz, 1H, Ar–H), 8.17 (d,
J = 8.1 Hz, 1H, Ar–H), 8.32 (s, 1H, Ar–H), 8.68 (s, 1H,
Ar–H), 9.80 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-
123
Med Chem Res
d6, d, ppm): 38.7 (1C, barbitone-CH2), 46.0 (1C, acetyl-
CH2), 121.5 (1C, C–Br), 122.0 (1C, thiazolidinone-C5),
143.2 (1C, arylidene-C), 149.0 (1C, C–Cl), 151.0 (1C, C–
OH), 158.0 (1C, thiazolidinone-C2), 115.2–148.0 (12C,
Ar–C), 151.9–172.1 (5C, C=O); LCMS (m/z): 629 (M?);
Anal. Calcd. for C25H15BrClN5O6S: C-47.75, H-2.40,
N-11.40; Found: C-47.78, H-2.33, N-11.44 %.
1-(2-(-5-((2,6-Dichloroquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8j)
Yield: 57 %; m.p.: 272–274 °C; IR (KBr) vmax/cm-1: 3650
(OH, phenolic), 3275 (N–H), 3035 (C–H, aromatic), 2917,
2870 (C–H, aliphatic), 1710, 1708, 1693 (C=O), 1571
(C=N), 1510 (C=C), 771 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 3.09 (s, 2H, CH2-barbitone ring), 4.40
(s, 2H, COCH2), 5.30 (brs, 1H, –OH), 6.97 (d, J = 7.3 Hz,
1H, Ar–H), 7.10 (t, J = 8.0 Hz, 2H, Ar–H), 7.18 (d,
J = 7.3 Hz, 1H, Ar–H), 7.65 (s, 1H, Ar–H), 7.85 (s, 1H,
arylidene –CH–), 7.82 (d, J = 8.1 Hz, 1H, Ar–H), 8.16 (d,
J = 8.1 Hz, 1H, Ar–H), 8.61 (s, 1H, Ar–H), 9.86 (s, 1H,
N–H); 13C NMR (100 MHz, DMSO-d6, d, ppm): 39.0 (1C,
barbitone-CH2), 46.1 (1C, acetyl-CH2), 122.0 (1C, thiazo-
lidinone-C5), 132.4 (1C, C–Cl), 143.1 (1C, arylidene-C),
149.1 (1C, C–Cl), 151.0 (1C, C–OH), 158.0 (1C, thiazo-
lidinone-C2), 115.2–145.0 (12C, Ar–C), 151.7–172.3 (5C,
C=O); LCMS (m/z): 583.0 (M?); Anal. Calcd. for
C25H15Cl2N5O6S: C-51.38, H-2.59, N-11.98; Found:
C-51.41, H-2.63, N-12.03 %.
1-(2-(-5-((2,7-Dichloroquinolin-3-yl)methylene)-2-
(2-hydroxyphenylimino)-4-oxothiazolidin-3-yl)-2-
oxoethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (8k)
Yield: 63 %; m.p.: 284–286 °C; IR (KBr) vmax/cm-1: 3637
(OH, phenolic), 3271 (N–H), 3035 (C–H, aromatic), 2911,
2871 (C–H, aliphatic), 1705, 1720, 1689 (C=O), 1570
(C=N), 1519 (C=C), 769 (C–Cl); 1H NMR (300 MHz,
DMSO-d6, d, ppm): 3.11 (s, 2H, CH2-barbitone ring), 4.36
(s, 2H, COCH2), 5.42 (brs, 1H, –OH), 6.90 (d, J = 7.1 Hz,
1H, Ar–H), 7.13 (t, J = 8.3 Hz, 2H, Ar–H), 7.20 (d,
J = 7.3 Hz, 1H, Ar–H), 7.64 (d, J = 8.2 Hz, 1H, Ar–H),
7.81 (s, 1H, arylidene –CH–), 7.93 (d, J = 7.2 Hz, 1H, Ar–
H), 8.21 (d, J = 8.1 Hz, 1H, Ar–H), 8.70 (s, 1H, Ar–H),
9.83 (s, 1H, N–H); 13C NMR (100 MHz, DMSO-d6, d,
ppm): 39.0 (1C, barbitone-CH2), 46.7 (1C, acetyl-CH2),
122.3 (1C, thiazolidinone-C5), 136.2 (1C, C–Cl), 143.3
(1C, arylidene-C), 150.5 (1C, C–Cl), 151.1 (1C, C–OH),
158.2 (1C, thiazolidinone-C2), 115.0–147.5 (12C, Ar–C),
151.7–172.1 (5C, C=O); LCMS (m/z): 583.0 (M?); Anal.
Calcd. for C25H15Cl2N5O6S: C-51.38, H-2.59, N-11.98;
Found: C-51.44, H-2.54, N-12.05 %.
Med Chem Res

