Design and synthesis of new 2-aryl, 3-benzyl- (1,3-oxazolidine or 1,3-thiazolidine)-4-ones as selective cyclooxygenase (COX-2) inhibitors

Article abstract of DOI:10.1007/s00044-009-9230-8

A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4- ones, possessing a methylsulfonyl pharmacophore, were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were performed to acquire structureactivity relationship data with respect to the point that molecular modeling studies showed that designed compounds bind in the primary binding site such that the C-2 para-SO₂Me substituent inserts into the 2° pocket present in COX-2 enzyme. COX- 1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC ₅₀ values in the highly potent 0.21 to 0.34 μM range, and COX-2 selectivity indexes in the 222.3 to>476 range. 3-Benzyl-2-(4- methylsulfonylphenyl)- 1,3-oxazolidine-4(5H)-one was identified as the most potent (IC₅₀ = 0.21 μM) and selective (S.I.>476) COX-2 inhibitor among the synthesized compounds. It also was a more selective COX-2 inhibitor than the parent reference compound celecoxib (S.I.>403). Birkhaeuser Boston 2009.

Full text of DOI:10.1007/s00044-009-9230-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2010) 19:782–793
DOI 10.1007/s00044-009-9230-8
ORIGINAL RESEARCH
Design and synthesis of new 2-aryl, 3-benzyl-
(1,3-oxazolidine or 1,3-thiazolidine)-4-ones
as selective cyclooxygenase (COX-2) inhibitors
A. Zarghi Æ H. Arefi Æ O. G. Dadrass Æ S. Torabi
Received: 3 March 2009 / Accepted: 2 July 2009 / Published online: 25 July 2009
¨
Ó Birkhauser Boston 2009
Abstract A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-
ones, possessing a methylsulfonyl pharmacophore, were synthesized to evaluate
their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro
COX-1 and COX-2 isozyme inhibition studies were performed to acquire structure-
activity relationship data with respect to the point that molecular modeling studies
showed that designed compounds bind in the primary binding site such that the C-2
para-SO2Me substituent inserts into the 2° pocket present in COX-2 enzyme. COX-
1 and COX-2 inhibition studies showed that all compounds were selective inhibitors
of the COX-2 isozyme with IC50 values in the highly potent 0.21 to 0.34 lM range,
and COX-2 selectivity indexes in the 222.3 to [476 range. 3-Benzyl-2-(4-meth-
ylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one was identified as the most potent
(IC50 = 0.21 lM) and selective (S.I. [ 476) COX-2 inhibitor among the synthe-
sized compounds. It also was a more selective COX-2 inhibitor than the parent
reference compound celecoxib (S.I. [ 403).
Keywords 1,3-oxazolidines ꢀ 1,3-thiazolidines ꢀ COX-2 inhibitors
A. Zarghi ꢀ H. Arefi
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C.),
Tehran, Iran
O. G. Dadrass ꢀ S. Torabi
School of Pharmacy, Azad University, Pharmaceutical Sciences Unit, Tehran, Iran
A. Zarghi (&)
Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University (M.C.),
P.O. Box: 14155-6153, Tehran, Iran
e-mail: azarghi@yahoo.com

