Design and synthesis of new 2,4,5-triarylimidazole derivatives as selective cyclooxygenase (COX-2) inhibitors

Article abstract of DOI:10.1007/s00044-011-9710-5

A new group of 2,4,5-triarylimidazole derivatives, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 structure-activity relati

Full text of DOI:10.1007/s00044-011-9710-5

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:1803–1810
DOI 10.1007/s00044-011-9710-5
ORIGINAL RESEARCH
Design and synthesis of new 2,4,5-triarylimidazole derivatives
as selective cyclooxygenase (COX-2) inhibitors
•
A. Zarghi S. Arfaei R. Ghodsi
•
Received: 5 December 2009 / Accepted: 13 June 2011 / Published online: 24 June 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A new group of 2,4,5-triarylimidazole deriva-
tives, possessing a methyl sulfonyl pharmacophore, were
synthesized and their biological activities were evaluated for
cyclooxygenase-2 (COX-2) inhibitory activity. In vitro
COX-1/COX-2 structure–activity relationships were deter-
mined by varying the substituents at the para position of
C-2 phenyl ring. Among the 2,4,5-triarylimidazoles, 2-
(4-hydroxy phenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H imidazole (11f) was identified as a selective COX-2
inhibitor (COX-2 IC50 = 0.15 lM; selectivity index = 75)
that was less potent than the reference drug celecoxib (COX-
2 IC50 = 0.06 lM; SI = 405). A molecular modeling
study where 11f was docked in the binding site of COX-2
showed that the methylsulfonyl pharmacophore group is
oriented in the vicinity of the COX-2 secondary pocket
(Arg513, Phe518, Gly519, and Val523). The structure–activity
data acquired indicate that COX-1/COX-2 inhibition is
sensitive to the nature of the C-2 phenyl substituents.
cyclooxygenase (COX) enzyme, which catalyzes the first
step of the biosynthesis of prostaglandins (PGs) from ara-
chidonic acid (Fu et al., 1990; Vane, 2000; Dannhardt and
Kiefer, 2001). However, the gastrointestinal (GI) toxicities
associated with widespread use of NSAIDs are proved to
be a major problem during long-term therapy. COX
activity has been found to be associated with at least two
isozymes, COX-1 and COX-2. The COX isoforms are
heme-containing enzymes that inhibit distinct expression
roles in several physiological processes. The COX-1 iso-
zyme is constitutively expressed in many tissues and
appears to be important for protection of gastric mucosa,
platelet aggregation, and renal blood flow (Smith and
DeWitt, 1996). In contrast, the COX-2 isozyme is inducible
and expressed by stimuli like mitogenes and oncogenes,
growth factors and disorders of water–electrolyte homeo-
stasis linking its involvement to pathological processes
such as inflammation and various types of cancer (Kanaoka
et al., 2007; Kawamori et al., 1998; Katori and Majima,
2000; Liao et al., 2007). Because PGs are involved in the
maintenance of GI mucosal integrity and because only
COX-1 is present in the normal GI mucosa, the GI side
effects of NSAIDs have been proposed to result from
inhibition of COX-1 activity (Eberhart and Dubois, 1995).
Thus, selective inhibition of COX-2 over COX-1 is useful
for the treatment of inflammation and inflammation-asso-
ciated disorders with reduced gastrointestinal toxicities
when compared with NSAIDs. Recent studies have shown
that COX-2 inhibition improves b-amyloid mediated sup-
pression of memory and synaptic plasticity (Ho et al.,
2006). This suggests that the selective COX-2 inhibitors
may prevent the progression of Alzheimer’s disease by
blocking the COX-2 mediated PGE2 response at synapses.
