Molecular modeling, synthesis and screening of some new 4-thiazolidinone derivatives with promising selective COX-2 inhibitory activity

Article abstract of DOI:10.1016/j.ejmech.2012.08.046

In order to develop new selective cyclooxygenase-2 inhibitors, a series of novel 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-thiazolidinones were designed. Molecular modeling studies with COX-2 enzyme were performed by using MOE program. The designed compounds with reasonable binding modes and high docking scores were synthesized. Their COX-1/COX-2 inhibitory activities were evaluated in vitro, using NS-398 and indomethacine as reference compounds. Compounds possessing methyl group (3d and 4d) on the phenyl ring exhibited highly COX-2 inhibitory selectivity and potency.

Full text of DOI:10.1016/j.ejmech.2012.08.046

European Journal of Medicinal Chemistry 57 (2012) 59e64
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Molecular modeling, synthesis and screening of some new 4-thiazolidinone
derivatives with promising selective COX-2 inhibitory activity
,
a
b
a
Oya Unsal-Tan a , Keriman Ozadali , Kevser Piskin , Ayla Balkan
*
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Ankara, Turkey
b Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to develop new selective cyclooxygenase-2 inhibitors, a series of novel 2-aryl-3-(4-sulfamoyl/
methylsulfonylphenylamino)-4-thiazolidinones were designed. Molecular modeling studies with COX-2
enzyme were performed by using MOE program. The designed compounds with reasonable binding
modes and high docking scores were synthesized. Their COX-1/COX-2 inhibitory activities were evalu-
ated in vitro, using NS-398 and indomethacine as reference compounds. Compounds possessing methyl
group (3d and 4d) on the phenyl ring exhibited highly COX-2 inhibitory selectivity and potency.
Ó 2012 Elsevier Masson SAS. All rights reserved.
Received 16 March 2012
Received in revised form
29 August 2012
Accepted 31 August 2012
Available online 7 September 2012
Keywords:
Cyclooxygenase enzyme
4-Thiazolidinone
Docking
1. Introduction
When the coxibs were marketed, evidence for a new side effect
appeared and rofecoxib was banned in 2004. Subsequently, some of
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the
most widely used therapeutics for the treatment of pain and
inflammation. The anti-inflammatory effect of NSAIDs arises from
their ability to inhibit cyclooxygenase (COX) enzyme. The discovery
of a second isoform of cyclooxygenase (COX-2), which is expressed
in inflammatory cells and the central nervous system, but not in the
gastric mucosa, offers the possibility of developing new NSAIDs
that lack the gastrointestinal side effects of currently available
NSAIDs [1,2]. These findings have led to drug discovery programs
aimed at identifying new anti-inflammatory agents that selectively
inhibit COX-2 activity. Then, several selective COX-2 inhibitors such
as celecoxib, rofecoxib and valdecoxib (coxibs) were approved and
marketed with reduced gastrointestinal side effects compared to
conventional NSAIDs (Fig. 1).
The general structure of coxibs consists of a central heterocyclic
core such as thiazole, triazole, imidazole, oxazole, pyrrole and
pyrazole, bearing two vicinal aryl or heteroaryl groups, in which
one of the two aryls has a sulfamoyl (SO2NH2) or methylsulfonyl
(SO2CH3) group.
Extensive structureeactivity studies demonstrated that
a SO2NH2 or SO2CH3 substitution on the phenyl ring of the inhibitor
provides COX-2 selectivity but no other substitutions are tolerated.
the other coxibs have been voluntarily withdrawn from the market
[3]. Some studies have suggested that rofecoxib’s adverse cardio-
vascular events may not be a class effect but rather an intrinsic
chemical property related to its metabolism [4]. In addition,
a recent meta-analysis of short-term and long-term clinical studies
that compared COX-2 selective inhibitors to placebo or traditional
NSAIDs concludes that cardiovascular events (mainly myocardial
infarctions) are comparable between COX-2 selective inhibitors and
the traditional NSAIDs ibuprofen and diclofenac [5].
On the other hand, in addition to their anti-inflammatory
activity, selective COX-2 inhibitors are known as attractive mole-
cules for cancer chemotherapy [6] and neurological diseases such
as Parkinson [7] and Alzheimer’s diseases [8]. Today, development
of new COX-2 inhibitors devoid of toxic effects is therefore
essential.