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783
Introduction
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of
inflammation and pain often is accompanied by adverse gastrointestinal and renal
side effects. Their anti-inflammatory activity results from inhibition of cycloox-
ygenases (COXs), which catalyzes the bioconversion of arachidonic acid to
prostaglandins. However, inhibition of COXs may lead to undesirable side effects.
It has been well established that there are at least two COX isozymes: COX-1 and
COX-2 (Fu et al., 1990). The constitutive COX-1 isozyme is produced in a variety
of tissues and seems to be important to the maintenance of physiological
functions, such as gastro protection and vascular homeostasis (Smith and DeWitt,
1996). Alternatively, the COX-2 isozyme is induced by mitogenic and
proinflammatory stimuli linking its involvement to inflammatory processes
(Herschman, 1996). Thus, selective inhibition of COX-2 compared with COX-1
is useful for the treatment of inflammation and inflammation-associated disorders
with reduced gastrointestinal toxicities compared with NSAIDs. In addition to the
role of COX-2 for the treatment of rheumatoid arthritis and osteoarthritis, it is
implicated in colon cancer and angiogenesis (Kawamori et al., 1998; Katori and
Majima, 2000). Recent studies have shown that the progression of Alzheimer’s
disease is reduced among some users of NSAIDs. Chronic treatment with selective
COX-2 inhibitors may slow the progress of Alzheimer’s disease without causing
gastrointestinal damage (Vane and Botting, 1998). Diarylheterocycles, and other
central ring pharmacophore templates, have been extensively studied as selective
COX-2 inhibitors (Penning et al., 1997; Prasit et al., 1999; Riendeau et al., 2002;
Zarghi et al., 2007a, 2007b, 2007c; Abouzid and Bekhit, 2008; Rammana Reddy
et al., 2008; Scholz et al., 2008). All of these tricyclic molecules possess 1,2-
diaryl substitution on a centeral hetero or carbocyclic ring system (see structures
A–F in Chart 1). The recent withdrawal of some diarylheterocyclic selective
COX-2 inhibitors, such as rofecoxib and valdecoxib, due to their adverse
´
cardiovascular side effects (Dogne et al., 2005; Solomon, 2005) clearly delineates
the need to explore and evaluate new structural ring templates possessing COX
inhibitory activity. Recently, we reported a group of 2,3-diaryl-1,3-thiazolidine-4-
ones possessing a COX-2 SO2Me pharmacophore at the para-position of C-2
phenyl ring in conjunction with different substituents at the para-position of the
N-3 phenyl ring (Zarghi et al., 2007c). For example, 3-(4-fluorophenyl)-2-(4-
methylsulfonylphenyl)-1,3-thiazolidine-4(5H)-one (see structure F) exhibited
highly selectivity for COX-2 inhibition. As part of our ongoing program to
design new types of tricyclic selective COX-2 inhibitors, we report the design,
synthesis, cyclooxygenase inhibitory, and some molecular modeling studies of a
group of 2-aryl, 3-benzyl-1,3-oxazolidine-4-one or 2-aryl, 3-benzyl-1,3-thiazoli-
dine-4-one derivatives possessing a COX-2 SO2Me pharmacophore at the para-
position of C-2 phenyl ring.

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SO2NH2
SO2Me
N
F3C
N
Me
F
Celecoxib (A)
SC57666 (B)
SO2Me
SO2NH2
Me
Cl
O
N
N
N
Me
Valdecoxib (C)
Etoricoxib (D)
NHSO2Me
SO2Me
S
O
N
O
O
F
F
F
E
Chart 1 Representative examples of selective COX-2 inhibitors
Results and discussions
Chemistry
The target 2-aryl, 3-benzyl-1,3-oxazolidine-4-one or 2-aryl, 3-benzyl-1,3-thiazol-
idine-4-one derivatives were synthesized by previously reported method (Zarghi
et al., 2007c) (Scheme 1). Accordingly, benzylamine (1) was treated with an
equimolar amount of 4-methylthiobenzaldehyde (2) and an appropriate acid (3) in
dry toluene under reflux to give 3-benzyl-2-(4-methylthiophenyl)-1,3-oxazolidine-
4(5H)-one or 3-benzyl-2-(4-methylthiophenyl)-1,3-thiazolidine-4(5H)-one (4, 20–
45%). Oxidation of 4 using 30% H2O2 in water-methanol in the presence of a trace
amount of WO3 afforded the 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine-
4(5H)-one (5a,80%) or 3-benzyl-2-(4-methyl sulfonylphenyl)-1,3-thiazolidine-
4(5H)-one (5b, 65%). Similarly, the analogues having the methyl group at the
C-5 atom (8 & 9, 5–20%) were synthesized using 2-hydroxy or 2-mercaptopropionic

