Synthesis and antibacterial and cytotoxic activities of new N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety

Article abstract of DOI:10.1002/ardp.201300466

Two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety (5a-j and 7a-j) were synthesized and assessed in vitro for their efficacy as antibacterial agents against gram-positive and gram-negative bacterial strains. Among the tested compounds, 7b, 7c, 7i, and 7j were found to be active against gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) with minimum inhibitory concentration (MIC) values in the range of 6.25-25 μg/mL, and some compounds were also tested against methicillin-resistant S. aureus (MRSA). Compounds 7c and 7j inhibited the growth of MRSA at MIC values of 6.25 and 12.5 μg/mL, respectively. The influence of the lipophilicity (C log P) on the biological profile (MIC) of the prepared products was also discussed. From the standpoint of structure-activity relationship studies, it was observed that the lipophilic profiles of the compounds were crucial for their antibacterial activities. Further, the results of the MTT cytotoxicity studies on a human cervical cancer cell line (HeLa) and a mouse embryonic fibroblast cell line (NIH 3T3) suggested that compounds 7b, 7c, 7i, and 7j were endowed with low levels of cytotoxicity. Two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety were assessed in vitro for their efficacy as antibacterial agents. Compounds 7b, 7c, 7i, and 7j were found to be active against Staphylococcus aureus and Streptococcus pyogenes. Compounds 7c and 7j also inhibited the growth of methicillin-resistant S. aureus. The lipophilicity profiles of the compounds were found to be crucial for their antibacterial activities.

Full text of DOI:10.1002/ardp.201300466

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
1
Full Paper
Synthesis and Antibacterial and Cytotoxic Activities of New
N-3 Substituted Thiazolidine-2,4-dione Derivatives Bearing
the Pyrazole Moiety
Nisheeth C. Desai, Hitesh M. Satodiya, Ghanshyam M. Kotadiya, and Hasit V. Vaghani
Division of Medicinal Chemistry, Department of Chemistry, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, Gujarat, India
Two new series of N-3 substituted thiazolidine-2,4-dione derivatives bearing the pyrazole moiety (5a–j
and 7a–j) were synthesized and assessed in vitro for their efficacy as antibacterial agents against gram-
positive and gram-negative bacterial strains. Among the tested compounds, 7b, 7c, 7i, and 7j were
found to be active against gram-positive bacteria (Staphylococcus aureus and Streptococcus pyogenes) with
minimum inhibitory concentration (MIC) values in the range of 6.25–25 mg/mL, and some compounds
were also tested against methicillin-resistant S. aureus (MRSA). Compounds 7c and 7j inhibited the
growth of MRSA at MIC values of 6.25 and 12.5 mg/mL, respectively. The influence of the lipophilicity
(C log P) on the biological profile (MIC) of the prepared products was also discussed. From the standpoint
of structure–activity relationship studies, it was observed that the lipophilic profiles of the compounds
were crucial for their antibacterial activities. Further, the results of the MTT cytotoxicity studies on a
human cervical cancer cell line (HeLa) and a mouse embryonic fibroblast cell line (NIH 3T3) suggested
that compounds 7b, 7c, 7i, and 7j were endowed with low levels of cytotoxicity.
Keywords: Antibacterial activity / Cytotoxic activity / Pyrazole / Thiazolidine-2,4-dione
Received: December 14, 2013; Revised: February 4, 2014; Accepted: February 18, 2014
DOI 10.1002/ardp.201300466
Introduction
It has been well established that thiazolidine-2,4-dione
motif has got a significant place in modern medicinal
chemistry. In recent years, thiazolidine-2,4-dione-based mol-
ecules have been reported as small molecule inhibitors of
numerous biological targets, including aldose reductase [9],
15-hydroxyprostaglandin dehydrogenase [10], and enzyme
MurD ligase [11]. Furthermore, they have been reported as
antihyperglycemic [12], bactericidal [13], pesticidal [14],
fungicidal [15], insecticidal [16], anticonvulsant [17], tuber-
culostatic [18], and anti-inflammatory [19]. There have been
many reports in the literature depicting the presence of
heterocyclic moieties such as thiazole, pyrazole, flavone,
chromone, and furan at C-5 position of thiazolidine-2,4-dione,
which is more potent and efficacious than a simple aryl
group [20–26]. It is also reported that thiazolidine-2,4-dione
bearing heteroaromatic moiety such as imidazolylmethyl-
phenyl, 1,2,4-triazole, and morpholine at N-3 position
contributes to antimicrobial and antimycotic activities [27].
Moreover, pyrazoles and their derivatives represent one of the
most important classes of heterocyclic compounds and have
attracted considerable attention from both synthetic and
The treatment of infectious diseases still remains an
important and challenging problem because of combination
factors such as emerging infectious diseases and increasing
number of multi-drug-resistant microbial pathogens with a
particular relevance for gram-positive bacteria [1–5]. The most
commonly encountered antibiotic-resistant bacteria, methi-
cillin-resistant Staphylococcus aureus (MRSA), have a major
impact on infections in both hospitals and community
settings [6, 7]. Unfortunately, as antibiotic-resistant organisms
have become more commonplace, the pipeline for the
discovery of new antimicrobial agents has decreased [8].
Thus, there is a pressing need for new antimicrobial agents
that are capable of treating resistant bacterial strains.
Correspondence: Prof. Nisheeth C. Desai, Division of Medicinal
Chemistry, Department of Chemistry, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002,
Gujarat, India.
E-mail: dnisheeth@rediffmail.com
Fax: þ91 278 2439852
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N. C. Desai et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
medicinal chemists due to their biological activities such as
antimicrobial [28], anti-viral [29], and anticancer [30]. Same
classes of compounds have also been reported to exhibit
significant cyclooxygenase (COX-2) inhibition [31], anti-
inflammatory [32], and antioxidant [33] activities. Also, the
azole group of heterocyclic compounds possesses significant
pharmacokinetic property, lipophilicity that influences the
ability of drug to reach the target by transmembrane diffusion
and shows promising activity against resistant TB by
inhibiting the biosynthesis of lipids [34, 35].
Previously, we have reported the synthesis and antimicro-
bial evaluation of thiazolidine-2,4-dione containing pyr-
azole [36] in which N-3 position of thiazolidine-2,4-dione
ring was substituted by propyl pyrrole (Fig. 1). It was our
observation that substitution at N-3 position enhanced the
antibacterial activity as compared to unsubstituted N-3
position of thiazolidine-2,4-dione ring. As a part of our
ongoing research program, we have synthesized two new
series of thiazolidine-2,4-dione bearing pyrazole moiety in
which N-3 position of thiazolidine-2,4-dione was substituted
by propyl morpholine and propyl indole. All the newly
synthesized compounds of both series 5a–j and 7a–j were
evaluated for antibacterial activity.
conditions and reagents applied for both the series were
different. To achieve compounds 5a–j, reactions of com-
pounds 3a–j were carried out with morpholine 4, powdered
potassium hydroxide and 1,3-dibromopropane in anhydrous
dimethylformamide. For the synthesis of compounds 7a–j,
compounds 3a–j were reacted with 1H-indole 6, sodium
hydride and tetrahydrofuran (THF).