Several new COX inhibitors were developed which selec-
tively inhibit the COX-2 isoenzyme without interfering
Keywords 2,4,5-Triarylimidazoles ꢀ
COX-2 inhibition ꢀ SAR
Introduction
The non-steroidal anti-inflammatory drugs (NSAIDs) are
commonly used for the treatment of pain, inflammation and
fever. NSAIDs were discovered to act via inhibition of the
A. Zarghi (&) ꢀ S. Arfaei ꢀ R. Ghodsi
Department of Medicinal Chemistry, School of Pharmacy,
Shahid Beheshti University of Medical Sciences,
P.O. Box 14155-6153, Tehran, Iran
e-mail: azarghi@yahoo.com
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Med Chem Res (2012) 21:1803–1810
with COX-1 enzymatic activity (Penning et al., 1997;
Prasit et al., 1999; Talley et al., 2000a, b; Riendeau et al.,
2002; Zarghi et al., 2007, 2009). These selective COX-2
inhibitors mainly belong to a class of diarylheterocycles
that possess two vicinal diaryl substitution attached to a
central hetero or carbocyclic ring system (see structures
1–6 in Chart 1). The recent withdrawal of some diaryl-
heterocyclic selective COX-2 inhibitors such as rofecoxib,
and valdecoxib due to their adverse cardiovascular side
Results and discussions
Chemistry
As shown in Scheme 1, the target 2,4,5-triarylimidazole
derivatives were synthesized from 1,2-diketone 9 and appro-
priate aldehyde 10 in the presence of NH4OAc under micro-
wave irradiation (Wolkenberg et al., 2004). 1,2-Diketone 9
was prepared as previously reported method (Singh et al.,
2004). Accordingly, 1-(4-(methylthio)phenyl)-2-phenyletha-
none 7 was prepared by a Friedel–Craft reaction of pheny-
lacetylchloride and thioanisole using AlCl3 as catalyst.
Consequently, 1-(4-(methylthio)phenyl)-2-phenylethanone 7
was oxidized to 1-(4-(methylsulfonyl)phenyl)-2-phenyletha-
none 8 using oxone in THF-H2O media. Then, oxidation of 8
using selenium dioxide gave (4-(methylsulfonyl)phenyl)-
2-phenyl ethanone-1,2-dione 9. The purity of all products was
determined by thin layer chromatography several solvent
systems of different polarity. All compounds were pure and
´
effects (Dogne et al., 2005) clearly delineates the need to
explore and evaluate new structural ring templates having
selective COX-2 inhibitory activity. As part of our ongoing
program to design new types of selective COX-2 inhibitors,
we now describe the design, synthesis, cyclooxygenase
inhibitory, and docking studies of a new group of 2,4,
5-triarylimidazole derivatives having an imidazole cental
ring scaffold and different substituents at the para position
of C-2 phenyl ring, in order to investigate the effect of
these substituents on the inhibition of COX-2 activity.
Chart 1 Representative
examples of selective COX-2
inhibitors
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Med Chem Res (2012) 21:1803–1810
1805
O
O
O
O
Oxone
SeO2
THF/H2O
MeO2S
MeO2S
MeS
7
8
9
MeO2S
N
AcOH/NH4OAC
MW
9
OHC
X
+
X
N
H
10
11a, X=H
11b, X=F
11c, X=Cl
11d, X=Me
11e, X=OMe
11f, X=OH
11g, X=NHCOMe
Scheme 1 Synthesis of 2,4,5-triarylimidazole derivatives
1
stable. The compounds were characterized by H nuclear
the cyclooxygenase pathway at sites of inflammation and
has less ulcerogenicity due to the low COX-1 inhibitory
activity.
magnetic resonance, infrared and CHN analysis.
The physical data of final synthesized derivatives are
summarized in Table 1.
Docking study
Enzyme inhibitory activity
The orientation of the most potent and selective COX-2
inhibitor, 2-(4-hydroxy phenyl)-4-(4-methylsulfonylphe-
nyl)-5-phenyl-1H-imidazole 11f in the COX-2 active site
was examined by a docking experiment (Fig. 1) (Goodsell
et al., 1996; Kurumbail et al., 1996). This molecular
modeling shows that it binds in the primary binding site
such that the C-2 p-SO2Me substituent inserts into the 2°
pocket present in COX-2. One of the O-atoms of
The ability of the 2,4,5-triarylimidazole 11a–g to inhibit
the COX-1 and COX-2 isozymes was determined using
chemiluminescent enzyme assays as previously described
(Zarghi et al., 2007). Enzyme inhibition data are given in
Table 2. In vitro COX-1/COX-2 inhibition studies showed
that the synthesized compounds 11a–g were selective
inhibitors of the COX-2 isozyme with IC50 values in the
moderately potent 0.15 to 0.35 lM range, and COX-2
selectivity indexes (SI) in the 29–75 range. The structure–
activity relationship study of these compounds indicated
that the order of COX-2 selectivity was OH [ F [ O-
Me [ H, Me [ NHCOMe [ Cl. These results showed
that the nature of substituent at para position of C-2
phenyl ring has an important role on selectivity and
potency. According to these results, 2-(4-hydroxyphenyl)-
4-(4-methylsulfonylphenyl)-5-phenyl-1H-imidazole 11f
was the most potent (IC50 = 0.15 lM), and selective
(SI = 75), COX-2 inhibitor among the synthesized com-
pounds. These data suggest that the compound 11f should
inhibit the synthesis of inflammatory prostaglandins via
p-SO2Me forms a hydrogen binding interaction with
´
amino group of Arg513 (distance = 4.2 A) whereas the
˚
other O-atom is close to other hydrogen of amino group of
´
˚
this amino acid (distance = 5.0 A). The NH of the central
1H-imidazole ring forms hydrogen bond (distance =
´
˚
4.3 A) with the C=O group of Tyr348. In addition, the OH
substituent at para position of C-2 phenyl ring is close to
hydroxyl group of Ser530 which can form hydrogen
binding interaction together and therefore, may explain the
higher potency of compound 11f compared with other
derivatives. These observations together with experimental
results provide a good explanation for selective inhibitory
activity of 11f.