Med Chem Res (2010) 19:782–793
785
SMe
CHO
NH2
HO
X
a
+
+
N
X
O
SMe
2
O
1
3
4
SO Me
2
b
N
X
O
SMe
5a, X= O
5b, X= S
CHO
Me
X
HO
+
NH2
N
a
+
X
O
O
SMe
Me
2
6
1
,
7a
X=O
7b, X=S
SO2 Me
SO2 Me
b
N
+
N
X
X
O
O
Me
Me
8a, X= O
9a, X= S
8b , X= O
9b , X= S
Scheme 1 Reagents and conditions: (a) Toluene, reflux, 24–48 hr; (b) 30% H2O2-WO3, water-methanol,
12 hr
acid (6). Because of the asymmetry of the acid, the reaction furnished a ca. 1:1
mixture of racemic diastereoisomers 8a and 8b or 9a and 9b characterized by a
different disposition of the substituents at C-2 and C-5. Because of similar retention
times between cis and trans isomers in different solvents, the separation was not
possible to be done by chromatography. Therefore, the racemic mixture was tested
as COX-2 inhibitors.
Enzyme inhibitory activity
It has been well established for the diarylheterocyclic class of COX-2 inhibitors that
a para-methylsulfonal substituent on one of the phenyl rings is a requirement for

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good COX-2 potency and selectivity. Accordingly, a group of 3-benzyl-2-(4-
methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one (5a, 8) and 3-benzyl-2-(4-meth-
ylsulfonylphenyl)-1,3-thiazolidine-4(5H)-one (5b, 9) were prepared to investigate
their COX-2 selectivity and potency. The ability of the synthesized compounds to
inhibit the COX-1 and COX-2 isozymes was determined by using chemiluminescent
enzyme assays (Table 1). In vitro COX-1/COX-2 inhibition studies showed that all
compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the
highly potent 0.21 to 0.34 lM range, and COX-2 selectivity indexes (SI) in the
222.3 to [476 range. In addition, compounds 5a and 5b did not inhibit COX-1 at a
concentration of 100 lM (IC50 values [100 lM). However, the racemic com-
pounds 8 and 9 showed less selectivity for COX-2 isozyme compared with
compounds 5a and 5b, which do not have a methyl group at C-5 position of the
central ring. According to these results, 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-
oxazolidine-4(5H)-one 5a was the most potent (IC50 = 0.21 lM), and selective
(SI [ 476), COX-2 inhibitor among the synthesized compounds. It also was more
selective COX-2 inhibitor than the parent reference compound celecoxib
(SI [ 403). These data suggest that the compound 5a should inhibit the synthesis
of inflammatory prostaglandins via the cyclooxygenase pathway at sites of
inflammation and be devoid of ulcerogenicity due to the absence of COX-1
inhibition.
Table 1 In vitro COX-1 and COX-2 enzyme inhibition data
X
R
N
O
Compound
R
X
IC50 (lM) (mean SD)a
COX-2 SIb
COX-1
COX-2
5a
H
O
S
[100
0.21 0.01
0.32 0.02
0.27 0.02
0.34 0.03
[476
[312.5
318.1
222.3
[403
5b
H
[100
8
Me
Me
O
S
85.9 5.8
75.6 4.5
24.3 1.6
9
Celecoxib
0.06
0
a
Values are mean values of two determinations acquired using an ovine COX-1/COX-2 assay kit, where
the deviation from the mean is \10% of the mean value
b
In vitro COX-2 selectivity index (COX-1 IC50/ COX-2 IC50
)

