Antimicrobial activity of thiazolyl benzenesulfonamide-condensed 2,4-thiazolidinediones derivatives

Article abstract of DOI:10.1007/s00044-012-0273-x

A new series of benzoyl chloride-substituted 2,4-thiazolidinedione derivatives have been synthesized by the condensation of 2-amino-4-aryl-thiazole and 4′-chlorosulfonyl benzylidine-2,4-thiazolidinedione. New compounds were evaluated for their in vitro antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. Furthermore, new products were tested for in vitro antituberculosis activity against Mycobacterium tuberculosis using isoniazid and rifampicin as control drugs. The results of bioassay demonstrated that some of the newly synthesized 2,4-thiazolidinedione derivatives emerged as lead molecules with excellent MIC (mg/mL) values against mentioned organisms compared to standard drugs. The structure of the final analogs has been confirmed on the basis of IR, ¹H NMR, mass spectral, and elemental analysis.

Full text of DOI:10.1007/s00044-012-0273-x

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-012-0273-x
ORIGINAL RESEARCH
Antimicrobial activity of thiazolyl benzenesulfonamide-condensed
2,4-thiazolidinediones derivatives
•
Nikhil M. Parekh Krunal V. Juddhawala
•
Bhaskar M. Rawal
Received: 6 April 2012 / Accepted: 6 October 2012
Ó Springer Science+Business Media New York 2012
Abstract A new series of benzoyl chloride-substituted
2,4-thiazolidinedione derivatives have been synthesized by
the condensation of 2-amino-4-aryl-thiazole and 40-chlo-
rosulfonyl benzylidine-2,4-thiazolidinedione. New com-
pounds were evaluated for their in vitro antibacterial
activity against Staphylococcus aureus, Bacillus subtilis,
Escherichia coli, and Pseudomonas aeruginosa. Further-
more, new products were tested for in vitro antituberculosis
activity against Mycobacterium tuberculosis using isonia-
zid and rifampicin as control drugs. The results of bioassay
demonstrated that some of the newly synthesized 2,4-
thiazolidinedione derivatives emerged as lead molecules
with excellent MIC (mg/mL) values against mentioned
organisms compared to standard drugs. The structure of the
wide range of heterocycles explored to develop privileged
candidates in drug discovery, thiazoles have been indenti-
fied to play an essential role in medicinal chemistry. Thia-
zolidinone are the derivatives of thiazolidine which belong
to prenominal group of heterocyclic compounds bearing
sulfur and nitrogen in a five-member ring (Patel et al., 2011;
Desai et al., 2011a, b). Countless research work on thia-
zolidinones has been accomplished in recent years (Malik
et al., 2011; Rekha et al., 2011; Aneja et al., 2011). The
nucleus is also well known as wonder nucleus because it
gives out different derivatives expressing newer leads for
multiple biological activities (Chawla et al., 2011). Over the
years, 4-thiazolidinones skeleton has been a fertile source of
biopotent heterocycles possessing diverse chemotherapeu-
tic activities (Bhargava and Chaurasia, 1969).
1
final analogs has been confirmed on the basis of IR, H
NMR, mass spectral, and elemental analysis.
In the recent past, 4-thiazolidinone scaffold and its
derivatives have fascinated significant interest of medicinal
chemists and have become an important class of heterocyclic
compounds because of their utility for miscellaneous
biological activities such as anti-inflammatory (Deep et al.,
2011; Kumar and Rajput, 2009; Ottana et al., 2005;
Geronikaki et al., 2008), analgesic (Tandon et al., 1985;
Knutsen et al., 2007), antimycobacterial (Kucukguzel et al.,
2002; Srivastav et al., 2005), antimicrobial (Desai et al.,
2011a, b; Patel and Patel, 2010; Ozkirimli et al., 2009;
Bondock et al., 2007; Madhukar et al., 2009; Fuloria et al.,
2009), antiarrhythmic (Amr et al., 2009), anti-HIV activity
(Kucukguzel et al., 2006; Barreca et al., 2001), and anti-
convulsant (Shiradkar et al., 2007). A crucial component in
drug designing program is the construction of new entities
with promising bioactivity and lesser side effects. Further-
more, minimal cytotoxic properties have been examined for
thiazolidinone derivatives earlier (Alegaon and Alagawadi,
2011), so from all these facts and non-toxic nature of thia-
zolidinone derivatives, it has been thought of interest to
Keywords Thiazole ꢀ 2,4-Thiazolidinedione ꢀ Synthesis ꢀ
Antibacterial ꢀ Antituberculosis
Introduction
Small-ring heterocycles holding nitrogen and sulfur have
been under investigation for a long time because of their
synthetic diversity and therapeutic relevance. Among the
N. M. Parekh (&)
Department of Applied Chemistry, S. V. National Institute
of Technology, Surat 395 007, Gujarat, India
e-mail: nikhilparekh2009@gmail.com
K. V. Juddhawala ꢀ B. M. Rawal
Department of Chemistry, Narmada College of Science
and Commerce, Zadeshwar, Bharuch 392 001, Gujarat, India
e-mail: juddhawalakrunal@yahoo.in
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Med Chem Res
synthesize some new benzoyl chloride-substituted 2,4-thia-
zolidinedione derivatives to furnish a possible antibacterial
and antituberculosis agents.