Structures of products 5a–j and 7a–j were confirmed on the
basis of their spectral data. In IR spectra, absorption bands
were displayed in the range of 2981–2995 cmꢀ1 and 2850–
2865 cmꢀ1 that were characteristic of alkyl chain present in all
targeted compounds, besides the disappearance of secondary
amine group stretching vibration due to its involvement in
alkylation. 1H NMR spectrum of compounds 5a–j and 7a–j
displayed three signals at d 4.20–4.24 (triplet), 2.65–2.74
(triplet), and 1.95–2.10 ppm (multiplet) due to protons of
propyl chain, which were enough to confirm that compounds
3a–j were substituted at N-3 position, along with the vanishing
of secondary amine singlet. In addition, 1H NMR spectra
revealed a singlet at d 8.36–8.46 and 8.50–8.60 ppm due to
methine proton that appeared as linker between pyrazole and
thiazolidine-2,4-dione heterocycles in compounds 5a–j and
7a–j, respectively. Moreover, compounds 5a–j displayed two
triplets at d 3.70–3.83 ppm and 2.30–2.34 ppm for morpholine
ring protons. 13C NMR spectrum of target compounds showed,
besides the expected aromatic signals, important signals in the
range of d 26.0–28.5, 42.0–42.5, and 52.0–53.5 ppm, which
were characteristic of three carbons present in the propyl
chain of final compounds. Mass spectra of all the title
compounds gave expected Mþ peak corresponding to the
proposed molecular mass. The obtained elemental analysis
values are in good agreement with theoretical data. Similarly,
the spectral values for all the compounds and C, H, N analysis
are presented in the experimental part.
Results and discussion
Chemistry
A general approach to synthesize the designed compounds is
outlined in Scheme 1. The intermediate compounds 5-((3-
(4-substituted phenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)thi-
azolidine-2,4-diones 3a–j were prepared according to the
reported procedure [36]. The resulting compounds 3a–j were
subjected to one-pot synthesis of N-3 substitution for
achieving the desired compounds 5a–j and 7a–j. Reaction
Figure 1. Effect of N-3 substitution on antimicrobial activity of previously synthesized compounds.
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
Thiazolidine-2,4-diones Bearing the Pyrazole Moiety
3
Scheme 1. Synthetic route for the preparation of the title compounds 5a–j and 7a–j.
Biological evaluation
Antibacterial activity
All the target compounds 5a–j and 7a–j were evaluated for
their in vitro antibacterial activity against S. aureus MTCC 96,
Streptococcus pyogenes MTCC 442 (gram-positive), Escherichia coli
MTCC 443, Pseudomonas aeruginosa MTCC 1688 (gram-negative),
and methicillin-resistant S. aureus ATCC 43300 by convention-
al broth dilution method [37–39]. Minimum inhibitory
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N. C. Desai et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
concentration (MIC) is defined as the concentration of the
compound required to obtain complete inhibition of bacterial
growth. MICs of synthesized compounds were compared with
ciprofloxacin and chloramphenicol and the results are reported
in Table 1. It was reported in our previous publication that
compounds 3a–j [36] did not exhibit antibacterial activity against
selected microorganisms. From the bioassay, final analogs with
electron-withdrawing (Cl or NO2) substituents were found to be
more active than the remaining final analogs against gram-
positive bacterial strains. Among the desired compounds, 7b, 7c,
7i, and 7j showed comparable antibacterial activity against
gram-positive strains and their MIC values were in the range of
6.25–25 mg/mL, as compared to the standard drugs ciprofloxacin
and chloramphenicol. Among all the final analogs, compound
7c (2,4-(Cl)2, Clog P¼ 8.76) endowed with chlorine exerted
highest inhibition against S. aureus at MIC of 6.25 mg/mL, while
compounds 7i (3-NO2, Clog P¼ 7.34) and 7j (4-NO2, Clog P¼ 7.34)
bearing electron-withdrawing nitro group showed also highest
inhibition against S. pyogenes at MIC of 6.25 mg/mL. Furthermore,
among the second-line active compounds, 7b (4-Cl, Clog P¼ 8.29)
and 7j (4-NO2, Clog P¼ 7.34) indicated MIC of 12.5 mg/mL against
S. pyogenes and S. aureus, respectively, in which compound 7j
showed better results against gram-positive bacteria. None of the
title compounds (5a–j and 7a–j) inhibited the growth of gram-
negative strains (E. coli MTCC 443 and P. aeruginosa MTCC 1688) at
100 mg/mL (Table 1).
On the basis of biological activity, it is assumed that strong
lipophilic character of molecule played an essential role in
producing antibacterial effect. These stuffs are seen as important
parameters related to membrane permeation in biological
system. Many of the processes of drug disposition depend on the
capability to cross membranes and hence there is a high
correlation with measures of lipophilicity [40]. In this context,
the presence of hydrophobic moiety would be important for
such activity. The octanol/water partition coefficient ClogP,
being a measure of hydrophobicity/lipophilicity, was calculated
using ChemBioDraw Ultra 11.0. The results obtained are given
in Table 1. The calculated values of C log P for compounds 7a–j
were about 2.32 higher than the values for the corresponding
compounds 5a–j. Consequently, compounds 7a–j have higher
lipophilic property compared to 5a–j.
Inactivity of compounds 5a–j (MIC > 100 mg/mL) against
S. aureus and S. pyogenes may be attributed to the hydrophilic
character of morpholine nucleus attached to thiazolidine-2,4-
dione ring via propyl chain that deters the penetration of
molecule into the bacterial cell. Replacement of morpholine in
Table 1. Results of in vitro antibacterial screening of compounds 5a–j and 7a–j.
Minimum inhibitory concentration (MIC; mg/mL)
Gram-negativeb) Gram-positivec)
Entry
-R
C log Pa)
Ec
Pa
250
Sa
Sp
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
7a
7b
7c
7d
7e
7f
-H
5.24
5.97
6.44
5.74
5.21
4.37
4.37
4.37
5.02
5.02
7.56
8.29
8.76
8.06
7.53
6.69
6.99
6.99
7.34
7.34
>1000
500
>1000
>1000
500
200
250
500
200
250
-4-Cl
500
1000
>1000
>1000
>1000
1000
250
-2,4-(Cl)2
-4-CH3
-4-OCH3
-2-OH
-3-OH
-4-OH
-3-NO2
-4-NO2
-H
250
200
250
200
200
1000
500
1000
>1000
200
250
1000
500
500
1000
200
200
>1000
100
>1000
500
1000
200
200
1000
1000
>1000
500
>1000
>1000
>1000
500
50
25
6.25
50
50
100
100
50
25
12.5
-4-Cl
12.5
-2,4-(Cl)2
-4-CH3
-4-OCH3
-2-OH
-3-OH
-4-OH
-3-NO2
-4-NO2
500
250
25
100
50
50
100
50
6.25
6.25
25
12.5
1000
>1000
>1000
500
>1000
1000
25
7g
7h
7i
7j
250
>1000
500
Ciprofloxacin
Chloramphenicol
25
100
12.5
25
50
a)
C log P calculated using the ChemBioDraw Ultra, version 11.0, software by Cambridge Soft.
Ec: Escherichia coli (MTCC-443); Pa: Pseudomonas aeruginosa (MTCC-1688).