For these reasons, in this project, with the help of molecular
modeling studies, the compounds expected to show selective
inhibitory activity on COX-2 enzyme and having thiazolidinone
structure as a central heterocyclic core were designed. We chose
thiazolidinone moiety as it was an important scaffold for COX-2
inhibition [9e11]. Some remarkable examples such as I [12] and II
[13] are givenFig.1. Lipinski’s “ruleof five” hasbeen alsocalculated as
an attempt to predict the drug-likeness of the designed compounds.
Ten new 2-aryl-3-(4-sulfamoyl/methylsulfonylphenylamino)-4-
thiazolidinones were selected for synthesis and evaluation of COX-
1 and COX-2 inhibitory activities.
* Corresponding author. Tel./fax: þ90 3123051872.
E-mail address: oyaunsal@hacettepe.edu.tr (O. Unsal-Tan).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.08.046

60
O. Unsal-Tan et al. / European Journal of Medicinal Chemistry 57 (2012) 59e64
SO2CH3
SO2NH2
SO2NH2
N
N
N
N
O
F3C
F3C
CH3
Br
O
SC-558
Rofecoxib
Celecoxib
SO2CH3
SO2CH3
SO2R1
NH
S
S
O
N
S
N
N
R2
O
O
F
3a-e, 4a-e
II (IC50 :0.32µM, SI>312)
I (IC50 :0.12µM, SI>833)
Fig. 1. Structures of the coxibs, the compounds having thiazolidinone scaffold with selective COX-2 inhibitor activity and the designed compounds (3aee and 4aee).
2. Results and discussion
improve the interactions between 3a and this hydrophobic cavity of
COX-2. In deciding the derivatives, compounds that does not disrupt
the general orientation (Fig. 3) and close S scores to 3a (Table 1) were
taken into account. Lipinski’s “rule of five” was also applied to these
derivatives. The designed compounds which accomplished this rule
(c Log P ꢀ 5, MW ꢀ 500, number of hydrogen bond donors ꢀ5 and
number of hydrogen acceptors ꢀ10) are seen in Table 1.
2.1. Molecular modeling
The molecular modeling studies were performed with the MOE
software program. First of all, we compared the binding mode of the
template compound 3a, obtained from docking study to that of SC-
558 of which X-ray crystal structure is available in Protein Data
Bank. It was observed that orientations of 3a and SC-558 were nearly
superimposed (Fig. 2). 4-Sulfamoylphenylamino moiety of 3a is
positioned in the COX-2 secondary pocket, surrounded by His90,
Ser353, Tyr355, Arg513 and Val523. It is considered that this
secondary pocket is responsible for the selectivity and occupied by
the p-SO2NH2 or p-SO2CH3 pharmacophore of selective COX-2
inhibitors [14]. NH of 4-sulfamoylphenylamino moiety did not
make any interaction. Apart from central pyrazole ring of SC-558,
2.2. Chemistry
The synthetic route used to synthesize 2-aryl-3-(4-sulfamoyl/
methylsulfonylphenylamino)-4-thiazolidinones (3aee and 4aee)
is outlined in Scheme 1. To synthesize the target compounds, 4-
thiazolidinones, the method described by Neuenfeldt et al. [15]
was preferred in this study, because this new method allows the
synthesis of 4-thiazolidinone derived from phenylhydrazines even
if they have electron withdrawing groups on the phenyl ring. Key
starting materials, hydrazones (1aee and 2aee) were prepared in
good yields (86e99%) by the condensation of sulfamoyl-/methyl-
sulfonylphenylhydrazine with the appropriate benzaldehydes in
ꢀ
thiazole (oxygen) formed a hydrogen bond (w2.2 A) with the NH
of Arg120. Phenyl ring of 3a is oriented in a hydrophobic cavity
formed by Phe381, Leu384, Tyr385, Trp387, Phe513 and Ser530.
According tothis, 3awas derived withthe substitutions whichmight
Fig. 2. The orientation of 3a (shown as yellow) in COX-2 active site (SC-558 is shown
as blue) (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.).