respective test compound in dimethylformamide were
placed on the solidified nutrient agar medium that had been
inoculated with the respective microorganism and the plates
were incubated for 24 h at (37 1) °C. A control disk
impregnated with an equivalent amount of dimethylform-
amide without any sample was also used and did not produce
any inhibition. Ciprofloxacin and flucanazole (100 lg/disk)
were used as control drugs for antibacterial and antifungal
activities, respectively. Each assay was performed in
triplicate.
Experimental
Materials and methods
Chemicals and solvents were obtained from commercial
sources and used as received throughout the investigation.
Melting points were determined in open capillaries on a
Veego electronic apparatus VMP-D (Veego Instrument
Corporation, Mumbai, India) and are uncorrected. IR
spectra (4,000–400 cm-1) of synthesized compounds were
recorded on a Shimadzu 8400-S FT-IR spectrophotometer
(Shimadzu India Pvt. Ltd., Mumbai, India) using KBr
pellets. Thin layer chromatography was performed on
object glass slides (2 9 9 9 7.5 cm) coated with silica
In vitro evaluation of antimycobacterial activity
The preliminary antimycobacterial assessment for the final
synthesized compounds was carried out using BACTEC
MGIT method. The mycobacterial growth indicator tubes
(MGIT) containing 4 mL of modified Middle brook 7H9
Broth Base were numbered as per the title compounds to be
tasted for antimycobacterial efficacy by means of various
concentrations prepared. The suspension was allowed to
stand for 20 min and the tubes were centrifuged at
3,000 rpm for 15 min. After that, prepared suspension of
104 to 107 CFU/mL of H37Rv Mycobacterium tuberculosis
strain was added in the medium to be incubated and
0.1 mL of egg-based medium (L. J) was also added. The
MGIT tubes were then tightly recapped, mixed well, and
incubated into BACTEC MGIT instrument at (37 1) °C
until positivity is observed. The readings were measured
daily starting from the second day of incubation. Positive
cultures were usually detected within 10 days. For reading
the actual results, the MGIT tubes were removed from
incubator and placed on the UV light next to a positive
control tube and an uninoculated tube (negative control).
Bright fluorescence detected by the corresponding MGIT
tube was noticed in the form of bright orange color in the
bottom of the tube and also an orange reflection on the
meniscus. The primary screening was conducted at con-
centration of 6.25 lg/mL against M. tuberculosis H37Rv in
BACTEC MGIT system. Compounds demonstrating 99 %
inhibition in the primary screen were described as most
potent compounds. All the other compounds to be tasted
were re-examined for their actual MIC using Lowenstein–
Jensen MIC method. The MIC was defined as the lowest
concentration inhibiting 99 % of the inoculums.
1
gel-G and spots were visualized under UV irradiation. H
NMR and 13C NMR spectra were recorded on a Varian
400 MHz model spectrometer (Varian India Pvt. Ltd.,
Mumbai, India) using DMSO as a solvent and TMS as
1
internal standard with H resonant frequency of 400 MHz
and 13C resonant frequency of 100 MHz. The 1H NMR and
13C NMR chemical shifts were reported as parts per million
(ppm) downfield from TMS (Me4Si) and were performed
at Centre for Excellence, Vapi, India. The splitting patterns
are designated as follows: s, singlet; br s, broad singlet;
d, doublet; t, triplet; q, quartet; m, multiplet. All new
compounds were subjected to elemental analysis using a
Heraeus Carlo Erba 1180 CHN analyzer (Hanau, Germany).
Kirby Bauer disk diffusion method for antibacterial
activity
The synthesized benzoyl chloride-substituted 2,4-thiazo-
lidinedione derivatives 6a–6i were examined for their
antimicrobial activity against several bacteria (Staphyloc-
coccus aureus MTCC 96, Bacillus subtilis MTCC 619,
Escherichia coli MTCC 739, and Pseudomonas aeruginosa
MTCC 741) using the Kirby Bauer disk diffusion method.
The Mueller–Hinton agar media were sterilized (auto-
claved at 120 °C for 30 min), poured at uniform depth of
5 mm, and allowed to solidify. The microbial suspension
(105 CFU/mL) (0.5 McFarland Nephelometery Standards)
was streaked over the surface of media using a sterile cotton
swab to insure even growth of the organisms. The com-
pounds to be tested were dissolved in dimethylformamide to
give solutions of 20–500 lg/mL. Sterile filter paper disks
measuring 6.25 mm in diameter (Whatman No. 1 filter
paper), previously soaked in a known concentration of the
Chemical synthesis
Synthesis of 2-amino-4-aryl-thiazole (1)
A mixture of acetophenone (0.1 mol), thiourea (0.2 mol),
and iodine (0.1 mol) was heated on a steam bath for 4 h.