Fig. 1 Comparison of the effect H O

N
of C-5 and N-3 substitution on O
OH O
antimicrobial activity of N
synthesized compounds N
2
N3 O
1S
4 O
5 R Bacterial strains Fungal strains
--- E. coli, P. aeruginosa NA

N -3 substitution

OH
H
N 2
N3
O
1S 4
5
C-5 substitution C-5 and N-3 substitution

H O
N
OH O
OH O
N 2 H N
N
N3 2
N3 O
1S
4 O 1S O
5 4
5

Cl
R N Cl
R N
R Bacterial strains Fungal strains R Bacterial strains Fungal strains
-8-CH2CH3 NA C.albicans, A.niger -8-CH2CH3 E. Coli, P. aeruginosa C. albicans, A.niger
-6-OCH3 NA C.albicans -6-OCH3 E. Coli NA
-8-OCH3 NA C.albicans -8-OCH3 E. Coli, P. aeruginosa, C. albicans
S. pyogenes

Antibacterial bioassay the desired concentration of synthesized compounds and

Newly synthesized compounds (3a–k, 6 and 8a–k) were
screened for their antibacterial activity against Gram-posi-
tive bacteria [S. aureus (MTCC-96), Streptococcus pyogenes
(MTCC-442)], and Gram-negative bacteria [E. coli (MTCC-
443), P. aeruginosa (MTCC-1688)]. All MTCC cultures
were collected from Institute of Microbial Technology,
Chandigarh. The activity of compounds was determined as
per National Committee for Clinical Laboratory Standards
(NCCLS) protocol using Mueller–Hinton Broth (Becton–
Dickinson, USA) (Finegold and Garrod, 1995; Desai et al.,
2012c). Compounds were screened for their antibacterial
activity as primary screening in six sets against E. coli,
S. aureus, P. aeruginosa, and S. pyogenes at different con-
centrations of 1000, 500, and 250 lg/mL. The compounds
were found to be active in primary screening were similarly
diluted to obtain 200, 125, 100, 62.5, 50, 25, and 12.5 lg/mL
concentrations for secondary screening to test in a second set
of dilution against all microorganisms. Inoculum size for test
strain was adjusted to 106 CFU/mL (Colony Forming Unit
per milliliter) by comparing the turbidity (turbidimetric
method). Mueller–Hinton Broth was used as nutrient med-
ium to grow and dilute the compound suspension for test
bacteria. 2 % DMSO was used as a diluent/vehicle to obtain
standard drugs were used against microbial strains. Synthe-
sized compounds were diluted to 1,000 lg/mL concentra-
tion, as a stock solution. Control tube containing no
antibiotic was immediately subcultured (before inoculation)
by spreading a loopful evenly over a quarter of plate of
medium suitable for the growth of test organisms. The tubes
were then incubated at 37 °C for 24 h for bacteria. 10 lg/mL
suspensions were further inoculated on an appropriate
media, and the growth was noted after 24 and 48 h. The
highest dilution (lowest concentration) preventing appear-
ance of turbidity was considered as MIC (lg/mL) i.e., the
amount of growth from the control tube before incubation
(which represents the original inoculum) was compared. A
set of tubes containing only seeded broth and solvent controls
were maintained under identical conditions, so as to make
sure that the solvent had no influence on strain growth. The
result of this was greatly affected by size of the inoculum.
Test mixture should contain 106 CFU/mL organisms. Stan-
dard drug used in the present study was ‘‘ampicillin’’ for
evaluating antibacterial activity which showed 250, 100,
100, and 100 lg/mL MIC against E. coli, P. aeruginosa,
S. aureus, and S. pyogenes, respectively. DMSO and steril-
ized water were used as a negative control and ampicillin as a
positive control.