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Table 1 Physical data of the synthesized compounds
MeO2S
N
X
N
H
Compound
X
Color
Mp (°C)
Yield (%)
Molecular formulaa
C22H18N2O2S
Molecular weight
11a
11b
11c
11d
11e
11f
11g
a
H
White
242–243
269–270
226–228
234–235
230–232
360
31
28
50
34
54
49
58
374.4
392.4
408.9
388.5
404.5
390.5
431.5
F
Pale yellow
White
C
22H17N2O2FS
22H17N2O2ClS
23H20N2O2S
23H20N2O3S
22H18N2O3S
24H21N3O3S
Cl
C
C
C
C
C
Me
Pale yellow
Pale yellow
Pale yellow
Pale yellow
OMe
OH
NHCOMe
340
Satisfactory analysis for C, H, N was obtained for all the compounds within 0.4% of the theoretical values
Experimental
Table 2 In vitro COX-1 and COX-2 enzyme inhibition data
MeO2S
Materials
N
All reagents purchased from the Aldrich (USA) or Merck
(Germany) Chemical Company and were used without
further purifications.
X
N
H
General
Melting points (mp) were determined using a Thomas
Hoover melting point apparatus (Philadelphia, USA).
Infrared spectra were acquired on a Perkin-Elmer 1420
ratio recording spectrometer. A Bruker FT-500 MHz
instrument (Brucker Biosciences, Germany) was used to
Compound
X
IC50 (lM)a
COX-2 SIb
COX-1
COX-2
11a
11b
11c
H
9.9
0.23
0.16
0.35
0.24
0.20
0.15
0.31
0.06
43.1
69.5
29.0
43.3
52.8
75.0
33.5
405
F
11.12
10.15
10.40
10.56
11.25
10.38
24.3
1
Cl
acquire H NMR spectra; chloroform-D used as solvent.
11d
11e
Me
Coupling constant (J) values are estimated in hertz (Hz)
and spin multiples are given as s (singlet), d (double), t
(triplet), q (quartet), m (multiplet), and br (broad). The
mass spectral measurements were performed on an
6410Agilent LCMS triple quadrupole mass spectrometer
(LCMS) with an electrospray ionization (ESI) interface.
Elemental analyses were carried out 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.
OMe
OH
11f
11g
Celecoxib
a
NHCOMe
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
)
Preparation of 1-(4-(methylthio)phenyl)-
2-phenylethanone 7
dichloromethane under Argon atmosphere. The tempera-
ture was kept at 0–5°C. Then, 1.5 ml (12 mmol) thioanisole
was added drop wise. After 2 hours, the temperature was
let to approach the room temperature and stirring continued
for 24 h. Then, the reaction mixture was added to crushed
2 ml (15.1 mmol) phenylacetyl chloride was added to a
suspension of 2.1 g (15.8 mmol) AlCl3 in 25 ml dried
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1807
Fig. 1 Compound 11f 2-(4-
hydroxyphenyl)-4-(4-
methylsulfonylphenyl)-5-
phenyl-1H-imidazole docked in
the active site of murine COX-2
isozyme
Trp387
Tyr348
Phe518
Ser530
Gly519
Val523
Ala527
Arg513
Arg120
Tyr355
ice and extracted with dichloromethane. The organic sol-
vent was washed with saturated NaHCO3 and dried with
sodium sulfate and then evaporated. The product was re-
crystallized in ethanol. Yield: 84%; white crystalline
powder; mp: 96–97°C; IR (KBr): m (cm-1) 1675 (C=O);
MS m/z (%): 242.2 (M?, 10), 197.1 (10), 151.1 (100),
123.1 (20), 91.0 (20), 79.1 (20).