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787
Docking study
The orientation of the highly potent and selective COX-2 inhibitors, 3-benzyl-2-(4-
methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one 5a and 3-benzyl-2-(4-methylsul-
fonyl phenyl)-1,3-thiazolidine-4(5H)-one 5b, and in the COX-2 active site was
examined by a docking experiment (Figs. 1, 2). This molecular modeling shows
that compound 5a binds in the primary binding site such that the C-2 para-SO2Me
substituent inserts into the 2° pocket present in COX-2. Both O-atoms of p-SO2Me
´
form hydrogen bonding interaction with NH groups of Arg513 (distances \ 4 A).
˚
The C=O of the central oxazolidine-4-one forms hydrogen bond (distance = 5.1
´
A) with the OH of Ser530. It was interesting to note that the O-atom of
˚
oxazolidine-4-one ring was forming a hydrogen bond with NH of Arg120
´
˚
(distance \ 6 A). These observations together with experimental results provide
a good explanation for the potent and selective inhibitory activity of 5a. Similarly,
molecular modeling study of compound 5b shows that it binds in the primary
binding site such that the C-2 para-SO2Me substituent inserts into the 2° pocket
present in COX-2 and form hydrogen bonding interaction with NH groups of
´
Arg513 (distances \ 4 A). The C=O of the central thiazolidine-4-one forms
˚
´
hydrogen bond (distance = 5.4 A) with the OH of Ser530. These data could
˚
reinforce that the compound 5a should inhibit the synthesis of inflammatory
prostaglandins via the cyclooxygenase pathway at sites of inflammation and be
devoid of ulcerogenicity due to the absence of COX-1 inhibition.
Phe518
Arg513
Val523
Trp387
Tyr385
Tyr355
Ala527
Arg120
Ser530
Fig. 1 Compound 5a 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one docked in the
active site of murine COX-2 isozyme. Hydrogen atoms of the amino acid residues have been removed to
improve clarity

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Phe518
Arg513
Val523
Tyr385
Ala527
Tyr355
Ser530
Arg120
Fig. 2 Compound 5b 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazolidine-4(5H)-one docked in the
active site of murine COX-2 isozyme. Hydrogen atoms of the amino acid residues have been removed to
improve clarity
Conclusions
This study indicates that 1)oxazolidine or thiazolidine moiety is a suitable scaffold
(template) to design COX-1/-2 inhibitors, 2) COX-1/-2 inhibition is sensitive to the
type of heteroatom (S or O) and substituent of the C-5 central ring, and 3) 3-benzyl-
2-(4-methylsulfonyl phenyl)-1,3-oxazolidine-4(5H)-one (5a) exhibited highly COX-2
inhibitory potency and selectivity.
Experimental
Materials
All reagents purchased from the Aldrich (USA) or Merck (Germany) Chemical
Company and were used without further purifications.
General
Melting points (mp) were determined using a Thomas Hoover capillary apparatus
(Philadelphia, PA). Infrared spectra were acquired on a Perkin-Elmer 1420 ratio
recording spectrometer (CA, USA). A Bruker FT-500 MHz instrument (Brucker