Fig. 3. Superimposition of the best poses of designed compounds (SC-558 is shown as
blue) (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.).

O. Unsal-Tan et al. / European Journal of Medicinal Chemistry 57 (2012) 59e64
61
Table 1
Screening Kit. NS-398 and indomethacine were used as reference
compounds. The results are given in Table 2.
Docking scores (S) and Lipinski parameters of the designed compounds.
In vitro COX-1/COX-2 inhibition studies showed that the
synthesized compounds inhibited COX-2 enzyme with a wide range
of IC50 values (14e121 mM). In contrast with the expectation that
R2
5''
3''
2''
Hx
replacement of SO2NH2 to SO2CH3 would result in a decrease in
activity and an increase in the selectivity [16], we observed an
increase both in the activity and selectivity (except 4b). The intro-
6''
S
'
'
3
2
Hb
Ha
N
NH
SO2R1
duction of a methyl group (3d, IC50 ¼ 24.5
compound, 3a (IC50 ¼ 78.2 M), improved the COX-2 inhibitory
activity. The same correlation was also observed between 4a
M). It can be assumed that
mM) into the template
O
m
'
'
5
6
(IC50 ¼ 20
m
M) and 4d (IC50 ¼ 14.4
m
a bulky group such as methyl is essential for improving the hydro-
phobic interactions between the compound and COX-2 enzyme. The
Compound
R1
R2
S
c Log Pa
MW
H-bond donor/
acceptor
presence of trifluoromethyl group (3e, IC50
¼
51.8 and 4e,
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
NH2
NH2
NH2
NH2
NH2
CH3
CH3
CH3
CH3
CH3
H
Cl
F
CH3
CF3
H
Cl
F
CH3
CF3
ꢁ7.77
ꢁ8.02
ꢁ7.77
ꢁ8.18
ꢁ7.86
ꢁ7.65
ꢁ7.86
ꢁ7.72
ꢁ7.83
ꢁ7.51
2.03
2.68
2.17
2.34
3.36
2.79
3.44
2.93
3.10
4.12
349
383
367
363
417
348
382
366
362
416
2/3
2/3
2/3
2/3
2/3
1/3
1/3
1/3
1/3
1/3
IC50 ¼ 37.8
m
M) which is bulkier than methyl group (3d and 4d)
caused a decrease in the activity. We concluded that the compounds
bearing halogen atoms on the phenyl ring (3b, 3c, 4b and 4c) were
non-selective in respect to their SI values (SI ¼ 0.67e1.38).
2-(4-Methylphenyl)-3-(4-methylsulfonylphenylamino)-4-
thiazolidinone, 4d, was the most potent (IC50 ¼ 14.4
mM) and
selective (SI ¼ 7.3) COX-2 inhibitor in this series. Also, its SO2CH3
derived counterpart, 3d showed remarkable COX-2 inhibitory
a
Calculated using Ligand Properties tool in MOE (The Molecular Operating Envi-
activity (IC50 ¼ 24.5 M) with reasonable selectivity (SI ¼ 3.5).
m
ronment, Version 2011.10).
3. Conclusion
the presence of acetic acid. 2-Aryl-3-(4-sulfamoyl-/methyl-
sulfonylphenylamino)-4-thiazolidinone derivatives (3aee and 4ae
e) were synthesized by treatment of 1 or 2 with a large excess of
mercaptoacetic acid in the absence of any solvent.
In the present study, novel 2-aryl-3-(4-sulfamoyl/methyl-
sulfonylphenylamino)-4-thiazolidinones were designed according
to their binding modes inside the COX-2 active site. Among them,
the compounds were chosen that obeyed the Lipinski’s “rule of
five” which is widely used as a filter for drug-like properties. The
designed compounds were synthesized and the structures of them
were elucidated by IR, 1He13C NMR, mass spectral and elemental
analysis data. The COX-1 and COX-2 inhibitory activities of these
compounds were evaluated.
When the results of the docking studies and inhibitory activities
are considered together, 2-aryl-3-(4-methylsulfonylphenylamino)-
4-thiazolidinones are appropriate scaffolds for the development of
new COX-2 inhibitors. Also, the inclusion of a methyl substituent on
the phenyl ring was favorable for activity and selectivity.