J = 8.51 Hz); MS m/z (%): 274.2 (M?, 5), 183.1(45),
151.9 (20), 121.0 (60), 91.0 (100), 76.1 (70).
Preparation of 1-(4-(methylsulfonyl)phenyl)-2-
phenylethane-1,2-dione 9
8 g (72 mmol) selenium dioxide was dissolved in a mixture
of 96 ml dioxane and 4 ml water by heating. Then it was
cooled to room temperature and 4 g (14.6 mmol) of 8 in
THF was added to above-mentioned solution and refluxed
overnight. The selenium was filtered off and the filtrate was
poured to crushed ice and extracted with ethyl acetate. The
organic phase was washed with water and dried with
sodium sulfate and then evaporated. The obtained product
was crystallized in ethyl acetate-hexane. mp: 118–120°C;
Preparation of 1-(4-(methylsulfonyl)phenyl)-2-
phenylethanone 8
1 g (4.1 mmol) of 8 was dissolved in 20 ml THF, and 6 g
oxone in THF/water was added. The mixture was stirred at
room temperature for 12 h. After evaporation of THF
(30 ml), the residue was extracted with chloroform. The
organic solvent was washed with saturated NaHCO3 and
dried with sodium sulfate and then evaporated. The product
was recrystallized in ethanol to obtain white crystalline
powder. mp: 169–170°C; IR (KBr): m (cm-1) 1695 (C=O),
1300, 1160 (SO2); 1H NMR (CDCl3): d 3.14 (s, 3H,
SO2Me), 4.36 (s, 2H, CH2), 7.29–7.41 (m, 5H, phenyl),
8.07 (d, 2H, 4-methylsulfonylphenyl H2 and H6, J =
8.51 Hz), 8.20 (d, 2H, 4-methyl sulfonylphenyl H3 and H5,
1
IR (KBr): m (cm-1) 1670 (C=O), 1300, 1155 (SO2); H
NMR (CDCl3): d 3.15 (s, 3H, SO2Me), 7.57–7.75 (m, 3H,
phenyl H3–H5), 8.02 (d, 2H, phenyl H2 and H6,
J = 8.08 Hz), 8.15 (d, 2H, 4-methylsulfonyl phenyl H2 and
H6, J = 8.50 Hz), 8.22 (d, 2H, 4-methylsulfonylphenyl H3
and H5, J = 8.50 Hz); MS m/z (%): 288.2 (M?, 5), 183.1
(100), 165.2 (20), 121.0 (80), 105.1 (90), 91.1 (50), 76.1
(30).
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General procedure for preparation of 2-(4-
substitutedphenyl)-4-(4-methylsulfonyl phenyl)-5-
phenyl-1H-imidazole 11a–g
2-(4-Methylphenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H-imidazole 11d
Yield: 34%; pale yellow crystalline powder; mp:
234–235°C; IR (KBr): m (cm-1) 3320 (NH), 1285, 1145
(SO2), H NMR (DMSO-D6): d 2.37 (s, 3H, Me), 3.20
(s, 3H, SO2Me), 7.31 (d, 2H, 4-methylphenyl H3 and H5,
J = 7.97 Hz), 7.35–7.55 (m, 5H, phenyl),7.75 (d, 2H,
4-methylsulfonylphenyl H2 and H6, J = 8.09 Hz), 7.84 (d,
2H, 4-methylphenyl H2 and H6, J = 8.47 Hz), 8.01 (d, 2H,
4-methylsulfonyl phenyl H3 and H5, J = 8.09 Hz), 12.82
(s, 1H, NH). Anal. Calcd. for C23H20N2O2S: C, 71.11; H,
5.19; N, 7.21. Found: C, 71.46; H, 5.32; N, 7.25.
Equivalent amounts of diketone 9 and appropriate aldehyde
10 along with 2 g ammonium acetate in 6 ml glacial acetic
acid were placed in microwave reactor for 10 min, while
the power was set at 180 W. After cooling, the solution
was neutralized with aqueous ammonia in which the
product precipitated immediately. The precipitate was fil-
tered and washed with water and recrystallized in methanol
(Yields: 28–58%).