The hydroiodide, thus separated, was filtered, washed with
123

Med Chem Res
ether, and dried. It was dissolved in hot water, filtered
while hot, and the clear solution neutralized with a strong
solution of ammonia. The solid separated was filtered,
washed with water, and recrystallized from benzene. Yield:
96 %, m.p. 145–150 °C, IR (KBr disk) 3385–3410 cm-1
(NH2), 1548, 1398 cm-1(C=N, C–N), 635 cm-1 (C–S).
The product was purified by recrystallization from ethanol.
Yield: 68 %, m.p. 177–182 °C, IR (KBr disk) 3360 cm-1
(NH), 1684 cm-1 (C=O), 1120 and 1310 cm-1 (SO2 symand
asym), 763 cm-1 (Cl), 628 cm-1 (C–S).
Synthesis of 4-[(z)-2,4-dioxo-1,3-thiazolidin-5-
ylidene)methyl]-N-(4-phenyl-1,3-thiazol-2-yl)benzene
sulfonamide (5)
Synthesis of 2,4-thiazolidinedione (2)
In a 250 mL three-necked round-bottomed flask, solution
containing (0.6 mol) chloroacetic acid dissolved in 60 mL
of water and (0.6 mol) thiourea dissolved in 60 mL of water
was added. The mixture was stirred for 15 min to form a
white precipitate, accompanied by considerable cooling. To
the contents of the flask, 60 mL of concentrated hydro-
chloric acid was then added slowly from a dropping funnel,
the flask was then connected with a reflux condenser and
gentle heat applied to effect complete solution, after which
the reaction mixture was stirred and refluxed for 8–10 h at
100–110 °C. On cooling the contents of the flask solidified
to a cluster of white needles, the product was filtered and
washed with water to remove traces of hydrochloric acid
and dried. It was purified by recrystallized from ethyl
alcohol. Yield: 85 %, m.p. 122–127 °C, IR (KBr disk)
3387 cm-1 (NH), 1684 cm-1 (C=O), 622 cm-1 (C–S).
2-Amino-4-aryl-thiazole (1) (0.1 mol) and 40-chlorosulfonyl-
5-benzylidine 2,4-thiazolidinedione (4) (0.1 mol) were added
to a mixture of 4 mL of dry pyridine and 20 mL acetic
anhydride. The mixture was refluxed for 2 h, reaction mixture
was poured into 20 mL of ice water, and the solid was filtered
and purified by recrystallization from ethanol to give product
as a white crystalline solid. Yield: 74 %, m.p. 187–192 °C, IR
(KBr disk) 3364 cm-1 (NH), 1678 cm-1 (C=O), 1120 and
1310 cm-1 (SO2 sym and asym), 626 cm-1 (C–S).
Synthesis of 4-(3-benzoyl-2,4-dioxo-thiazolidin-5-
ylidenemethyl)-N-(4-phenyl-thiazol-2-yl)-
benzenesulfonamide (6)
A mixture of 4-[(z)-2,4-dioxo-1,3-thiazolidin-5-ylidene)
methyl]-N-(4-ohenyl-1,3-thiazol-2-yl)benzene sulfonamide
(5) (0.01 mol) and benzoyl chloride derivatives (0.01 mol)
in DMF were refluxed for 4 h. Progress of reaction was
monitored by TLC using ethanol:toluene (1:4) as eluent.
After the completion of reaction, the content was added to
cold water. The solid product (6) was obtained and filtered,
dried, and purified by crystallization from ethanol. Yield:
75 %, m.p. 211 °C, IR (KBr disk) 3375 cm-1 (NH),
1678 cm-1 (C=O), 764 (Cl). Similarly, other compounds
6a–6i were prepared by above method from intermediate (5)
and various benzoyl chloride derivatives and purified by
recrystallization from ethanol (Table 1).
Synthesis of 5-benzylidine 2,4-thiazolidinedione (3)
In a 250 mL three-necked round-bottomed flask provided
with a dean-stark apparatus, benzaldehyde (0.188 mol) and
2,4-thiazolidinedione (0.188 mol) were together suspended
in ethanol. To this, a catalytic amount of piperidine (1 mL)
was added. The mixture was stirred and refluxed. After the
complete removal of water and when the temperature
reached above 110 °C, the reaction mixture was stirred for
a further 1 h. On cooling, the product precipitated out from
ethanol. The compound was filtered and washed with cold
toluene and dry ethanol. Yield: 93 %, m.p. 238–243 °C, IR
(KBr disk) 3360 cm-1 (NH), 1684 cm-1 (C=O), 628 cm-1
(C–S).