Sa: Staphylococcus aureus (MTCC-96); Sp: Streptococcus pyogenes (MTCC-442).
b)
c)
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
Thiazolidine-2,4-diones Bearing the Pyrazole Moiety
5
compounds 5a–j with the more lipophilic indole nucleus
increased C log P, ensuing the improvement in antibacterial
activity of compounds 7a–j (MIC ¼ 6.25–100 mg/mL). The
most active compounds 7b, 7c, 7i, and 7j against S. aureus
and S. pyogenes (MIC ¼ 6.25–25mg/mL) were also tested against
methicillin-resistant S. aureus (MRSA isolate ATCC 43300) and
the results are given in Table 2. Compounds 7c and 7j exhibited
more potent activity than the standard drugs against
methicillin-resistant S. aureus. Compound 7c, with MIC value
of 6.25mg/mL against MRSA, showed fourfold more potency
than ciprofloxacin (MIC ¼ 25mg/mL) and eightfold more
activity than chloramphenicol (MIC¼ 50 mg/mL). In addition,
compound 7j endowed with nitro group showed twofold more
activity at MIC value of 12.5 mg/mL than ciprofloxacin and
fourfold higher potency than chloramphenicol against MRSA.
Table 3. Cytotoxic activity of compounds 7a–j against HeLa and
NIH 3T3 cell lines.
Cytotoxicity (IC50 mM)a)
Entry
HeLab)
NIH 3T3c)
7a
7b
7c
7d
7e
7f
7g
7h
7i
>100
>100
>100
>100
>100
65.30
70.50
80.42
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
7j
a)
The concentrations required to inhibit 50% of cell growth.
Human cervical cancer cell line.
Mouse embryonic fibroblast cell line.
b)
c)
Cytotoxicity study
After having identified numerous active antibacterial agents,
the next step was to examine the toxicity of drug contenders.
In vitro cytotoxicity of compounds 7a–j was determined against
mouse embryonic fibroblast cell line (NIH 3T3) and human
cervical cancer cell line (HeLa) using MTT colorimetric assay
by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bro-
mide (MTT) colorimetric assay [41, 42], which measures the
reduction of the tetrazolium bromide salt into a formazan dye
by mitochondrial dehydrogenases in treated versus untreated
cells. The IC50 values obtained for these compounds are shown
in Table 3. The results of cytotoxicity studies revealed that
compounds 7f, 7g, and 7h showed moderate toxicity against
HeLa cell line, while remaining compounds 7a–7e, 7i, and 7j
accounted for no toxicity at a concentration of 100 mM
(IC50 > 100 mM). Moreover, none of the derivatives showed
cytotoxicity against NIH 3T3 cell lines (IC50 > 100 mM).
ꢁ On the basis of the results of biological activity, it has
been observed that compounds 7a–j were superior than
compounds 5a–j.
ꢁ On the basis of the previous observations [36] and results
reported in the present study, it was clear that the
substituent on N-3 position having higher lipophilic
property was necessary for the antibacterial activity
(morpholine < pyrrole < indole).
ꢁ Compared to our previous results on NCD1–10 (Fig. 1),
compounds 5a–j showed a decrease in the activity. This is
due to the introduction of morpholine moiety at N-3
position of 5-((3-(substituted phenyl)-1-phenyl-1H-pyrazol-4-
yl)methylene)thiazolidine-2,4-dione (Table 1), which might
be hindering the binding of molecule to the strains.
ꢁ On the other hand, compounds 7a–j showed increase in
the activity compared to compounds 5a–j and our previous
results of NCD1–10 (Fig. 1). This is due to the presence of
indole group (Table 1) in molecular framework.
ꢁ The type of substitution on the phenyl ring of series 7a–j
is also important. It was noticed that compounds 7b,
7c, 7i, and 7j possessing an electron-withdrawing
substituent (–NO2 and –Cl) on the phenyl ring showed
enhancement in the activity against S. aureus and S.
pyogenes (MIC ¼ 6.25–25 mg/mL) as compared to electron-
donating groups.
Structure–activity relationship
From the results of antimicrobial activity, the following
structure–activity relationship may be predicted.
ꢁ Structure–activity relationship of the synthesized com-
pounds depends on structural skeleton and electronic
environment of the molecules.
Table 2. Inhibitory activity (MIC, mg/mL) of compounds 7b, 7c, 7i,
and 7j against methicillin-resistant S. aureus.
Entry
MRSAa)
ꢁ The four molecules 7b, 7c, 7i, and 7j were screened against
methicillin-resistant S. aureus. Among these, compounds 7c
and 7j showed better activity than two references
ciprofloxacin and chloramphenicol. This may be due to
presence of chloro and nitro groups.
ꢁ Moreover, the position of substituents (i.e., o, m, and p) on
the phenyl ring may not have any further influence on the
antibacterial activity of compounds.
7b
7c
7i
>50
6.25
50
7j
12.5
25
50
Ciprofloxacin
Chloramphenicol
a)
Methicillin-resistant S. aureus (ATCC 43300).
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N. C. Desai et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
ꢁ Taking into account the series of compounds 7a–j, it was
assumed that the presence of hydroxyl group increased the
cytotoxic activity (compounds 7f, 7g, and 7h).
General procedure for the synthesis of 5-((3-(aryl)-1-
phenyl-1H-pyrazol-4-yl)methylene)-3-(3-
morpholinopropyl)thiazolidine-2,4-diones (5a–j)
A mixture of compounds 3a–j (1 mmol), powdered KOH (1 mmol),
and 1,3-dibromopropane (1 mmol) in anhydrous dimethylform-
amide (10 mL) was separately stirred for 30 min at room
temperature. A solution of morpholine 4 (1 mmol) and powdered
KOH (1 mmol) in anhydrous dimethylformamide (5 mL) was
added to the stirred reaction mixture, which was then heated at
90°C for 8–10 h. After cooling the mixture at room temperature,
water (20 mL) was added and the product was extracted in diethyl
ether (3 ꢂ 20 mL). The ether extracts were washed with water and
dried over MgSO4, and ether was evaporated in vacuum, followed
by the purification of resulting residue by silica gel column
chromatography (chloroform/methanol, 9:1).
Conclusion
We focused our work on the development of new agents
based on thiazolidine-2,4-dione containing pyrazole deriva-
tives in which N-3 position of thiazolidine-2,4-dione was
substituted with propyl morpholine (5a–j) and propyl indole
(7a–j) compact system with the hope of generating new
bioactive molecules that could be useful as potent antibac-
terial agents. The newly synthesized compounds were
investigated for their in vitro antibacterial activity by
conventional broth dilution method and in vitro cytotoxicity
activity using MTT colorimetric assay method. This study
demonstrated that substitution of propyl indole (higher
C log P values) at N-3 position and electron-withdrawing
groups (nitro and chloro) on phenyl ring results in an
enhancement of antibacterial activity against gram-positive
bacterial strains. Albeit, it was observed that the strong
lipophilic character of the molecule plays an imperative role
in producing antibacterial effect. Many of the synthesized
motifs (7b, 7c, 7i, and 7j) possessing atoms/groups such as
chloro and nitro at ortho, meta, or para positions were
identified as the most compelling antibacterial agents. In
particular, compounds 7c and 7j exhibited a high level of
antibacterial activity against S. aureus and MRSA with no
toxicity. However, additional studies regarding the mecha-
nism of action are necessary for a complete understanding of
antimicrobial activity of these compounds.