Med Chem Res (2010) 19:782–793
789
Biosciences, USA) was used to acquire 1HNMR spectra; chloroform-D was used as
solvent. Mass spectra were acquired with a Finnigan TSQ-70 mass spectrometer
(CA, USA). Electron-impact ionization was performed at an ionizing energy of
70 eV; the source temperature was 250°C. Elemental analyses were performed with
a Perkin Elmer Model 240-C apparatus (Perkin Elmer, Norwalk, CT, USA). The
results of the elemental analyses (C,H,N) were within 0.4% of the calculated
amounts.
General procedure for preparation of 3-benzyl-2-(4-methylsulfonyl phenyl)-
(1,3-oxazolidine or 1,3-thiazolidine)-4(5H)-one (4)
To a stirred solution of benzylamine (5 mmol) in dry toluene (25 ml), mercaptoacetic
acid or hydroxyacetic acid (8 mmol) and 4-methylthiobenzaldehyde (5 mmol) were
added. The reaction mixture was refluxed for 24–48 h. After cooling, the organic phase
was washed by a solution of NaHCO3 and distilled water. The organic solvent was dried
(Na2SO4) and removed under reduced pressure. The oily residue was purified by plate
chromatography using EtOAc-Hexane (2:1) as mobile phase (Yields: 20–45%).
3-Benzyl-2-(4-methylthiophenyl)-1,3-oxazolidine-4(5H)-one (4a)
Yield, 20%; yellow oily compound; purified by plate chromatography (solvent:
EtOAc: Hexane; 2:1); IR (KBr) : t cm-1 1695 (C=O); MS: m/z (%): 299.2 (M?,
10), 240.1 (10), 150.9 (100), 146.1 (50), 104.1 (80), 91.0 (100); 1HNMR(CDCl3): d
ppm 2.55 (S, 3H, SCH3), 3.58 (d, 1H, CH2N, J = 14.8 Hz), 4.44 (d, 1H, CH2O,
J = 12.5 Hz), 4.60 (d, 1H, CH2O, J = 12.5 Hz), 5.03 (d, 1H, CH2N, J = 14.8 Hz),
5.75 (S, 1H, CH), 7.12–7.23 (m, 3H, benzyl H3-H5), 7.30–7.36 (m, 6H, benzyl H2 &
H6, 4-methylthio phenyl H2, H3, H5 & H6).
3-Benzyl-2-(4-methylthiophenyl)-1,3-thiazolidine-4(5H)-one (4b)
Yield, 45%; white crystalline powder; mp 100–101°C; IR (KBr): t cm-1 1680
(C=O); MS: m/z (%): 315.2 (M?, 40), 240.2 (50), 224.1 (50), 193.2 (35), 135.2 (35),
1
104.0 (45), 91.4 (100); HNMR(CDCl3): d ppm 2.55 (S, 3H, SCH3), 3.57 (d, 1H,
CH2N, J = 14.7 Hz), 3.81 (d, 1H, CH2S, J = 15.5 Hz), 3.93 (d, 1H, CH2S,
J = 15.5 Hz), 5.18 (d, 1H, CH2N, J = 14.7 Hz), 5.39 (S, 1H, CH), 7.13–7.20 (m,
5H, benzyl H3-H5, 4-methylthio phenyl H3 & H5), 7.28–7.36 (m, 5H, benzyl H2 &
H6, 4-methylthio phenyl H2& H6).
Anal. Calcd. for C17H17NOS2: C, 64.73; H, 5.43; N, 4.44. Found: C, 64.55; H,
5.72; N, 4.29.
General procedure for preparation of 3-benzyl-2-(4-methylsulfonyl phenyl)-
(1,3-oxazolidine or 1,3-thiazolidine)-4(5H)-one (5)
To a solution of 4 (2 mmol) in methanol (25 ml), 30 ml of 30% H2O2 and 100 mg
of WO3 as catalyst were added. The reaction mixture was stirred for 12 hr. After
evaporating methanol, the aqueous phase was extracted by dichloromethane