1
2,5-Diphenyl-4-(4-methylsulfonylphenyl)-1H-imidazole
11a
2-(4-Methoxyphenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H-imidazole 11e
Yield: 31%; white crystalline powder; mp: 242–243°C; IR
1
(KBr): m (cm-1) 3320 (NH), 1300, 1150 (SO2), H NMR
Yield: 54%; pale yellow crystalline powder; mp:
230–232°C; IR (KBr): m (cm-1) 3300 (NH), 1290, 1145
(SO2), H NMR (DMSO-D6): d 3.05 (s, 3H, SO2Me), 3.90
(s, 3H, OMe), 7.01 (d, 2H, 4-methoxyphenyl H3 and H5,
J = 8.11 Hz), 7.43–7.58 (m, 7H, phenyl and 4-methoxy-
phenyl H2 and H6), 7.80 (d, 2H, 4-methylsulfonylphenyl H2
and H6, J = 7.99 Hz), 7.90 (d, 2H, 4-methylsulfonyl phe-
nyl H3 and H5, J = 7.99 Hz), 9.78 (s, 1H, NH). Anal.
Calcd. for C23H20N2O3S: C, 68.30; H, 4.98; N, 6.93.
Found: C, 68.02; H, 4.68; N, 6.98.
(DMSO-D6): d 3.21 (s, 3H, SO2Me), 7.38–7.53 (m, 6H,
phenyl), 7.56 (d, 2H, 5-phenyl H2 and H6, J = 8.16 Hz), 7.78
(d, 2H, 4 methylsulfonylphenyl H2 and H6, J = 7.41 Hz),
7.84 (d, 2H, 2-phenyl H2 and H6, J = 8.13 Hz), 8.11 (d, 2H,
4-methylsulfonylphenyl H3 and H5, J = 7.41 Hz), 12.91(s,
1H, NH). Anal. Calcd. for C22H18N2O2S: C, 70.56; H, 4.84;
N, 7.48. Found: C, 70.85; H, 5.02; N, 7.19.
1
2-(4-Fluorophenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H-imidazole 11b
2-(4-Hydroxyphenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H-imidazole 11f
Yield: 28%; pale yellow crystalline powder; mp:
269–270°C; IR (KBr): m (cm-1) 3290 (NH), 1310, 1155
(SO2), H NMR (DMSO-D6): d 2.90 (s, 3H, SO2Me), 6.98
(t, 2H, 4-fluorophenyl H3 and H5), 7.23 (m, 3H, phenyl
H3–H5), 7.56 (d, 2H, phenyl H2 and H6, J = 7.80 Hz), 7.63
(d, 2H, 4-methylsulfonylphenyl H2 and H6, J = 6.80 Hz),
7.71 (d, 2H, 4-fluorophenyl H2 and H6, J = 7.84 Hz), 7.97
(d, 2H, 4-methyl sulfonylphenyl H3 and H5, J = 6.80 Hz),
9.78 (s, 1H, NH). Anal. Calcd. forC22H17N2O2FS: C,
67.33; H, 4.37; N, 7.14. Found: C, 67.65; H, 4.70; N, 7.01.
1
Yield: 49%; pale yellow crystalline powder; mp: 360°C; IR
(KBr): m (cm-1) 3550 (OH), 3300 (NH), 1290, 1150 (SO2),
1H NMR (DMSO-D6): d 3.21 (s, 3H, SO2Me), 6.88 (d, 2H,
4-hydroxyphenyl H3 and H5, J = 7.85 Hz), 7.43–7.51 (m,
3H, phenyl H3–H5), 7.54 (d, 2H, phenyl H2 and H6,
J = 7.96 Hz), 7.76 (d, 2H, 4-methylsulfonylphenyl H2 and
H6, J = 8.27 Hz), 7.83 (d, 2H, 4-hydroxyphenyl H2 and
H6, J = 7.98 Hz), 7.92 (d, 2H, 4-methylsulfonyl phenyl H3
and H5, J = 8.27 Hz), 9.77 (s, 1H, OH), 12.60 (s, 1H, NH).
Anal. Calcd. for C22H18N2O3S: C, 66.67; H, 4.65; N, 7.17.
Found: C, 66.92; H, 4.88; N, 6.95.