5-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-3-(3-
morpholinopropyl)thiazolidine-2,4-dione (5a)
Yield 62%; m.p. 245–147°C. IR (KBr, vmax cmꢀ1): 3076, 3028 (C–H,
–
aromatic), 2981, 2850 (C–H, alkyl), 1768, 1719 (C O), 1650
–
1
–
–
(CH C), 1565 (C N), 1378 (C–N), 1263 (C–O–C), 635 (C–S). H NMR
–
–
(400 MHz, DMSO-d6): d 9.01 (s, 1H, pyrazole ring), 8.40 (s, 01H,
–
CH C), 7.30–7.90 (m, 10H, aromatic-H), 4.20 (t, J ¼ 4.38 Hz, 2H,
–
CH2), 3.70 (t, J ¼ 4.53 Hz, 4H, morpholine), 2.65 (t, J ¼ 4.07 Hz, 2H,
CH2), 2.30 (t, J ¼ 4.53 Hz, 4H, morpholine), 1.96 (m, 2H, CH2).
13C NMR (100 MHz, DMSO-d6): d 26.6, 42.5, 52.5, 63.0 (2), 66.8 (2),
113.0, 120.1 (2), 122.0, 126.2, 127.6 (2), 128.7, 129.2 (2), 129.7 (2),
130.3, 133.0, 139.5, 143.5, 150.4, 164.2, 173.2. MS m/z 475 (Mþ1).
Anal. calcd. for C26H26N4O3S: C, 65.80; H, 5.52; N, 11.81; S, 6.76.
Found: C, 65.68; H, 5.35; N, 11.89; S, 6.85.
5-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(5b)
Yield 65%; m.p. 207–209°C. IR (KBr, vmax cmꢀ1): 3070, 3031 (C–H,
–
aromatic), 2985, 2852 (C–H, alkyl), 1770, 1720 (C O), 1652
–
–
–
(CH C), 1560 (C N), 1379 (C–N), 1260 (C–O–C), 775 (C–Cl), 633
–
–
1
(C–S). H NMR (400 MHz, DMSO-d6): d 9.07 (s, 1H, pyrazole ring),
8.46 (s, 1H, CH C), 7.37–7.90 (m, 9H, aromatic-H), 4.21
Experimental
–
–
(t, J ¼ 4.36 Hz, 2H, CH2), 3.75 (t, J ¼ 4.53 Hz, 4H, morpholine),
2.66 (t, J ¼ 4.07 Hz, 2H, CH2), 2.32 (t, J ¼ 4.52 Hz, 4H, morpholine),
1.97 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.6, 42.0, 52.1,
62.9 (2), 66.5 (2), 113.0, 120.2 (2), 122.0, 126.1, 128.5 (2), 129.0 (4),
130.3, 131.5, 134.2, 139.7, 143.0, 150.7, 164.0, 173.2. MS m/z 509
(Mþ1). Anal. calcd. for C26H25ClN4O3S: C, 61.35; H, 4.95; N, 11.01;
S, 6.30. Found: C, 61.23; H, 4.86; N, 11.16; S, 6.13.
General methods
All the reagents were analytically pure. All the solvents were dried
by standard methods in advance and distilled before use. Melting
points were determined on an electro thermal melting point
apparatus and were reported uncorrected. TLC on silica gel plates
(Merck, 60, F) was used for reaction monitoring. Column
chromatography on silica gel (Merck, 70–230 and 230–400 mesh
ASTH for flash chromatography) was applied when necessary to
isolate and purify the reaction products. Elemental analyses for C,
H, N, and S were carried out on a 204Q CHN Rapid Analyzer
(Perkin-Elmer). IR spectra of all the compounds were recorded on
5-((3-(2,4-Dichlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(5c)
Yield 65%; m.p. 270–272°C. IR (KBr, vmax cmꢀ1): 3075, 3025 (C–H,
1
a Perkin-Elmer FT-IR spectrophotometer in KBr. H NMR spectra
–
aromatic), 2987, 2859 (C–H, alkyl), 1771, 1715 (C O), 1651
were recorded on a Varian Gemini 400 MHz spectrometer in
DMSO-d6 with TMS as an internal reference. 13C NMR spectra
were recorded in DMSO-d6 on a Varian Mercury-400 (100 MHz)
spectrometer. Chemical shifts were expressed in ppm, and
coupling constants (J) were given in Hz. Mass spectra were
scanned on a Shimadzu LCMS 2010 spectrometer and the signals
were given in m/z. Anhydrous reactions were carried out in oven-
dried glassware in nitrogen atmosphere.
–
–
–
(CH C), 1567 (C N), 1371 (C–N), 1265 (C–O–C), 770 (C–Cl), 630
–
–
1
(C–S). H NMR (400 MHz, DMSO-d6): d 9.00 (s, 1H, pyrazole ring),
8.38 (s, 1H, CH C), 7.25–7.95 (m, 8H, aromatic-H), 4.20
–
–
(t, J ¼ 4.37 Hz, 2H, CH2), 3.75 (t, J ¼ 4.51 Hz, 4H, morpholine),
2.67 (t, J ¼ 4.07 Hz, 2H, CH2), 2.30 (t, J ¼ 4.52 Hz, 4H, morpholine),
2.01 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.5, 42.0, 52.1,
63.0 (2), 66.8 (2), 113.2, 119.9 (2), 122.3, 126.1, 127.5, 128.0, 129.2
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
Thiazolidine-2,4-diones Bearing the Pyrazole Moiety
7
(2), 130.1 (2), 130.9, 133.5, 135.6, 139.7, 143.3, 150.1, 164.2, 173.0.
MS m/z 544 (Mþ1). Anal. calcd. for C26H24Cl2N4O3S: C, 57.46; H,
4.45; N, 10.31; S, 5.90. Found: C, 57.61; H, 4.37; N, 10.47; S, 5.76.
(t, J ¼ 4.39 Hz, 2H, CH2), 3.81 (t, J ¼ 4.52 Hz, 4H, morpholine), 2.67
(t, J ¼ 4.01 Hz, 2H, CH2), 2.30 (t, J ¼ 4.52 Hz, 4H, morpholine), 2.05
(m, 2H, CH2). 13C NMR (100MHz, DMSO-d6): d 26.1, 42.2, 52.1, 63.2
(2), 66.7 (2), 113.3, 115.5 (2), 120.1 (2), 120.4, 122.0, 126.3, 129.6 (2),
130.3, 130.8, 134.5, 139.9, 143.0, 150.4, 157.1, 164.2, 173.2. MS m/z
491 (Mþ1). Anal. calcd. for C26H26N4O4S: C, 63.66; H, 5.34; N, 11.42;
S, 6.54. Found: C, 63.75; H, 5.21; N, 11.56; S, 6.69.
3-(3-Morpholinopropyl)-5-((1-phenyl-3-p-tolyl-1H-pyrazol-
4-yl)methylene)thiazolidine-2,4-dione (5d)
Yield 61%; m.p. 198–200°C. IR (KBr, vmax cmꢀ1): 3072, 3025 (C–H,
–
aromatic), 2980, 2855 (C–H, alkyl), 1768, 1719 (C O), 1651
–
1
5-((3-(4-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
–
–
(CH C), 1570 (C N), 1376 (C–N), 1260 (C–O–C), 636 (C–S). H NMR
–
–
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(400 MHz, DMSO-d6): d 9.10 (s, 1H, pyrazole ring), 8.40 (s, 1H,
–
CH C), 7.32–7.95 (m, 9H, aromatic-H), 4.21 (t, J ¼ 4.39 Hz, 2H,
–
(5h)
Yield 67%; m.p. 287–289°C. IR (KBr, vmax cmꢀ1): 3635 (OH, phenolic),
3076, 3024 (C–H, aromatic), 2980, 2851 (C–H, alkyl), 1761, 1726
CH2), 3.80 (t, J ¼ 4.53 Hz, 4H, morpholine), 2.65 (t, J ¼ 4.07 Hz, 2H,
CH2), 2.44 (s, 3H, CH3), 2.31 (t, J ¼ 4.52 Hz, 4H, morpholine), 2.00
(m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 21.1, 26.5, 42.0, 52.3,
62.5 (2), 66.7 (2), 113.1, 119.9 (2), 122.0, 126.1, 128.0 (2), 129.3 (2),
129.7 (2), 130.0, 130.6, 131.7, 139.5, 143.1, 150.4, 164.2, 173.3. MS
m/z 489 (Mþ1). Anal. calcd. for C27H28N4O3S: C, 66.37; H, 5.78; N,
11.47; S, 6.56. Found: C, 66.52; H, 5.70; N, 11.59; S, 6.70.