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Med Chem Res (2010) 19:782–793
(2 9 30 ml). The collected organic phase was washed by a solution of NaHCO3 and
distilled water. The organic solvent was dried (Na2SO4) and removed under reduced
pressure. The obtained solid was purified by column chromatography using
chloroform-methanol (7:3) as mobile phase (Yields: 65–80%).
3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine 4(5H)-one (5a)
Yield, 80%; pale yellow powder; mp 158–160°C; IR (KBr): t cm-1 1695 (C=O);
MS: m/z (%): 331.6 (M?, 10), 224.1 (10), 146.1 (20), 104.1 (50), 91.1 (100), 77
(50); 1HNMR(CDCl3): d ppm 3.11 (S, 3H, SO2CH3), 3.68 (d, 1H, CH2N,
J = 14.9 Hz), 4.27 (d, 1H, CH2O, J = 12.9 Hz), 4.65 (d, 1H, CH2O, J = 12.9 Hz),
5.01 (d, 1H, CH2N, J = 14.9 Hz), 5.87 (S, 1H, CH), 7.10–7.34 (m, 5H, benzyl H2-
H6), 7.52 (d, 2H, 4-methylsulfonyl phenyl H2 & H6, J = 8.3 Hz), 8.02 (d, 2H, 4-
methylsulfonyl phenyl H3 & H5, J = 8.3 Hz); Anal. Calcd. for C17H17NO4S: C,
61.61; H, 5.17; N, 4.23. Found: C, 61.45; H, 4.92; N, 4.25.
3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazolidine 4(5H)-one (5b)
Yield, 65%; white crystalline powder; mp 200–201°C; IR (KBr): t cm-1 1695
(C=O); MS: m/z (%): 347.2 (M?, 10), 256.3 (70), 193.3 (20), 147.3 (100), 118.3
(45), 91.2 (100), 77.2 (60); 1HNMR(CDCl3): d ppm 3.12 (S, 3H, SO2CH3), 3.65 (d,
1H, CH2N, J = 15.1 Hz), 3.85 (d, 1H, CH2S, J = 16.5 Hz), 4.01 (d, 1H, CH2S,
J = 16.5 Hz), 5.41 (d, 1H, CH2N, J = 15.1 Hz), 5.44 (S, 1H, CH), 7.24–7.44 (m,
5H, benzyl H2-H6), 7.51 (d, 2H, 4-methylsulfonyl phenyl H2 & H6, J = 8.4 Hz),
8.04 (d, 2H, 4-methylsulfonyl phenyl H3 & H5, J = 8.4 Hz); Anal. Calcd. for
C17H17NO3S2: C, 58.77; H, 4.93; N, 4.03. Found: C, 58.55; H, 5.12; N, 4.19.
General procedure for preparation of 3-benzyl-5-methyl-2-(4-
methylthiophenyl)-(1,3-oxazolidine or 1,3-thiazolidine)-4(5H)-one (7)
The compounds 7a and 7b were prepared according to the procedure as described
for 4 using 2-hydroxy or 2-mercaptopropionic acid. The obtained products were
purified by column chromatography using EtOAc-Hexane (2:1) as mobile phase
(Yields: 10–35%).
3-Benzyl-5-methyl-2-(4-methylthiophenyl)-1,3-oxazolidine 4(5H)-one (7a)
Two isomers were obtained. Yield, 10%; pale yellow oily semisolid; IR (KBr): t
cm-1 1700 (C=O); MS: m/z (%): 313.4 (M?, 5), 225.8 (50), 210.1 (20), 177.1 (20),
118.1 (35), 105.1 (70), 91.0 (100).
3-Benzyl-5-methyl-2-(4-methylthiophenyl)-1,3-thiazolidine 4(5H)-one (7b)
Two isomers were obtained. Yield, 35%; pale yellow powder; IR (KBr): t cm-1
1700 (C=O); MS: m/z (%):329.1 (M?, 30), 240.8 (100), 192.8 (30), 177.8 (30),