4-(3-Benzoyl-2,4-dioxo-thiazolidin-5-ylidenemethyl)-N-(4-phe
nyl-thiazol-2-yl)-benzenesulfonamide (6a) Yield: 75 %;
m.p. 211 °C (dec.); IR (KBr, cm-1): 1328 (C–N), 1548
(C=N), 1120 and 1310 (SO2 sym and asym), 1685 (C=O),
600–800 (C–S), 3198 cm-1 (–NH–), 3032–3059 cm-1
Synthesis of 40-chlorosulfonyl-5-benzylidine-2,4-
thiazolidinedione (4)
1
(–C–H) stretching of aromatic rings, H NMR (400 MHz,
5-Benzylidine 2,4-thiazolidinedione (0.04 mol) was placed
in a 100 mL round-bottomed flask equipped with a condenser
and a dropping funnel. Chlorosulfonic acid (0.16 mol) was
added at room temperature using the dropping funnel. The
reaction was found to be exothermic. After addition of
chlorosulfonic acid completed, the reaction mass was
refluxed for 1 h on a water bath. The reaction was cooled and
poured in a thin stream with stirring into crushed ice
contained in a 1 L beaker. The product was filtered and dried.
DMSO-d6) d 4.02 (s, 1H, NH), 4.42 (s, 2H, CH2),
6.64–7.80 (m, 16H, Ar–H), 8.10 (s, 1H, –NH); 13C NMR
(400 MHz, DMSO-d6) d 125.4–138.1 (18C, –Ar–C), 150.8
and 103.4 (C-7 and C-8, C of thiazole ring, respectively,
164.3 and 165.1 (C-24 and C-22, –C=O of thiazolidinone
ring), 165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C26H17O5N3S3: C, 56.02 %; H, 3.13 %; N, 7.67 %; found:
C, 56.14 %; H, 3.16 %; N, 7.75 %.
123

Med Chem Res
1
(–C–H) stretching of aromatic rings, 752 cm-1 (Cl), H
Table 1 Physical data of synthesized compounds
NMR (400 MHz, DMSO-d6) d 4.08 (s, 1H, NH), 4.45 (s,
2H, CH2), 6.77–7.88 (m, 15H, Ar–H), 8.12 (s, 1H, –NH);
13C NMR (400 MHz, DMSO-d6) d 20.8 (C-32, C-CH3 of
phenyl ring), 125.4–138.1 (18C, –Ar–C), 150.8 and 103.4
(C-7 and C-8, C of thiazole ring, respectively, 164.3 and
165.1 (C-24 and C-22, –C=O of thiazolidinone ring), 165.7
(C-31, –Ar.-thiazolidinone ring linkage), 173.2 (C-10,
C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H19O5N3S3: C, 57.74 %; H, 3.41 %; N, 7.48 %. found:
C, 57.70 %; H, 3.37 %; N, 7.50 %.
Sr. no.
R
Molecular formula
M.P. (°C)
% yield
6a
6b
6c
6d
6e
6f
H
C26H17O5N3S3
C27H19O5N3S3
C27H19O5N3S3
C27H19O5N3S3
211
241
253
268
247
260
278
262
285
75
71
67
61
59
63
65
74
69
2-CH3
3-CH3
4-CH3
2-Cl
C
C
C
27H16O5N3S3Cl
27H16O5N3S3Cl
27H16O5N3S3Cl
3-Cl
6g
6h
6i
4-Cl
2-NO2
4-NO2
C26H16O7N4S3
C26H16O7N4S3
4-[3-(2-Chloro-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide
(6e) Yield:
4-[3-(2-Methyl-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide (6b) Yield:
59 %; m.p. 247 °C (dec.); IR (KBr, cm-1) : 1328 (C–N),
1578 (C=N), 1140 and 1304 (SO2 sym and asym), 1668
(C=O), 600–800 (C–S), 3200 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 752 cm-1 (Cl),
1H NMR (400 MHz, DMSO-d6) d 4.14 (s, 1H, NH), 4.45
(s, 2H, CH2), 6.70–7.88 (m, 15H, Ar–H), 8.10 (s, 1H,
–NH); 13C NMR (400 MHz, DMSO-d6) d 125.4–138.1
(18C, –Ar–C), 132.6 (C-26, C–Cl of phenyl ring), 150.8
and 103.4 (C-7 and C-8, C of thiazole ring, respectively,
164.3 and 165.1 (C-24 and C-22, –C=O of thiazolidinone
ring), 165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H16O5N3S3Cl: C, 53.65; H, 3.41; N, 7.48; found: C,
53.77 %; H, 3.49 %; N, 7.39 %.