–
–
–
(C O), 1648 (CH C), 1560 (C N), 1373 (C–N), 1258 (C–O–C), 635
–
–
–
(C–S). 1H NMR (400 MHz, DMSO-d6): d 9.05 (s, 1H, pyrazole ring), 8.31
(s, 1H, CH C), 7.28–7.92 (m, 9H, aromatic-H), 5.08 (br s, 1H, OH),
–
–
4.21 (t, J ¼ 4.39Hz, 2H, CH2), 3.80 (t, J ¼ 4.53 Hz, 4H, morpholine),
2.67 (t, J ¼ 4.00Hz, 2H, CH2), 2.32 (t, J ¼ 4.53 Hz, 4H, morpholine),
2.09 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.0, 42.1, 52.0,
63.4 (2), 66.9 (2), 113.3, 116.5 (2), 120.2 (2), 122.0, 125.7, 126.5,
128.9 (2), 129.1 (2), 130.3, 139.2, 143.3, 150.7, 158.5, 164.8, 173.0.
MS m/z 491 (Mþ1). Anal. calcd. for C26H26N4O4S: C, 63.66; H, 5.34;
N, 11.42; S, 6.54. Found: C, 63.71; H, 5.21; N, 11.30; S, 6.45.
5-((3-(4-Methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(5e)
Yield 59%; m.p. 261–263°C. IR (KBr, vmax cmꢀ1): 3079, 3022 (C–H,
–
aromatic), 2987, 2861 (C–H, alkyl), 1765, 1720 (C O), 1651
–
1
3-(3-Morpholinopropyl)-5-((3-(3-nitrophenyl)-1-phenyl-1H-
–
–
(CH C), 1569 (C N), 1376 (C–N), 1266 (C–O–C), 630 (C–S). H NMR
–
–
pyrazol-4-yl)methylene)thiazolidine-2,4-dione (5i)
(400 MHz, DMSO-d6): d 9.02 (s, 1H, pyrazole ring), 8.36 (s, 1H,
Yield 68%; m.p. 214–216°C. IR (KBr, vmax cmꢀ1): 3069, 3017 (C–H,
–
CH C), 7.32–7.90 (m, 9H, aromatic-H), 4.20 (t, J ¼ 4.35 Hz, 2H,
–
–
CH2), 4.12 (s, 3H, OCH3), 3.80 (t, J ¼ 4.53 Hz, 4H, morpholine), 2.66
(t, J ¼ 4.08 Hz, 2H, CH2), 2.30 (t, J ¼ 4.53 Hz, 4H, morpholine), 2.05
(m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.2, 42.5, 52.1, 55.6,
62.9 (2), 67.0 (2), 113.1, 114.2 (2), 120.4 (2), 122.0, 125.1, 126.0,
128.7 (2), 129.1 (2), 130.3, 139.5, 143.3, 150.1, 160.5, 164.3, 173.1.
MS m/z 505 (Mþ1). Anal. calcd. for C27H28N4O4S: C, 64.27; H, 5.59;
N, 11.10; S, 6.35. Found: C, 64.41; H, 5.51; N, 10.98; S, 6.51.
aromatic), 2983, 2862 (C–H, alkyl), 1760, 1711 (C O), 1652
–
–
–
(CH C), 1553 (C N), 1470 (NO ), 1370 (C–N), 1260 (C–O–C), 637
–
–
2
1
(C–S). H NMR (400 MHz, DMSO-d6): d 9.07 (s, 1H, pyrazole ring),
8.31 (s, 1H, CH C), 7.25–7.90 (m, 9H, aromatic-H), 4.22
–
–
(t, J ¼ 4.40 Hz, 2H, CH2), 3.82 (t, J ¼ 4.50 Hz, 4H, morpholine),
2.65 (t, J ¼ 4.02 Hz, 2H, CH2), 2.31 (t, J ¼ 4.50 Hz, 4H, morpholine),
2.00 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.1, 42.5, 52.2,
63.2 (2), 66.8 (2), 113.0, 120.1 (2), 122.4, 122.7, 124.3, 126.2, 129.3
(2), 130.5, 130.9, 133.6, 134.0, 139.7, 143.1, 148.5, 150.3, 164.2,
173.1. MS m/z 520 (Mþ1). Anal. calcd. for C26H25N5O5S: C, 60.10; H,
4.85; N, 13.48; S, 6.17. Found: C, 59.99; H, 4.93; N, 13.61; S, 6.29.
5-((3-(2-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(5f)
Yield 64%; m.p. 285–287°C. IR (KBr, vmax cmꢀ1): 3632 (OH, phenolic),
3075, 3021 (C–H, aromatic), 2985, 2857 (C–H, alkyl), 1761, 1719
3-(3-Morpholinopropyl)-5-((3-(4-nitrophenyl)-1-phenyl-1H-
–
–
–
pyrazol-4-yl)methylene)thiazolidine-2,4-dione (5j)
(C O), 1650 (CH C), 1560 (C N), 1375 (C–N), 1261 (C–O–C), 637
–
–
–
(C–S). 1H NMR (400 MHz, DMSO-d6): d 9.00 (s, 1H, pyrazole ring), 8.36
(s, 1H, CH C), 7.32–7.90 (m, 9H, aromatic-H), 5.02 (br s, 1H, OH),
Yield 69%; m.p. 257–259°C. IR (KBr, vmax cmꢀ1): 3070, 3017 (C–H,
–
–
–
aromatic), 2988, 2860 (C–H, alkyl), 1760, 1711 (C O), 1655
–
–
(CH C), 1553 (C N), 1463 (NO ), 1357 (C–N), 1268 (C–O–C), 635
–
2
–
–
4.22 (t, J ¼ 4.39Hz, 2H, CH2), 3.81 (t, J ¼ 4.53 Hz, 4H, morpholine),
2.65 (t, J ¼ 4.06Hz, 2H, CH2), 2.31 (t, J ¼ 4.53 Hz, 4H, morpholine),
2.05 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.1, 42.0, 52.1,
63.2 (2), 67.0 (2), 113.0, 117.9, 120.0 (2), 120.7, 121.8, 122.4, 126.0,
129.3 (2), 130.2. 130.7, 131.5, 139.7, 143.9, 150.4, 155.1, 164.7, 173.1.
MS m/z 491 (Mþ1). Anal. calcd. for C26H26N4O4S: C, 63.66; H, 5.34;
N, 11.42; S, 6.54. Found: C, 63.77; H, 5.25; N, 11.29; S, 6.65.