The structures of the target compounds 3aee and 4aee were
elucidated by using spectral methods (IR, 1He13C NMR, ESI-MS) and
elemental analysis. In the IR spectra of 3aee and 4aee, the bands
were seen at around 3280 and 1680 cmꢁ1 due to NH and CO
stretching, respectively. In addition to these bands, asymmetric and
symmetric SO2 stretching bands at around 1320 and 1150 cmꢁ1 were
observed respectively. In the 1H NMR spectra, the appearance of the
signals belong to Ha, Hb and Hx (around 3.80, 3.90 and 5.90 ppm,
respectively) protons of 4-thiazolidinone confirmed the structure of
the compounds. The signals of the amine protons were also seen at
around 8.70 or 6.10 ppm according to the solvent used. The forma-
tion of the thiazolidinone ring was also proved by the appearance of
the peaks at around 29, 61 and 169 (C5, C2 and CO respectively) ppm
in the 13C NMR. In the ESI mass spectra of 3aee and 4aee, in addition
to [M]þ, R2C6H4CS fragments formed by the cleavage of S1eC5 and
C2eN3 bonds of 4-thiazolidinone were observed.
4. Experimental
4.1. Chemistry
2.3. Cyclooxygenase inhibitory activity
Melting points were determined with a Thomas-Hoover Capil-
lary Melting Point Apparatus (Philadelphia, PA, USA) and are
uncorrected. ATR-FTIR spectra were obtained using the MIRacle
ATR accessory (Pike technologies) in conjunction with a Spectrum
The inhibitory effect of the target compounds 3aee and 4aee on
COX-1 and COX-2 enzymes were evaluated using COX Inhibitor
O
HC
i
+
R1SO2
NHNH2
R2
R2
S
ii
R1SO2
NHN CH
R2
N
NH
SO2R1
O
1a-e, 2a-e
3a-e, 4a-e
Scheme 1. Synthesis of the compounds, i: acetic acid, reflux, ii: mercaptoacetic acid, 60 ꢂC.

62
O. Unsal-Tan et al. / European Journal of Medicinal Chemistry 57 (2012) 59e64
(1H; d; thiazol., H5a, J ¼ 16), 3.78 (1H; d; thiazol., H5b, J ¼ 16). 13
C
Table 2
In vitro COX-1 and COX-2 enzyme inhibition data for the synthesized compounds.
NMR (DMSO-d6, 100 MHz); 169.7 (CO), 149.9, 139.4, 135.1, 134.0,
130.1, 129.4, 127.9, 112.0, 61.3 (C2), 29.5 (C5). IR; 3286 (NH), 1675
(C]O), 1319, 1147 (SO2). ESI-MS (m/z); 383 [M]þ, 228
[M ꢁ C7H4SCl]þ. Anal. Calcd. for C15H14ClN3O3S2: C, 46.93; H, 3.68;
N, 10.95; S, 16.70. Found: C, 46.58; H, 3.83; N, 10.61; S, 17.04.
Compound
R1
R2
COX-1
IC50
COX-2
IC50 (m
M)a
SIb
(
m
M)a
3a
3b
3c
3d
3e
4a
4b
4c
NH2
NH2
NH2
NH2
NH2
CH3
CH3
CH3
CH3
CH3
H
Cl
F
CH3
CF3
H
Cl
F
96.4
38.9
42.1
85.5
54.5
63.2
83.0
62.7
104.7
61.1
205.4
78.2
45.5
63.0
24.5
51.8
20.0
121.7
45.4
14.4
37.8
1.0
1.23
0.85
0.67
3.49
1.05
3.16
0.68
1.38
7.27
1.61
4.1.2.3. 2-(4-Fluorophenyl)-3-(4-aminosulfonylphenylamino)-4-
thiazolidinone 3c. 37% Yield, mp 129 ꢂC. 1H NMR (DMSO-d6,
0
400 MHz); 8.67 (1H; br; NH), 7.55 (4H; m; eC4H4SO2NH2, H3 and
0
00
00
00
00
H5 , eC4H4F, H2 and H6 ), 7.20e7.16 (2H; t; eC4H4F, H3 and H5
,
4d
4e
CH3
CF3
0
0
J ¼ 8.8), 7.05 (2H; br; NH2), 6.69 (2H; d; eC4H4SO2NH2, H2 and H6 ,
J ¼ 8), 5.88 (1H; br; thiazol., H2), 3.93 (1H; d; thiazol., H5a, J ¼ 15.6),
3.78 (1H; d; thiazol., H5b, J ¼ 15.6). IR; 3279 (NH), 1668 (C]O),1326,
1153 (SO2). ESI-MS (m/z); 367 [M]þ, 228 [M ꢁ C7H4SF]þ. Anal. Calcd.