Med Chem Res (2010) 19:782–793
791
160.6 (35), 105.1 (40), 91.0 (100). Anal. Calcd. for C18H19NOS2: C, 65.62; H, 5.81;
N, 4.25. Found: C, 65.85; H, 6.10; N, 4.21.
General procedure for preparation of 3-benzyl-2-(4-methylsulfonyl phenyl)-5-
methyl-(1,3-oxazolidine or 1,3-thiazolidine)-4(5H)-one (8 and 9)
The compounds 8 and 9 were prepared according to the procedure as described for 5
(Yields: 20–45%). Due to the asymmetry of the acid, the reaction gave a mixture of
racemic diastereoisomers (1:1) 8a and 8b or 9a and 9b characterized by a different
disposition of the substituents at C-2 and C-5. Because of similar retention times
between cis and trans isomers in different solvents, the separation was not possible
to be done by chromatography. Therefore, the purified racemic mixture was
considered to be tested as COX-2 inhibitors.
3-Benzyl-5-methyl-2-(4-methylsufonylphenyl)-1,3-oxazolidine 4(5H)-one (8)
Two isomers (8a and 8b; ratio: 1:1) were obtained. Yield, 20%; pale yellow oily
semisolid; mp 39–40°C; IR (KBr): t cm-1 1700 (C=O), 1300, 1150 (SO2); MS: m/z
(%): 345.4 (M?, 5), 255.8 (10), 210.1 (10), 185.1 (10), 132.1 (45), 105.1 (70), 91.0
(100);1HNMR(CDCl3): d ppm 1.53 (d, 3H, CH3, J = 7.8 Hz), 1.63 (d, 3H, CH3,
J = 7.8 Hz), 3.03 (S, 6H, SO2CH3), 3.67 (dd, 2H, CH2, J = 15.2 Hz), 4.55 (q, 1H,
MeCHO), 4.77 (q, 1H, MeCHO), 4.90 (d, 2H, CH2, J = 15.1 Hz), 5.01 (d, 2H, CH2,
J = 15.1 Hz), 5.79 (S, 1H, CHPhenyl), 5.83 (S, 1H, CHPhenyl), 7.04–7.34 (m, 10H,
benzyl), 7.48 (d, 2H, 4-methylsulfonyl phenyl H2 & H6, J = 7.6 Hz), 7.51 (d, 2H, 4-
methylsulfonyl phenyl H2 & H6, J = 7.6 Hz), 7.98 (d, 2H, 4-methylsulfonyl phenyl
H3 & H5, J = 7.6 Hz); 8.01 (d, 2H, 4-methylsulfonyl phenyl H3 & H5, J = 7.6 Hz).
Anal. Calcd. for C18H19NO4S: C, 62.59; H, 5.54; N, 4.05. Found: C, 62.87; H, 5.91;
N, 3.78.
3-Benzyl-5-methyl-2-(4-methylsufonylphenyl)-1,3-thiazolidine 4(5H)-one (9)
Two isomers (9a and 9b; ratio: 1:1) were obtained. Yield, 45%; pale yellow powder;
mp 99–101°C; IR (KBr): t cm-1 1700 (C=O), 1310, 1150 (SO2); MS: m/z (%):
361.1 (M?, 5), 328.9 (30), 240.2 (90), 160.6 (70), 136.8 (30), 105.9 (40), 91.1
(100);1HNMR(CDCl3): d ppm 1.53 (d, 3H, CH3, J = 7.7 Hz), 1.62 (d, 3H, CH3,
J = 7.7 Hz), 3.03 (S, 3H, SO2CH3), 3.06 (S, 3H, SO2CH3), 3.58 (d, 1H, CH2,
J = 14.7 Hz), 3.63 (q, 1H, MeCHS), 3.70 (d, 1H, CH2, J = 14.7 Hz), 3.77 (q, 1H,
MeCHS), 5.21 (S, 1H, CHPhenyl), 5.33 (S, 1H, CHPhenyl), 5.50 (dd, 2H, CH2),
6.91–7.30 (m, 10H, benzyl), 7.38 (d, 2H, 4-methylsulfonyl phenyl H2 & H6,
J = 8.2 Hz), 7.46 (d, 2H, 4-methylsulfonyl phenyl H2 & H6, J = 8.2 Hz), 7.98 (d,
2H, 4-methylsulfonyl phenyl H3 & H5, J = 8.2 Hz); 8.02 (d, 2H, 4-methylsulfonyl
phenyl H3 & H5, J = 8.2 Hz). Anal. Calcd. for C18H19NO3S2: C, 59.81; H, 5.30; N,
3.87. Found: C, 60.05; H, 5.46; N, 4.01.

792
Med Chem Res (2010) 19:782–793
In vitro COX inhibition assays
The ability of the test compounds listed in Table 1 to inhibit ovine COX-1 and
COX-2 (IC50 value, lM) was determined using chemiluminescent enzyme assays
kit (Cayman Chemical, Ann Arbor, MI, USA) according to our previously reported
method (Zarghi et al., 2007c).
Molecular modeling (docking) studies
Docking studies were performed using Autodock software Version 3.0 (CA, USA).
The coordinates of the x-ray crystal structure of the selective COX-2 inhibitor SC-
558 bound to the murine COX-2 enzyme was obtained from the RCSB Protein Data
Bank (1cx2) and hydrogens were added. The ligand molecules were constructed
using the Builder module and were energy minimized for 1000 iterations reaching a
˚
convergence of 0.01 kcal/mol A. The energy minimized ligands were superimposed
on SC-558 in the PDB file 1cx2 after which SC-558 was deleted. The purpose of
docking is to search for favorable binding configuration between the small flexible
˚
ligands and the rigid protein. Protein residues with atoms [7.5 A from the docking
box were removed for efficiency. Searching is conducted within a specified 3D
docking box using annealing based on the Monte Carlo method and MMFF94
molecular mechanics force field for 8000 iterations. These docked structures were
very similar to the minimized structures obtained initially. The quality of the docked
structures was evaluated by measuring the intermolecular energy of the ligand-
enzyme assembly (Kurumbail et al., 1996).
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