1
(C–S). H NMR (400 MHz, DMSO-d6): d 9.05 (s, 1H, pyrazole ring),
–
8.38 (s, 1H, CH C), 7.32–7.97 (m, 9H, aromatic-H), 4.22
–
(t, J ¼ 4.43 Hz, 2H, CH2), 3.83 (t, J ¼ 4.50 Hz, 4H, morpholine),
2.65 (t, J ¼ 4.02 Hz, 2H, CH2), 2.34 (t, J ¼ 4.51 Hz, 4H, morpholine),
2.09 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 26.5, 42.0, 52.3,
63.1 (2), 66.5 (2), 113.0, 119.8 (2), 122.0, 124.2 (2), 126.0 (3), 129.4
(2), 130.3, 139.1, 139.8, 143.5, 148.5, 150.4, 164.3, 173.2. MS m/z
520 (Mþ1). Anal. calcd. for C26H25N5O5S: C, 60.10; H, 4.85;
N, 13.48; S, 6.17. Found: C, 60.23; H, 4.92; N, 13.59; S, 6.03.
5-((3-(3-Hydroxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)-3-(3-morpholinopropyl)thiazolidine-2,4-dione
(5g)
General procedure for the synthesis of 3-(3-(1H-indol-1-yl)-
propyl)-5-((3-(aryl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
thiazolidine-2,4-diones (7a–j)
NaH (3.0 mmol) was added in portions to a stirred solution of
compounds 3a–j (1 mmol) in anhydrous THF (20 mL) cooled in an
Yield 62%; m.p. 260–262°C. IR (KBr, vmax cmꢀ1): 3630 (OH, phenolic),
3071, 3021 (C–H, aromatic), 2982, 2859 (C–H, alkyl), 1761, 1720
–
–
–
(C O), 1651 (CH C), 1560 (C N), 1375 (C–N), 1261 (C–O–C), 634
–
–
–
(C–S). 1H NMR (400 MHz, DMSO-d6): d 9.03 (s, 1H, pyrazole ring), 8.36
–
–
(s, 1H, CH C), 7.32–7.90 (m, 9H, aromatic-H), 5.00 (br s, 1H, OH), 4.21
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

8
N. C. Desai et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
–
–
ice bath. The resulting mixture was then allowed slowly to warm
at room temperature. After stirring for 30 min, a solution of 1,3-
dibromopropane (1 mmol), 1H-indole 6 (1 mmol) in anhydrous
THF (10 mL) was added to the stirred reaction mixture, which
was then heated for 5–6 h at reflux temperature. When TLC
monitoring showed complete consumption of the starting
material, excess solvent was evaporated under reduced pressure
to leave a residue that was treated with ice water (100 mL). The
resulting solid was subjected for purification by silica gel column
chromatography (benzene/acetonitrile, 7:3).
(CH C), 1560 (C N), 1370 (C–N), 635 (C–S). 1H NMR (400 MHz,
–
–
–
DMSO-d ): d 9.05 (s, 1H, pyrazole ring), 8.57 (s, 1H, CH C), 7.27–
–
6
7.89 (m, 14H, aromatic-H), 6.35 (d, J ¼ 7.03 Hz, 1H, indole), 4.24 (t,
J ¼ 4.35 Hz, 2H, CH2), 2.71 (t, J ¼ 4.15 Hz, 2H, CH2), 2.48 (s, 3H,
CH3), 2.03 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 21.2, 27.9,
42.5, 53.2, 101.0, 109.5, 113.0, 120.4, 119.9 (2), 120.5, 121.9, 122.4,
126.2, 126.9, 128.4 (2), 128.7, 129.5 (2), 129.9 (2), 130.2, 130.7,
131.7, 136.5, 139.8, 143.0, 150.5, 164.2, 173.3. MS m/z 519 (Mþ1).
Anal. calcd. for C31H26N4O2S: C, 71.79; H, 5.05; N, 10.80; S, 6.18.
Found: C, 71.70; H, 5.20; N, 10.67; S, 6.05.
3-(3-(1H-Indol-1-yl)propyl)-5-((1,3-diphenyl-1H-pyrazol-4-
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(4-methoxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
(7e)
yl)methylene)thiazolidine-2,4-dione (7a)
Yield 61%; m.p. 225–227°C. IR (KBr, vmax cmꢀ1): 3070, 3023 (C–H,
–
–
aromatic), 2990, 2852 (C–H, alkyl), 1770, 1719 (C O), 1657 (CH C),
Yield 63%; m.p. 218–220°C. IR (KBr, vmax cmꢀ1): 3073, 3028 (C–H,
–
–
1
–
1569 (C N), 1378 (C–N), 630 (C–S). H NMR (400 MHz, DMSO-d ): d
9.10 (s, 1H, pyrazole ring), 8.57 (s, 1H, CH C), 7.20–7.90 (m, 15H,
–
6
–
aromatic), 2994, 2865 (C–H, alkyl), 1770, 1716 (C O), 1650
–
–
–
(CH C), 1562 (C N), 1375 (C–N), 631 (C–S). 1H NMR (400 MHz,
–
–
–
–
aromatic-H), 6.35 (d, J ¼ 7.01 Hz, 1H, indole), 4.20 (t, J ¼ 4.35 Hz, 2H,
CH2), 2.72 (t, J ¼ 4.16 Hz, 2H, CH2), 2.05 (m, 2H, CH2). 13C NMR
(100 MHz, DMSO-d6): d 28.0, 42.3, 53.0, 100.4, 109.6, 113.0, 119.1,
120.1 (2), 120.5, 121.7, 122.0, 127.3 (2), 128.7, 128.9 (2), 129.3 (2),
126.2, 126.7, 128.9, 130.0, 133.2, 136.4, 139.5, 143.1, 150.2, 164.3,
173.0. MS m/z 505 (Mþ1). Anal. calcd. for C30H24N4O2S: C, 71.41; H,
4.79; N, 11.10; S, 6.35. Found: C, 71.57; H, 4.66; N, 11.20; S, 6.23.
–
DMSO-d ): d 9.11 (s, 1H, pyrazole ring), 8.60 (s, 1H, CH C), 7.30–
–
6
7.95 (m, 14H, aromatic-H), 6.36 (d, J ¼ 7.03 Hz, 1H, indole), 4.19
(s, 3H, OCH3), 4.23 (t, J ¼ 4.35 Hz, 2H, CH2), 2.70 (t, J ¼ 4.12 Hz, 2H,
CH2), 2.00 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 27.8, 42.0,
53.3, 55.6, 100.2, 109.5, 113.0, 114.6 (2), 119.5, 119.9 (2), 120.8,
121.7, 122.0, 125.3, 126.7, 127.0, 128.1 (3), 129.2 (2), 130.3, 136.1,
139.5, 143.0, 150.1, 160.2, 164.0, 173.0. MS m/z 535 (Mþ1). Anal.
calcd. for C31H26N4O3S: C, 69.64; H, 4.90; N, 10.48; S, 6.00. Found:
C, 69.72; H, 4.75; N, 10.60; S, 6.17.
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(4-chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
(7b)
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(2-hydroxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
Yield 64%; m.p. 182–184°C. IR (KBr, vmax cmꢀ1): 3077, 3020 (C–H,
–
–
aromatic), 2990, 2859 (C–H, alkyl), 1770, 1723 (C O), 1657 (CH C),
1565 (C N), 1378 (C–N), 771 (C–Cl), 631 (C–S). H NMR (400MHz,
DMSO-d ): d 9.02 (s, 1H, pyrazole ring), 8.60 (s, 1H, CH C), 7.20–7.95
(m, 14H, aromatic-H), 6.32 (d, J ¼ 7.01Hz, 1H, indole), 4.23 (t,
J ¼ 4.31Hz, 2H, CH2), 2.74 (t, J ¼ 4.16Hz, 2H, CH2), 2.03 (m, 2H, CH2).