for C15H14FN3O3S2: C, 49.04; H, 3.84; N, 11.44; S, 17.45. Found: C,
48.92; H, 3.62; N, 11.58; S, 17.55.
NS-398
Indomethacine
205.4
0.04
0.68
18.3
a
The in vitro test compound concentration required to produce 50% inhibition of
M) is the mean of two determinations acquired
enzymatic activity. The result (IC50, m
using the COX Inhibitor Screening Assay Kit (Catalog No. 560131, Cayman Chemicals
Inc., Ann Arbor, MI, USA).
b
In vitro COX-2 selectivity index (COX-1 IC50/COX-2 IC50).
4.1.2.4. 2-(4-Methylphenyl)-3-(4-aminosulfonylphenylamino)-4-
thiazolidinone 3d. 45% Yield, mp 167 ꢂC. 1H NMR (DMSO-d6,
0
400 MHz); 8.66 (1H; br; NH), 7.57 (2H; d; eC4H4SO2NH2, H3 and
BX FTIR spectrometer (Perkin Elmer) and were reported in cmꢁ1
.
H5 , J ¼ 8.4), 7.31 (2H; br; eC4H4CH3, H2 and H6 ), 7.18 (2H; d; e
0
00
00
The 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra (DMSO-d6
or CDCl3) were recorded on a Varian Mercury 400 FT NMR spec-
trophotometer using TMS as an internal reference (chemical shift
C4H4CH3, H3 and H5 , J ¼ 8), 7.08 (2H; br; NH2), 6.72 (2H; d; e
00
00
0
0
C4H4SO2NH2, H2 and H6 , J ¼ 8.4), 5.84 (1H; br; thiazol., H2), 3.92
(1H; d; thiazol., H5a, J ¼ 16), 3.79 (1H; d; thiazol., H5b, J ¼ 16), 2.29
(3H; s; eCH3). 13C NMR (DMSO-d6, 100 MHz); 169.8 (CO), 150.1,
138.7, 136.8, 134.3, 129.8, 129.3, 127.5, 111.8, 61.3 (C2), 29.3 (C5), 21.6
(CH3). IR; 3279 (NH), 1677 (C]O), 1318, 1147 (SO2). ESI-MS (m/z);
363 [M]þ, 228 [M ꢁ C8H7S]þ. Anal. Calcd. for C16H17N3O3S2: C,
52.88; H, 4.71; N, 11.56; S, 17.64. Found: C, 52.72; H, 4.96; N, 11.98, S,
17.91.
represented in
d ppm).
The ESI-MS spectra were measured on a micromass ZQ-4000
single quadruple mass spectrometer. Elemental analyses (C, H, N)
were performed on Leco CHNS 932 analyzer.
4.1.1. General procedure for preparation of phenylhydrazones 1aee
and 2aee
Equimolar amount of appropriate phenylhydrazine and benz-
aldehyde were dissolved in methanol. Acetic acid (1 drop) was
added to reaction medium as a catalytic reagent. The mixture was
then heated with a DeaneStark separator for 4 h. The solvent was
evaporated and hydrazones were obtained.