2-(4-Chlorophenyl)-4-(4-methylsulfonylphenyl)-5-phenyl-
1H-imidazole 11c
Yield: 50%; white crystalline powder; mp: 226–228°C; IR
2-(4-Acetamidophenyl)-4-(4-methylsulfonylphenyl)-5-
phenyl-1H-imidazole 11g
1
(KBr): m (cm-1) 3290 (NH), 1290, 1150 (SO2), H NMR
(DMSO-D6): d 3.21 (s, 3H, SO2Me), 7.31–7.54 (m, 5H,
phenyl H3–H5 and 4-chlorophenyl H3 and H5), 7.58 (d, 2H,
phenyl H2 and H6, J = 8.39 Hz), 7.79 (d, 2H, 4-meth-
ylsulfonylphenyl H2 and H6, J = 8.51 Hz), 7.84 (d, 2H,
4-chlorophenyl H2 and H6, J = 8.42 Hz), 8.11 (d, 2H,
4-methylsulfonylphenyl H3 and H5, J = 8.51 Hz), 12.95
(s, 1H, NH). Anal. Calcd. for C22H17N2O2ClS: C, 64.62;
H, 4.19; N, 6.85. Found: C, 64.85; H, 4.30; N, 6.71.
Yield: 58%; pale yellow crystalline powder; mp: 340°C; IR
(KBr): m (cm-1) 3350, 3300 (NH), 1675 (C=O),1310, 1160
(SO2), H NMR (DMSO-D6): d 2.08 (s, 3H, COMe), 3.21
(s, 3H, SO2Me), 7.01 (d, 2H, 4-acetamidophenyl H3 and
H5, J = 8.11 Hz), 7.45–7.55 (m, 5H, phenyl), 7.70 (d, 2H,
4-methylsulfonylphenyl H2 and H6, J = 8.27 Hz), 7.84 (d,
2H, 4-acetamidophenyl H2 and H6, J = 8.11 Hz), 8.01 (d,
1
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1809
Ho L, Qin W, Stetka BS, Pasinetti GM (2006) Is there a future for
cyclo-oxygenase in Alzheimer’s disease? CNS Drugs 20:85–98
Kanaoka S, Takai T, Yoshida K (2007) Cyclooxygenase-2 and tumor
biology. Adv Clin Chem 43:59–78
Katori M, Majima M (2000) Cyclooxygenase-2: its rich diversity of
roles and possible application of its selective inhibitors. Inflamm
Res 49:367–392
Kawamori T, Rao CV, Seibert K, Reddy BS (1998) Chemopreventive
activity of celecoxib, a specific cyclooxygenase-2 inhibitor,
against colon carcinogenesis. Cancer Res 58:406–412
Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA,
Pak JY, Gildehaus D, Miyashiro JM, Penning TD, Seibert K,
Isakson PC, Stallings WC (1996) Structural basis for selective
inhibition of cyclooxygenase-2 by anti-inflammatory agents.
Nature 384:644–648
Liao Z, Mason KA, Milas L (2007) Cyclo-oxygenase-2 and its
inhibition in cancer: is there a role? Drug 67:821–845
Penning TD, Tally JJ, Bertenshaw SR, Carter JS, Collins PW, Docter
S, Graneto MJ, Lee LF, Malecha JW, Miyashiro JM, Rogers R,
Rogier DJ, Yu SS, Anderson GD, Burton EG, Cogburn JN,
Gregory SA, Koboldt CM, Perkins WE, Seibert K, Veenhuizen
AW, Zhang YY, Isakson PC (1997) Synthesis and biological
evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2
inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoro-
methyl)-1H pyrazol-1-yl] benzenesulfonamide (SC-b58635,
celecoxib). J Med Chem 40:1347–1365
Prasit P, Wang Z, Brideau C, Chan CC, Charlson S, Cromlish W,
Ethier D, Evans JF, Ford-Hutchinson AW, Gauthier JY, Gordon
R, Guay J, Gresser M, Kargman S, Kennedy B, Leblanc Y, Leger
S, Mancini JO, Neil GP, Quellet M, Percival MD, Perrier H,
Riendeau D, Rodger I, Tagari P, Therien M, Vikers P, Wong E,
Xu L, Young RN, Zamboni R, Boyce S, Rupniak N, Forrest M,
Visco D, Patrick D (1999) The discovery of rofecoxib, [MK 966,
Vioxx, 4-(40-methylsulfonylphenyl)-3-phenyl-2(5H)-furanone],
an orally active cyclooxygenase-2-inhibitor. Bioorg Med Chem
Lett 9:1773–1778
2H, 4-methylsulfonylphenyl H3 and H5, J = 8.27 Hz),
10.36 (s, 1H, NH), 12.75 (s, 1H, NH). Anal. Calcd. for
C24H21N3O3S: C, 66.80; H, 4.90; N, 9.74. Found: C, 67.05;
H, 4.58; N, 9.88.