71 %; m.p. 241 °C (dec.); IR (KBr, cm-1) : 1330 (C–N),
1558 (C=N), 1124 and 1314 (SO2 sym and asym), 1678
(C=O), 600–800 (C–S), 3200 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 1H NMR
(400 MHz, DMSO-d6) d 2.35 (s, 3H, CH3), 4.12 (s, 1H,
NH), 4.40 (s, 2H, CH2), 6.70–7.80 (m, 15H, Ar–H), 8.10 (s,
1H, –NH); 13C NMR (400 MHz, DMSO-d6) d 13.7 (C-32,
C–CH3 of phenyl ring), 125.4–138.1 (18C, –Ar–C), 150.8
and 103.4 (C-7 and C-8, C of thiazole ring, respectively,
164.3 and 165.1 (C-24 and C-22, –C=O of thiazolidinone
ring), 165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H19O5N3S3: C, 57.74 %; H, 3.41 %; N, 7.48 %. found:
C, 57.88 %; H, 3.34 %; N, 7.55 %.
4-[3-(3-Chloro-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide
(6f) Yield:
4-[3-(3-Methyl-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
63 %; m.p. 260 °C (dec.); IR (KBr, cm-1) : 1326 (C–N),
1588 (C=N), 1140 and 1304 (SO2 sym and asym), 1670
(C=O), 600–800 (C–S), 3212 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 752 cm-1 (Cl),
1H NMR (400 MHz, DMSO-d6) d 4.14 (s, 1H, NH), 4.45
(s, 2H, CH2), 6.70–7.88 (m, 15H, Ar–H), 8.10 (s, 1H,
–NH); 13C NMR (400 MHz, DMSO-d6) d 125.5–138.1
(18C, –Ar–C), 133.9 (C-27, C–Cl of phenyl ring), 150.7
and 103.2 (C-7 and C-8, C of thiazole ring, respectively,
164.3 and 165.2 (C-24 and C-22, –C=O of thiazolidinone
ring), 165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H16O5N3S3Cl: C, 53.65; H, 3.41; N, 7.48; found: C,
53.71 %; H, 3.45 %; N, 7.49 %.
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide
(6c) Yield:
67 %; m.p. 253 °C (dec.); IR (KBr, cm-1) : 1340 (C–N),
1568 (C=N), 1144 and 1334 (SO2 sym and asym), 1668
(C=O), 600–800 (C–S), 3210 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 1H NMR
(400 MHz, DMSO-d6) d 2.38 (s, 3H, CH3), 4.18 (s, 1H,
NH), 4.47 (s, 2H, CH2), 6.70–7.80 (m, 15H, Ar–H), 8.10 (s,
1H, –NH); 13C NMR (400 MHz, DMSO-d6) d 20.4 (C-32,
C–CH3 of phenyl ring), 125.4–138.1 (18C, –Ar–C), 150.7
and 103.4 (C-7 and C-8, C of thiazole ring, respectively,
164.2 and 165.1 (C-24 and C-22, –C=O of thiazolidinone
ring), 165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H19O5N3S3: C, 57.74 %; H, 3.41 %; N, 7.48 %. found:
C, 57.78 %; H, 3.44 %; N, 7.45 %.
4-[3-(4-Chloro-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide
(6g) Yield:
4-[3-(4-Methyl-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
65 %; m.p. 278 °C (dec.); IR (KBr, cm-1) : 1326 (C–N),
1588 (C=N), 1140 and 1304 (SO2 sym and asym), 1670
(C=O), 600–800 (C–S), 3212 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 1H NMR
(400 MHz, DMSO-d6) d 4.44 (s, 1H, NH), 4.40 (s, 2H,
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide
(6d) Yield:
61 %; m.p. 268 °C (dec.); IR (KBr, cm-1) : 1340 (C–N),
1568 (C=N), 1144 and 1334 (SO2 sym and asym), 1668
(C=O), 600–800 (C–S), 3210 cm-1 (–NH–), 3035–3060 cm-1
123

Med Chem Res
CH2), 6.77–7.80 (m, 15H, Ar–H), 8.10 (s, 1H, –NH); 13C
was synthesized by refluxing acetophenone and thiourea.