4.1.2.5. 2-(4-Trifluoromethylphenyl)-3-(4-aminosulfonylphenylamino)-
4-thiazolidinone 3e. 49% Yield, mp 193 ꢂC. 1H NMR (DMSO-d6,
0
400 MHz); 8.79 (1H; br; NH), 7.76 (2H; d; eC4H4SO2NH2, H3 and
0
H5 , J ¼ 8), 7.67e7.59 (4H; m; C6H4CF3), 7.10 (2H; br; NH2), 6.75 (2H; d;
0
0
eC4H4SO2NH2, H2 and H6 , J ¼ 8.8), 6.03 (1H; br; thiazol., H2), 3.99
(1H; d; thiazol., H5a, J ¼ 16), 3.83 (1H; d; thiazol., H5b, J ¼ 16). IR; 3271
(NH), 1676 (C]O), 1320, 1151 (SO2). ESI-MS (m/z); 417 [M]þ, 228
[M ꢁ C8H4SF3]þ. Anal. Calcd. for C16H14F3N3O3S2: C, 46.04; H, 3.38; N,
10.07; S, 15.36. Found: C, 45.82; H, 3.77; N, 10.48; S, 15.69.
4.1.2. General procedure for preparation of 4-thiazolidinones 3aee
and 4aee
A mixture of phenylhydrazones 2aee or 3aee (1 mmol) and
excess of mercaptoacetic acid (1 ml) was heated at 60e80 ꢂC until
the reaction was completed. Ethyl acetate (5 ml) was added, the
organic layer was washed with saturated NaHCO3 (3 ꢃ 20 ml),
water (1 ꢃ 10 ml), dried with Na2SO4 and concentrated to give an
oily residue. The oily residue was purified by column chromatog-
raphy on silica gel using hexaneeethyl acetate as eluent (3:7).
4.1.2.6. 2-Phenyl-3-(4-methylsulfonylphenylamino)-4-thiazolidinone
4a. 57% Yield, mp 181 ꢂC. 1H NMR (CDCl3, 400 MHz); 7.77 (2H;
0
0
d; eC4H4SO2CH3, H3 and H5 , J ¼ 8), 7.41e7.25 (5H; m; C6H5), 6.78
0
0
(2H; d; eC4H4SO2CH3, H2 and H6 , J ¼ 8), 6.06 (1H; br; NH), 5.72
(1H; d; thiazol., H2, J ¼ 2), 3.88 (1H; dd; thiazol., H5a, J ¼ 2, J ¼ 16),
3.78 (1H; d; thiazol., H5b, J ¼ 16), 2.99 (3H; s; eSO2CH3). 13C NMR
(DMSO-d6, 100 MHz); 169.8 (CO), 151.5, 140.0, 131.0, 129.5, 129.3,
128.0, 112.3, 61.9 (C2), 44.8 (SO2CH3), 29.6 (C5). IR; 3280 (NH),
1691 (C]O), 1319, 1134 (SO2). ESI-MS (m/z); 348 [M]þ, 227
[M ꢁ C7H5S]þ. Anal. Calcd. for C16H16N2O3S2: C, 55.15; H, 4.63; N,
8.04; S, 18.40. Found: C, 54.82; H, 4.83; N, 8.48, S, 18.85.
4.1.2.1. 2-Phenyl-3-(4-aminosulfonylphenylamino)-4-thiazolidinone
3a. 45% Yield, mp 176 ꢂC. 1H NMR (DMSO-d6, 400 MHz); 8.70 (1H;
0
0
br; NH), 7.57 (2H; d; eC4H4SO2NH2, H3 and H5 , J ¼ 8), 7.41e7.33
0
(5H; m; C6H5), 7.07 (2H; br; NH2), 6.72 (2H; d; eC4H4SO2NH2, H2
0
and H6 , J ¼ 8.4), 5.88 (1H; br; thiazol., H2), 3.93 (1H; d; thiazol., H5a
,
J ¼ 15.6), 3.79 (1H; d; thiazol., H5b, J ¼ 15.6). 13C NMR (DMSO-d6,
100 MHz); 169.5 (CO), 149.7, 139.9, 134.2, 129.3, 128.9, 128.1, 127.4,
111.9, 61.4 (C2), 29.4 (C5). IR; 3270 (NH), 1680 (C]O), 1319, 1146
(SO2). ESI-MS (m/z); 349 [M]þ, 228 [M ꢁ C7H5S]þ. Anal. Calcd. for
4.1.2.7. 2-(4-Chlorophenyl)-3-(4-methylsulfonylphenylamino)-4-
thiazolidinone 4b. 39% Yield, mp 163 ꢂC. 1H NMR (CDCl3,
0
0
400 MHz); 7.78 (2H; d; eC4H4SO2CH3, H3 and H5 , J ¼ 8.4), 7.38
00
00
00
C
15H15N3O3S2: C, 51.56; H, 4.33; N, 12.03; S, 18.35. Found: C, 51.32;
(2H; d; eC4H4Cl, H3 and H5 , J ¼ 8.8), 7.29 (2H; d; eC4H4Cl, H2 and
00
0
0
H, 4.80; N, 12.35; S, 18.78.