In vitro cyclooxygenase (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
(catalog number 560101, Cayman Chemical, Ann Arbor,
MI, USA) according to our previously reported method
(Zarghi et al., 2007).
Molecular modeling (docking) studies
Docking studies were performed using Autodock software
Version 3.0. 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 pur-
pose of docking is to search for favorable binding config-
uration between the small flexible ligands and the rigid
˚
protein. Protein residues with atoms greater than 7.5 A
Riendeau D, Percival MD, Brideau C, Dube CS, Ethier D, Falgueyret
JP, Friesen RW, Gordon R, Greig G, Guay J, Girard Y, Prasit P,
Zamboni R, Rodger IW, Gresser M, Ford-Hutchinson A, Young
RN, Chan CC (2002) Etoricoxib (MK-0663): preclinical profile
and comparison with other agents that selectively inhibit
cyclooxygenase-2. J Pharmacol Exp Ther 296:558–566
Singh SK, Saibaba V, Ravikumar V, Rao CS, Akhila V, Rao YK
(2004) Synthesis and biological evaluation of 2,3-diarylpyra-
zines and quinoxalines as selective COX-2 inhibitors. Bioorg
Med Chem 12:1881–1893
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 itera-
tions. 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).
Smith WL, DeWitt DL (1996) Prostaglandin endoperoxide
synthases-1 and -2. Adv Immunol 62:167–215
H
Talley JJ, Bertenshaw SR, Brown DL, Carter JS, Graneto MJ, Kellogg
MS, Koboldt CM, Yuan J, Zhang YY, Seibert K (2000a) N-[[(5-
Methyl-3-phenyl isoxazol-4-yl)-phenyl]sulfonyl]propanamide,
sodium salt, parecoxib sodium: a potent and selective inhibi-
tor of COX-2 for parenteral administration. J Med Chem 43:
1661–1663
Talley JJ, Brown DL, Carter JS, Graneto MJ, Koboldt CM, Masferrer
JL, Perkins WE, Rogers RS, Shaffer AF, Zhang YY, Zweifel BS,
Seibert K (2000b) 4-[5-Methyl-3-phenylisoxazol-4-yl]-benzene-
sulfonamide, valdecoxib: a potent and selective inhibitor of
COX-2. J Med Chem 43:775–777
References
Dannhardt G, Kiefer W (2001) Cyclooxygenase inhibitors-current
status and future prospects. Eur J Med Chem 36:109–126
´
Dogne JM, Supuran CT, Pratico D (2005) Cardiovascular effects of
the coxibs. J Med Chem 48:2251–2257
Eberhart CE, Dubois RN (1995) Eicosanoids and the gastrointestinal
tract. Gastroenterology 109:285–301
Fu JY, Masferrer JL, Seibert K, Raz A, Needleman P (1990) The
induction and suppression of prostaglandin H2 synthase (cyclo-
oxygenase) in human monocytes. J Biol Chem 265:16737–16740
Goodsell DS, Morris GM, Olson AJ (1996) Automated docking
of flexible ligands: applications of AutoDock. J Mol Recognit 9:
1–5
Vane JR (2000) The fight against rheumatism: from willow bark to
COX-1 sparing drugs. J Physiol Pharmacol 51:573–586
Wolkenberg SE, Wisnoski DD, Leister WH, Wang Y, Zhao Z,
Lindsley CW (2004) Efficient synthesis of imidazoles from
aldehydes and 1,2-diketones using microwave irradiation. Org
Lett 6:1453–1456
123

1810
Med Chem Res (2012) 21:1803–1810
Zarghi A, Najafnia L, Daraie B, Dadrass OG, Hedayati M (2007)
Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives as
selective cyclooxygenase (COX-2) inhibitors. Bioorg Med Chem
Lett 17:5634–5637
Zarghi A, Zebardast T, Daraie B, Hedayati M (2009) Design and
synthesis of new 1,3-benzthiazinan-4-one derivatives as selec-
tive cyclooxygenase (COX-2) inhibitors. Bioorg Med Chem
17:5369–5373
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