123
 Med Chem Res

Table 3 Calculated log P values of compounds 3a–k, 6 and 8a–k antibacterial activity was observed. Compounds (8d, 8e, 8f,
Compounds C log P Compounds C log P
and 8h) of the series displayed both antibacterial as well as
antifungal activity. These compounds possessed electron
3a 2.21 8a 0.48 donating groups like methyl, methoxy, and ethyl. On the
3b 2.71 8b 0.98 other hand, it may be noted that without any substitution in
3c 2.71 8c 0.98 compounds 3a and 8a or the presence of halogen atom on
3d 2.71 8d 0.98 quinoline ring in compounds 3i, 3j, 3k, 8i, 8j, and 8k did
3e 3.24 8e 1.51 not exhibit antimicrobial activity against the panel of
3f 2.46 8f 0.73 microorganisms. Furthermore, it was our observation on
3g 2.46 8g 0.73 the data of activity that substitution on 7th position in both
3h 2.46 8h 0.73 series (3a–k and 8a–k) lowered the activity.
3i 3.10 8i 1.36 According to the data listed in Table 3, it may be
3j 2.95 8j 1.21 hypothesized that lipophilicity (C log P) has no decisive
3k 2.95 8k 1.21 influence on antimicrobial activity for compounds (3a–k, 6
6 -2.43 and 8a–k). Therefore, it is necessary to think that the
structural or electronic parameters may have a greater
impact on the activity (Stefania et al., 2012; Tomasz et al.,
Antifungal bioassay 2011).

Same compounds (3a–k, 6 and 8a–k) were tested for

antifungal activity as primary screening in six sets against
C. albicans, A. niger, and A. clavatus at various concen-
trations of 1000, 500, and 250 lg/mL. Compounds found
to be active in primary screening were similarly diluted to
obtain 200, 125, 100, 62.5, 50, 25, and 12.5 lg/mL con-
centrations for secondary screening to test in a second set
of dilution against all microorganisms. Griseofulvin was
used as a standard drug for antifungal activity, which
showed 500, 100, and 100 lg/mL MIC against C. albicans
(MTCC 227), A. niger (MTCC 282), and A. clavatus
(MTCC 1323). For fungal growth, in the present protocol,
we used Sabourauds dextrose broth at 28 °C in aerobic
condition for 48 h.
The cytotoxic potential of compounds 3e, 6, 8d, 8e, 8f,
and 8h was also determined in human cancer cell lines such
as A549, HL-60, and HepG2 according protocols (Skehan
et al., 1990). All of the tested compounds did not show
significant cytotoxic activity and showed the selectivity, in
that they possess potent antibacterial and antifungal
activity without the cytotoxicity in mammalian cells (Ryu
et al., 2003).
Structure–activity relationship (SAR)
From the results of antimicrobial activity, the following
structure activity relationship may be predicted.
The SAR of final compounds (3a–k, 6 and 8a–k) was
determined on the basis of antimicrobial activity data
presented in Tables 1 and 2. Figure 1 revealed that when
quinoline ring is introduced to C-5 position of compound
(1) it was contributed in antifungal activity. Similarly N-3
position of 2-(2-hydroxyphenylimino)thiazolidin-4-one (1)
was substituted by barbitone via acetyl linker, significant
Conclusion
In the present article, we have reported the synthesis,
characterization, and antimicrobial activity of some novel
C-5 and N-3 substituted derivatives of 4-thiazolidinone
containing quinoline and barbitone heterocycles. Parent
compound (1) could be easily converted into compounds
(3a–k) by introducing quinoline moiety at C-5. By insert-
ing quinoline moiety at C-5 of compounds (4), the for-
mation of compounds (7a–k) took place, which was further
reacted with barbitone, to furnished compounds (8a–k). It
may be concluded that both C-5 and N-3 positions of
4-thiazolidinone were responsible for broad-spectrum
antimicrobial activity of the title compounds. In addition,
compounds 8d, 8e, 8f, and 8h having electron donating
groups (methyl, methoxy and ethyl) on quinoline moiety at
6th and 8th positions, displayed maximum antibacterial and
antifungal activities. Thus, for a compound, optimum
electron density is inevitable so as to gain significant
antimicrobial activity.
Acknowledgments We would like to express our sincere gratitude
to the Department of Chemistry, DST-FIST Sponsored Department
Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar
University, Bhavnagar for providing research and library facilities.
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