H6 , J ¼ 8.8), 6.78 (2H; d; eC4H4SO2CH3, H2 and H6 , J ¼ 8.4), 6.10
(1H; br; NH), 5.71 (1H; d; thiazol., H2, J ¼ 1.6), 3.88 (1H; dd;
thiazol., H5a, J ¼ 1.6, J ¼ 16.2), 3.79 (1H; d; thiazol., H5b, J ¼ 16), 3.00
(3H; s; eSO2CH3). 13C NMR (DMSO-d6, 100 MHz); 169.8 (CO), 151.4,
139.6, 135.6, 131.1, 130.1, 129.2, 128.3, 112.4, 61.7 (C2), 44.7
(SO2CH3), 29.4 (C5). IR; 3282 (NH), 1689 (C]O), 1319, 1136 (SO2).
ESI-MS (m/z); 382 [M]þ, 227 [M ꢁ C7H4SCl]þ. Anal. Calcd. for
4.1.2.2. 2-(4-Chlorophenyl)-3-(4-aminosulfonylphenylamino)-4-
thiazolidinone 3b. 59% Yield, mp 180 ꢂC. 1H NMR (DMSO-d6,
0
400 MHz); 8.63 (1H; br; NH), 7.56 (2H; d; eC4H4SO2NH2, H3 and
0
H5 , J ¼ 8), 7.46e7.40 (4H; m; C6H4), 7.01 (2H; br; NH2), 6.70 (2H; d;
0
0
eC4H4SO2NH2, H2 and H6 , J ¼ 8.8), 5.88 (1H; br; thiazol., H2), 3.93

O. Unsal-Tan et al. / European Journal of Medicinal Chemistry 57 (2012) 59e64
63
C16H15ClN2O3S2: C, 50.19; H, 3.95; N, 7.32; S, 16.75. Found: C, 49.86;
H, 4.33; N, 7.60; S, 17.02.
quantify the PGF2a levels produced in the presence of test samples.
The IC50 values (the concentration of the test compound causing
50% inhibition) were calculated from the concentrationeinhibition
response curves (duplicate determinations).
4.1.2.8. 2-(4-Fluorophenyl)-3-(4-methylsulfonylphenylamino)-4-
thiazolidinone 4c. 43% Yield, mp 143 ꢂC. 1H NMR (DMSO-d6,
0
400 MHz); 8.90 (1H; br; NH), 7.66 (2H; br; eC4H4SO2CH3, H3 and
4.3. Molecular modeling
0
00
00
00
H5 ), 7.50 (2H; br; eC4H4F, H2 and H6 ), 7.29 (2H; t; eC4H4F, H3 and
00
0
0
H5 , J ¼ 8.8), 6.78 (2H; d; eC4H4SO2CH3, H2 and H6 , J ¼ 8.4), 5.92
(1H; br; thiazol., H2), 3.98 (1H; d; thiazol., H5a, J ¼ 16), 3.82 (1H;
d; thiazol., H5b, J ¼ 16), 3.09 (3H; s; eSO2CH3). IR; 3270 (NH), 1682
(C]O), 1321, 1141 (SO2). ESI-MS (m/z); 366 [M]þ, 227
[M ꢁ C7H4SF]þ. Anal. Calcd. for C16H15FN2O3S2: C, 52.45; H, 4.13; N,
7.65; S, 17.50. Found: C, 52.34; H, 3.98; N, 8.04; S, 17.69.