13C NMR (100 MHz, DMSO-d6): d 28.1, 42.1, 53.5, 101.2, 109.6, 113.0,
119.3, 120.0 (2), 120.6, 121.7, 122.0, 126.1, 126.7, 128.1, 128.9 (2),
129.4 (4), 130.0, 131.2, 134.3, 136.0, 139.7, 143.0, 150.4, 164.2,
173.2. MS m/z 539 (Mþ1). Anal. calcd. for C30H23ClN4O2S: C, 66.84;
H, 4.30; N, 10.39; S, 5.95. Found: C, 66.77; H, 4.46; N, 10.23; S, 6.04.
–
–
(7f)
1
–
–
Yield 61%; m.p. 201–203°C. IR (KBr, vmax cmꢀ1): 3630 (OH,
phenolic), 3076, 3025 (C–H, aromatic), 2986, 2857 (C–H, alkyl),
–
–
6
–
–
–
1765, 1716 (C O), 1657 (CH C), 1569 (C N), 1372 (C–N), 628 (C–S).
–
–
–
1H NMR (400 MHz, DMSO-d6): d 9.10 (s, 1H, pyrazole ring), 8.55
–
–
(s, 1H, CH C), 7.35–7.95 (m, 14H, aromatic-H), 6.36 (d, J ¼ 7.01 Hz,
1H, indole), 5.00 (br s, 1H, OH), 4.22 (t, J ¼ 4.32 Hz, 2H, CH2), 2.71
(t, J ¼ 4.14 Hz, 2H, CH2), 2.03 (m, 2H, CH2). 13C NMR (100 MHz,
DMSO-d6): d 28.0, 42.3, 53.1, 101.0, 109.5, 113.2, 117.1, 119.8,
120.0 (2), 120.5, 120.9, 121.5, 121.7, 122.3, 126.2, 126.9, 128.5,
129.6 (2), 130.1, 130.6, 131.7, 136.5, 139.5, 143.0, 150.1, 155.0,
164.3, 173.0. MS m/z 521 (Mþ1). Anal. calcd. for C30H24N4O3S:
C, 69.21; H, 4.65; N, 10.76; S, 6.16. Found: C, 69.09; H, 4.79;
N, 10.59; S, 6.08.
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(2,4-dichlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
(7c)
Yield 68%; m.p. 208–210°C. IR (KBr, vmax cmꢀ1): 3072, 3019 (C–H,
–
–
–
–
aromatic), 2981, 2855 (C–H, alkyl), 1771, 1720 (C O), 1650 (CH C),
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(3-hydroxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
1560 (C N), 1375 (C–N), 766 (C–Cl), 631 (C–S). 1H NMR (400 MHz,
–
–
–
–
DMSO-d ): d 9.08 (s, 1H, pyrazole ring), 8.52 (s, 1H, CH C), 7.27–7.95
6
(7g)
(m, 13H, aromatic-H), 6.33 (d, J¼ 7.03 Hz, 1H, indole), 4.21 (t,
J¼ 4.33 Hz, 2H, CH2), 2.72 (t, J¼ 4.15 Hz, 2H, CH2), 2.05 (m, 2H, CH2).
13C NMR (100 MHz, DMSO-d6): d 28.5, 42.2, 53.1, 101.2, 109.5, 113.0,
119.2, 119.8 (2), 120.5, 121.3, 122.0, 126.1, 126.9, 127.5, 128.2, 128.7,
129.3 (2), 130.0 (2), 131.0, 133.6, 135.5, 136.3, 139.1, 143.0, 150.7,
164.0, 173.2. MS m/z 573 (Mþ1). Anal. calcd. for C30H22Cl2N4O2S: C,
62.83; H, 3.87; N, 9.77; S, 5.59. Found: C, 62.70; H, 3.99; N, 9.92; S, 5.44.
Yield 65%; m.p. 245–247°C. IR (KBr, vmax cmꢀ1): 3637 (OH,
phenolic), 3075, 3025 (C–H, aromatic), 2987, 2860 (C–H, alkyl),
–
–
–
1765, 1716 (C O), 1661 (CH C), 1569 (C N), 1375 (C–N), 628 (C–S).
–
–
–
1H NMR (400 MHz, DMSO-d6): d 9.11 (s, 1H, pyrazole ring), 8.51 (s,
–
–
1H, CH C), 7.35–7.95 (m, 14H, aromatic-H), 6.30 (d, J ¼ 7.00 Hz,
1H, indole), 5.07 (br s, 1H, OH), 4.23 (t, J ¼ 4.32 Hz, 2H, CH2), 2.73 (t,
J ¼ 4.14 Hz, 2H, CH2), 2.02 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-
d6): d 28.5, 42.5, 53.2, 100.5, 109.6, 113.1, 115.9 (2), 119.4, 119.9 (2),
120.1, 120.8, 121.7, 122.3, 126.1, 126.8, 128.5, 129.5 (2), 130.2,
130.7, 134.7, 136.3, 139.5, 143.1, 150.2, 157.1, 164.2, 173.2. MS m/z
521 (Mþ1). Anal. calcd. for C30H24N4O3S: C, 69.21; H, 4.65; N,
10.76; S, 6.16. Found: C, 69.05; H, 4.76; N, 10.85; S, 6.30.
3-(3-(1H-Indol-1-yl)propyl)-5-((1-phenyl-3-p-tolyl-1H-
pyrazol-4-yl)methylene)thiazolidine-2,4-dione (7d)
Yield 68%; m.p. 233–235°C. IR (KBr, vmax cmꢀ1): 3077, 3020 (C–H,
–
–
aromatic), 2985, 2854 (C–H, alkyl), 1771, 1726 (C O), 1655
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
Thiazolidine-2,4-diones Bearing the Pyrazole Moiety
9
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(4-hydroxyphenyl)-1-
phenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione
S. pyogenes, and MRSA at different concentrations of 1000, 500,
and 250 mg/mL. The compounds found to be active in primary
screening were similarly diluted to obtain 200, 125, 100, 62.5,
50, 25, and 12.5 mg/mL concentrations for secondary screening
to test in a second set of dilution against all microorganisms.
Inoculum size for test strain was adjusted to 108 CFU/mL
(colony forming unit per milliliter) by comparing the
turbidity (turbidimetric method). Mueller Hinton broth was
used as nutrient medium to grow and dilute the compound
suspension for test organisms. Two percent DMSO was used
as a diluent/vehicle to obtain the desired concentration of
synthesized compounds and standard drugs to test upon
standard microbial strains. Synthesized compounds were
diluted to 1000 mg/mL concentration, as stock solution. The
control tube containing no antibiotic was immediately sub-
cultured (before inoculation) by spreading a loopful evenly over
a quarter of plate of medium suitable for the growth of test
organisms. The culture tubes were then incubated for 24 h
at 37°C and the growth was monitored visually and spectro-
photometrically. Ten micrograms per milliliter of suspensions
were further inoculated on an appropriate media and the
growth was noted after 24 and 48 h. The lowest concentration
(highest dilution) required to arrest the growth of bacteria was
regarded as MIC, i.e., the amount of growth from the control
tube before incubation (which represents the original inoculum)
was compared. Solvent had no influence on strain growth. The
result of this was greatly affected by the size of inoculums.