Two stretching bands in the range of 3,200–3,400 cm-1 in
the FT-IR spectrum of compound 1 confirm the presence
of an amino group. Compound 4 was synthesized in three
steps and in the first step chloroacetic acid heated with
thiourea at reflux temperature to give compound 2 with the
removal of 1 mol of water molecule. In the second step,
compound 2 was condensed with benzaldehyde in toluene
and catalytic amount of piperidine to produce compound
3. Upon chlorosulfonation of compound 3 in the last step
using chlorosulfonic acid, compound 4 was yielded as
confirmed by the IR spectrum. The IR spectrum of com-
pound 4 shows stretching band at 1,144 and 1,334 cm-1
(symm and asym), respectively, confirms the presence of
–SO3H group. The IR spectra of compound 4 displayed
stretching band at 3,335 cm-1 indicating the presence of
secondary amino group. Compound 5 was produced by the
condensation reaction between compounds 1 and 4 in the
presence of pyridine and acetic anhydride and the correct
synthesis is confirmed by the removal of –SO3H band from
the IR spectrum present in compound 4. Compound 6 was
synthesized by the reaction between various aniline and
chloroacetyl chloride in the presence of benzene. Finally,
compounds 5 and 6 on condensation in the presence of
dimethylformamide gave a series of thiazolidinedione
derivatives (6a–6i). The IR spectra of compounds 6a–6i
NMR (400 MHz, DMSO-d6)
d 125.4–138.1 (18C,
–Ar–C), 137.2 (C-28, C–Cl of phenyl ring), 150.8 and
103.4 (C-7 and C-8, C of thiazole ring, respectively, 164.3
and 165.1 (C-24 and C-22, –C=O of thiazolidinone ring),
165.7 (C-31, –Ar.-thiazolidinone ring linkage), 173.2
(C-10, C–NH linkage of Ar-thiazole ring; Anal. Calcd. for
C27H16O5N3S3Cl: C, 53.65; H, 3.41; N, 7.48; found: C,
53.62 %; H, 3.43 %; N, 7.53 %.
4-[3-(2-Nitro-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide (6h) Yield:
74 %; m.p. 262 °C (dec.); IR (KBr, cm-1) : 1326 (C–N),
1588 (C=N), 1140 and 1304 (SO2 sym and asym), 1670
(C=O), 600–800 (C–S), 3212 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 1036 and
1
1322 cm-1 (NO2), H NMR (400 MHz, DMSO-d6) d 4.44
(s, 1H, NH), 4.40 (s, 2H, CH2), 6.77–7.80 (m, 15H, Ar–H),
8.10 (s, 1H, –NH); 13C NMR (400 MHz, DMSO-d6) d
125.4–138.1 (18C, –Ar–C), 147.2 (C-26, C–NO2 of phenyl
ring), 150.8 and 103.4 (C-7 and C-8, C of thiazole ring,
respectively, 164.3 and 165.1 (C-24 and C-22, –C=O of
thiazolidinone ring), 165.7 (C-31, –Ar.-thiazolidinone ring
linkage), 173.2 (C-10, C–NH linkage of Ar-thiazole ring;
Anal. Calcd. for C26H16O7N4S3: C, 52.69; H, 2.77; N, 9.45;
found: C, 52.62 %; H, 2.72 %; N, 9.41 %.
revealed stretching band at 1,328 and 1,548 cm-1
,
4-[3-(4-Nitro-benzoyl)-2,4-dioxo-thiazolidin-5-ylidenemethyl]-
N-(4-phenyl-thiazol-2-yl)-benzenesulfonamide (6i) Yield:
69 %; m.p. 285 °C (dec.); IR (KBr, cm-1) : 1326 (C–N),
1588 (C=N), 1140 and 1304 (SO2 sym and asym), 1670
(C=O), 600–800 (C–S), 3212 cm-1 (–NH–), 3035–3060
cm-1 (–C–H) stretching of aromatic rings, 1036 and
respectively, confirm the presence of (C–N) and (C=N).
Bands at 1,120 and 1,310 cm-1 indentified the presence of
–SO2 (sym and asym), while –C=O group demonstrated a
sharp band at 1,685 cm-1. The thiazolidinone ring was
confirmed by the presence of characteristic –C–S
stretching band at 600–800 cm-1. The band at 3,198
cm-1 confirms the presence of –NH linkage in the com-
pound. The 1H NMR spectra of compounds 6a–6i showed
the signal at 4.02 ppm due to –NH linkage in the com-
pound. A singlet peak was observed at 4.42 ppm due to the
presence of –methylene proton in the compound, while an
–NH of thiazolidinone showed peak at 8.10 ppm. All the
remaining aromatic proton atoms revealed corresponding
peak in the range of 6.64–7.80 ppm. 13C NMR spectral
assigned signals in the range between 164.3 and 165.1 due
to presence of ketone (–C=O) functional group of thia-
zolidinone ring, 165.7 range confirmed the –C=O linkage
of Ar-thiazolidinone ring, 150.8 and 103.4 ppm range
indicates the presence of thiazole ring, 173.2 ppm indi-
cates the presence of –NH linkage of Ar-thiazole ring,
147.2–151.8 range showed the presence of –C–NO2
functional group, 132.6–137.2 range indicates the pres-
ence of –C–Cl group in the compound, 13.7–20.5 range
showed the presence of –C–CH3 group in the molecules,
while remaining aromatic carbons resonated in the range
of 125.4–138.1.