Molecular modeling studies were performed with MOE (The
Molecular Operating Environment) Version 2011.10, software
available from Chemical Computing Group Inc., 1010 Sherbrooke
Street West, Suite 910, Montreal, Canada H3A2R7, http://www.
chemcomp.com. The ligands were built using the builder tool of
the MOE program and subjected to energy minimization
(MMFF94x, gradient: 0.05). The X-ray crystallographic structure of
COX-2 complexed with 1-phenylsulfonamide-3-trifluoromethyl-5-
(4-bromophenyl)pyrazole SC-558 (PDB: 1CX2) was obtained from
the Protein Data Bank [14]. The errors of the protein were corrected
by the Structure Preparation process in MOE. After correction,
hydrogens were added and partial charges (Gasteiger method-
ology) were calculated. Energy minimization (MMFF94x, gradient:
0.05) was performed. The default Triangle Matcher placement
method was used for docking. GBVI/WSA dG scoring function which
estimates the free energy of binding of the ligand from a given pose
was used to rank the final poses. The each ligandeenzyme complex
with lowest S score was selected.
4.1.2.9. 2-(4-Methylphenyl)-3-(4-methylsulfonylphenylamino)-4-
thiazolidinone 4d. 34% Yield, mp 159 ꢂC. 1H NMR (DMSO-d6,
0
0
400 MHz); 8.84 (1H; br; NH), 7.64 (2H; d; eC4H4SO2CH3, H3 and H5 ,
00
00
J ¼ 8.4), 7.29 (2H; br; eC4H4CH3, H2 and H6 ), 7.15 (2H; d; eC4H4CH3,
00
00
0
0
H3 and H5 , J ¼ 7.6), 6.76 (2H; d; eC4H4SO2CH3, H2 and H6 , J ¼ 8.4),
5.82 (1H; br; thiazol., H2), 3.91 (1H; d; thiazol., H5a, J ¼ 16), 3.77 (1H;
d; thiazol., H5b, J ¼ 16), 3.06 (3H; s; eSO2CH3), 2.27 (3H; s; eCH3).13
C
NMR(DMSO-d6,100MHz);169.7 (CO),151.6,138.9,137.0,131.0,129.9,
129.3, 128.1, 112.2, 61.9 (C2), 44.8 (SO2CH3), 29.5 (C5), 21.4 (CH3). IR;
3281 (NH),1703(C]O),1319,1138 (SO2). ESI-MS(m/z);362[M]þ, 227
[M ꢁ C8H7S]þ. Anal. Calcd. for C17H18N2O3S2: C, 56.33; H, 5.01; N,
7.73; S, 17.69. Found: C, 56.16; H, 4.83; N, 8.23; S, 17.96.
Acknowledgment
4.1.2.10. 2-(4-Trifluoromethylphenyl)-3-(4-methylsulfonylphenylam-
ino)-4-thiazolidinone 4e. 37% Yield, mp 108e10 ꢂC. 1H NMR (CDCl3,
The authors gratefully acknowledge the financial support of the
Turkish Scientific Research Institution (TUBITAK, 111S060).
0
0
400 MHz); 7.80 (2H; d; eC4H4SO2CH3, H3 and H5 , J ¼ 8.4), 7.68 (2H;
00
00
00
d; eC4H4CF3, H3 and H5 , J ¼ 8.4), 7.46 (2H; d; eC4H4CF3, H2
00
0
0
and H6 , J ¼ 8), 6.80 (2H; d; eC4H4SO2CH3, H2 and H6 , J ¼ 8.4), 6.15
(1H; br; NH), 5.77 (1H; d; thiazol., H2, J ¼ 1.6), 3.92 (1H; dd;
thiazol., H5a, J ¼ 1.6, J ¼ 16.2), 3.80 (1H; d; thiazol., H5b, J ¼ 16), 2.99
(3H; s; eSO2CH3). IR; 3280 (NH), 1968 (C]O), 1322, 1140 (SO2). ESI-
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:http://dx.doi.org/10.1016/j.ejmech.2012.
08.046.
MS (m/z); 416 [M]þ, 227 [M
ꢁ
C8H4SF3]þ. Anal. Calcd. for
C
17H15F3N2O3S2: C, 49.03; H, 3.63; N, 6.73; S, 15.40. Found: C, 48.92;
H, 3.86; N, 7.06; S, 15.76.
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