The test mixture should contain 108 CFU/mL organisms. DMSO
and sterilized distilled water were used as negative control,
while ciprofloxacin and chloramphenicol (1 U strength) were
used as positive control. Standard drugs used in the present
study was “ciprofloxacin and chloramphenicol” for evaluating
antibacterial activity.
(7h)
Yield 61%; m.p. 222–224°C. IR (KBr, vmax cmꢀ1): 3630 (OH,
phenolic), 3075, 3027 (C–H, aromatic), 2980, 2857 (C–H, alkyl),
–
–
–
1765, 1716 (C O), 1665 (CH C), 1569 (C N), 1373 (C–N), 632 (C–S).
–
–
–
1H NMR (400 MHz, DMSO-d6): d 9.07 (s, 1H, pyrazole ring), 8.51 (s,
–
–
1H, CH C), 7.35–7.95 (m, 14H, aromatic-H), 6.31 (d, J ¼ 7.00 Hz,
1H, indole), 5.11 (br s, 1H, OH), 4.23 (t, J ¼ 4.30 Hz, 2H, CH2), 2.69 (t,
J ¼ 4.13 Hz, 2H, CH2), 2.00 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-
d6): d 28.1, 42.1, 53.0, 101.2, 109.5, 113.0, 116.4 (2), 119.7, 119.9 (2),
120.5, 121.7, 122.2, 125.5, 126.0, 126.7, 128.3, 128.9 (2), 129.6 (2),
130.3, 136.6, 139.5, 143.2, 150.1, 158.3, 164.2, 173.0. MS m/z 521
(Mþ1). Anal. calcd. for C30H24N4O3S: C, 69.21; H, 4.65; N, 10.76; S,
6.16. Found: C, 69.09; H, 4.79; N, 10.61; S, 6.28.
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(3-nitrophenyl)-1-phenyl-
1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione (7i)
Yield 62%; m.p. 258–260°C. IR (KBr, vmax cmꢀ1): 3078, 3030 (C–H,
–
–
aromatic), 2985, 2853 (C–H, alkyl), 1760, 1720 (C O), 1669
1
–
–
(CH C), 1558 (C N), 1473 (NO ), 1369 (C–N), 630 (C–S). H NMR
–
–
2
(400 MHz, DMSO-d6): d 9.05 (s, 1H, pyrazole ring), 8.50 (s, 1H,
–
CH C), 7.35–7.90 (m, 14H, aromatic-H), 6.30 (d, J ¼ 7.02 Hz, 1H,
–
indole), 4.24 (t, J ¼ 4.29 Hz, 2H, CH2), 2.69 (t, J ¼ 4.12 Hz, 2H, CH2),
2.00 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 28.0, 42.3, 53.0,
100.5, 109.6, 113.5, 119.3, 119.9 (2), 120.7, 121.3, 122.0, 122.5,
123.6, 126.1, 126.7, 128.3, 129.3 (2), 130.1, 130.6, 133.4, 133.6,
136.5, 139.9, 143.1, 148.2, 150.3, 164.0, 173.1. MS m/z 550 (Mþ1).
Anal. calcd. for C30H23N5O4S: C, 65.56; H, 4.22; N, 12.74; S, 5.83.
Found: C, 65.42; H, 4.37; N, 12.81; S, 5.68.
3-(3-(1H-Indol-1-yl)propyl)-5-((3-(4-nitrophenyl)-1-phenyl-
1H-pyrazol-4-yl)methylene)thiazolidine-2,4-dione (7j)
Preliminary in vitro cytotoxic activities (MTT assay)
Mouse embryonic fibroblast cell line (NIH 3T3) and human
cervical cancer cell line (HeLa) were used for in vitro cytotoxicity
testing of compounds 7a–j. NIH 3T3 and HeLa cells were
cultured in DMEM supplemented with 10% heat-inactivated FBS
under a humidified 5% CO2 atmosphere. The cells were grown
up to three passages and approximately 1 ꢂ 104 cells were
seeded into each well of a 96-well plate and allowed to incubate
overnight to allow cells to attach to the substrate. After 24 h, the
medium was replaced with DMEM supplemented with 10% FBS
containing various concentrations of test compounds and
incubated for 48 h. Then 10 mL of MTT solution (5 mg/mL in
PBS) was added to each well. After incubation for 4 h, the
medium was removed and the resulting formazan crystals
were dissolved in 100 mL of DMSO. After shaking for 10 min, the
optical density was measured at 570 nm using a microtiter ELISA
reader. The assay was conducted four times. The IC50 values were
defined as the concentrations inhibiting 50% of cell growth and
are reported in Table 3.
Yield 65%; m.p. 285–287°C. IR (KBr, vmax cmꢀ1): 3080, 3033 (C–H,
–
–
aromatic), 2987, 2861 (C–H, alkyl), 1760, 1727 (C O), 1665
1
–
–
(CH C), 1558 (C N), 1481 (NO ), 1369 (C–N), 630 (C–S). H NMR
–
–
2
(400 MHz, DMSO-d6): d 9.11 (s, 1H, pyrazole ring), 8.52 (s, 1H,
–
CH C), 7.35–7.90 (m, 14H, aromatic-H), 6.30 (d, J ¼ 7.02 Hz, 1H,
–
indole), 4.23 (t, J ¼ 4.30 Hz, 2H, CH2), 2.71 (t, J ¼ 4.12 Hz, 2H, CH2),
2.10 (m, 2H, CH2). 13C NMR (100 MHz, DMSO-d6): d 28.4, 42.0, 53.2,
100.7, 109.3, 113.0, 119.5, 119.9 (2), 120.5, 121.7, 122.1, 124.1 (2),
126.0 (3), 126.7, 128.4, 129.1 (2), 130.3, 136.1, 139.0, 139.7, 143.1,
147.5, 150.2, 164.5, 173.2. MS m/z 550 (Mþ1). Anal. calcd. for
C30H23N5O4S: C, 65.56; H, 4.22; N, 12.74; S, 5.83. Found: C, 65.40;
H, 4.13; N, 12.80; S, 5.91.
Biological assays
Antibacterial assay
Antibacterial studies of the newly synthesized compounds 5a–j
and 7a–j were carried out against the representative panel of
gram-positive (S. aureus (MTCC-96), S. pyogenes (MTCC-442)), gram-
negative (E. coli (MTCC-443) and P. aeruginosa (MTCC-1688)), and
methicillin-resistant S. aureus (ATCC 43300) strains. All MTCC
and ATCC 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). Primary screening was done first for antibac-
terial activity in six sets against E. coli, S. aureus, P. aeruginosa,
The authors are thankful to the University Grants Commission, New
Delhi and Department of Science and Technology, New Delhi for
financial support under the NON-SAP and DST-FIST programs,
respectively. We are also thankful to Professor Bharti Dave, Head,
Department of Life Sciences, M. K. Bhavnagar University, Bhavnagar
for critical reading of the manuscript. One of the authors, G. M.
ß 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

10
N. C. Desai et al.
Arch. Pharm. Chem. Life Sci. 2014, 347, 1–10
Kotadiya is thankful to UGC, New Delhi for providing “Research
Fellowships in Science to Meritorious Students”.
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www.archpharm.com