1
1322 cm-1 (NO2), H NMR (400 MHz, DMSO-d6) d 4.44
(s, 1H, NH), 4.40 (s, 2H, CH2), 6.77–7.80 (m, 14H, Ar–H),
8.10 (s, 1H, –NH); 13C NMR (400 MHz, DMSO-d6) d
125.4–138.1 (18C, –Ar–C), 150.8 and 103.4 (C-7 and C-8,
C of thiazole ring respectively, 151.8 (C-28, C-NO2 of
phenyl ring), 164.3 and 165.1 (C-24 and C-22, –C=O of
thiazolidinone ring), 165.7 (C-31, –Ar.-thiazolidinone ring
linkage), 173.2 (C-10, C–NH linkage of Ar-thiazole ring;
Anal. Calcd. for C26H16O7N4S3: C, 52.69; H, 2.77; N, 9.45;
found: C, 52.60 %; H, 2.67 %; N, 9.34 %.
Result and discussion
Chemistry
All the reaction was carried out under conventional methods.
4-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-N-(4-phenyl-
thiazol-2-yl)-benzenesulfonamide (5) was key interme-
diate required to synthesized target product. Compound 1
123

Med Chem Res
Antibacterial activity
against Gram-positive bacteria B. subtilis with 4 mm les-
ser zone of inhibition (22 mm). Compound 6e having
electron-donating group (–Cl) at C-3 position and 6h
having electron-withdrawing group (–NO2) at C-4 position
of phenyl ring was found half-fold active (MIC, 12.5 lg/
mL) against B. subtilis as compared to most active analogs
6d and 6f tested against the same strain. Compound 6c
having electron-donating group (–CH3) at C-4 position of
phenyl ring showed good activity (MIC, 50 lg/mL,
23-mm zone of inhibition) against B. subtilis. Compound
6b having electron-donating group (–CH3) at C-3 position
of the phenyl ring found half-fold active (MIC, 100 lg/
mL) as compared to compound 6b.
The antimicrobial bioassay results presented in Table 2
revealed that some of the compounds showed excellent
activity against all the mentioned bacteria. Final thiazo-
lidinedione compounds 6d and 6f having electron-donating
group (–Cl) at C-2 and C-4 positions, respectively, of the
phenyl ring exhibited excellent activity (MIC, 6.25 lg/mL,
24 mm zone of inhibition) against Gram-positive bacteria
S. aureus. Compound 6e having electron-donating group
(–Cl) at C-3 position of the phenyl ring was found half-
fold active (MIC, 12.5 lg/mL) against S. aureus as com-
pared to most active analogous 6d and 6e tested against
the same strain. Compound 6i having two electron-
withdrawing group (–NO2) at C-2 and C-4 position of the
phenyl ring showed similar inhibitory concentration of
12.5 lg/mL against S. aureus with 1 mm lesser zone of
inhibition (23 mm). Compound 6h having electron-
withdrawing group (–NO2) at C-4 position was found half-
fold active (MIC, 25 lg/mL) against S. aureus as com-
pared to compound 6h. Compound 6c having electron-
donating group (–CH3) at C-4 position of phenyl ring
exhibited good activity (MIC, 50 lg/mL, 22 mm zone of
inhibition against S. aureus). Compound 6b having elec-
tron-donating group (–CH3) at C-3 position of the phenyl
ring found half-fold active (MIC, 100 lg/mL) compared to
compound 6b. Final thiazolidinedione compounds 6d and
6f having electron-donating group (–Cl) at C-2 and C-4
positions, respectively, of the phenyl ring exhibited
excellent activity (MIC, 6.25 lg/mL, 26-mm zone of
inhibition) against Gram-positive bacteria B. subtilis.
Compound 6i having two electron-withdrawing group
(–NO2) at C-2 and C-4 position of the phenyl ring
exhibited similar inhibitory concentrations at 6.25 lg/mL
Compound 6d having electron-donating group (–Cl) at
C-2 position of phenyl ring was found to contribute
Table 3 Antituberculosis activity of synthesized compounds
MIC (lg/mL)
M. tuberculosis
(H37RV)
Compounds
MTCC 200
125
6a
6b
125
6c
250
6d
62.5
6e
62.5
6f
62.5
6g
1,000
500
6h
6i
1,000
Standard drugs
Refampicin
Isoniazid
40
0.2
Table 2 Antibacterial activity of synthesized compounds
Comp. nos.
R
Gram negative
Zone of inhibition (MIC)
Gram positive
Zone of inhibition (MIC)
E. coli
P. aeruginosa
S. aureus
B. subtilis
6a
H
22 (62.5)
18 (100)
22 (50)
22 (62.5)
19 (100)
22 (50)
21 (62.5)
18 (100)
22 (50)
24 (25)
6b
3-CH3
4-CH3
2-Cl
18 (100)
23 (50)
6c
6d
25 (12.5)
24 (25)
24 (12.5)
24 (25)
24 (6.25)
26 (12.5)
24 (6.25)
21 (62.5)
25 (25)
26 (6.25)
25 (12.5)
26 (6.25)
24 (25)
6e
3-Cl
6f
4-Cl
23 (25)
22 (12.5)
22 (62.5)
24 (25)
6g
3-NO2
4-NO2
2,4-NO2
22 ( 62.5)
24 (50)
6h
24 (12.5)
22 (6.25)
33 (B1)
6i
24 (12.5)
30 (B1)
22 (100)
31 (B1)
23(12.5)
32 (B1)
Ciprofloxacin (100 lg/disk)
The data outside of the bracket shows the zone of inhibition of compound and the data in parenthesis shows the MIC of compounds
The bold entries indicate the best compound of the series display inhibition at lowest minimum inhibition concentration
123

Med Chem Res
promising activity (MIC, 12.5 lg/mL, 25-mm zone of
inhibition against E. coli). Compound 6i having two
electron-withdrawing group (–NO2) at C-2 and C-4 posi-
tions of the phenyl ring exhibited similar inhibitory con-
centration of 12.5 lg/mL against E. coli with 1 mm lesser
zone of inhibition (24 mm) than 6d. Compound 6e having
electron-donating group (–Cl) at C-3 position and 6f hav-
ing electron-donating group (–Cl) at C-4 position of the
phenyl ring was found half-fold active (MIC, 25 lg/mL)
against E. coli as compared to most active analogs 6d
tested against the same strain. Compound 6c having
electron-donating group (–CH3) at C-4 position and 6h
having electron-withdrawing group (–NO2) at C-4 position
of phenyl ring showed good activity (MIC, 50 lg/mL)
against Gram-negative bacteria E. coli where 6b having
electron-donating group (–CH3) at C-3 position of the
phenyl ring found half-fold active (MIC, 100 lg/mL).
Compound 6d having electron-donating group (–Cl) at C-2
position of phenyl ring appeared with remarkable activity
against Gram-negative bacteria P. aeruginosa at 12.5 lg/
mL of MIC with 25-mm zone of inhibition. Compound 6f
having electron-donating group (–Cl) at C-4 position of the
phenyl ring exhibited similar inhibitory concentration of
12.5 lg/mL against P. aeruginosa with 2 mm of lesser
zone of inhibition (23 mm) than 6d where the half-fold
activity was observed (MIC, 25 lg/mL) for compound 6e
which having electron-donating group (–Cl) at C-3 position
and 6h having electron-withdrawing group (–NO2) at C-4
position of phenyl ring against the same bacteria. Com-
pound 6c having electron-donating group (–CH3) at C-4
Scheme 1 Synthesis of novel
2,4-thiazolidinedione
derivatives reagents: a I2,
NH3ꢀH2O, reflux 4 h, 80–90 °C;
b H2O, Conc. HCl, reflux
8–10 h, 100–110 °C;
O
CH3
NH2
N
S
a
S
+
H2N
NH2
c benzaldehyde, piperidine,
toluene, reflux 1 h, 110 °C;
d chlorosulfonicacid, reflux 1 h,
90–95 °C; e dry pyridine, acetic
anhydride, reflux 2 h; f DMF,
reflux 4 h
1
O
O
O
OH
S
NH
b
c
NH
+
S
H2N
NH2
O
Cl
S
O
3
2
O
d
NH
O
S
O
S
Cl
4
O
O
S
O
e
HN
S
4
1
+
O
N
S
NH
O
5
O
O
S
Cl
R
O
HN
S
f
O
5
N
+
S
N
R
O
O
6
123

Med Chem Res
position showed good activity (MIC, 50 lg/mL), where
compound 6b having electron-donating group (–CH3) at
C-3 position and 6i having two electron-withdrawing group
(–NO2) at C-2 and C-4 positions of the phenyl ring found to
be half-fold active (MIC, 100 lg/mL) than 6c against
Gram-negative bacteria P. aeruginosa.
benzoyl chloride derivatives as coupling components could
be useful for derivatization to develop more effective
antibacterial and antituberculosis agents.
Acknowledgments The authors are thankful to the Department of
Chemistry, Narmada College of Commerce and Science, Bharuch for
providing research facility. The authors are also thankful to Prof. Dr.
Bhaskar M. Rawal and Nikhil M. Parekh for their help during the
research work.
Antituberculosis activity
In vitro tuberculosis activities of compounds 6a–6i were
assessed against M. tuberculosis H37Rv. The results indi-
cated that both thiazolidinedione analogs were active
against mycobacteria. Preliminary antituberculosis screen-
ing results using BACTEC MGIT method revealed that
final thiazolidinedione analogs 6d, 6e, and 6f having
electron-donating group at C-2, C-3, and C-4 positions of
the phenyl ring displayed highest inhibition at a constant
concentration level (62.5 lg/mL) against M. tuberculosis
H37Rv (Table 3).
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