Design, synthesis and biological evaluation of new 2,3-diarylquinoline derivatives as selective cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2009.12.060

A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity (COX-2 IC₅₀ = 0.07 μM; selectivity index = 687.1) that was more selective than the reference drug celecoxib (COX-2 IC₅₀ = 0.06 μM; selectivity index = 405). A molecular modeling study where 8 was docked in the binding site of COX-2 indicated that the p-MeSO₂ COX-2 pharmacophore group on the C-2 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket (Arg⁵¹³, Phe⁵¹⁸ and Val⁵²³) and the carboxylic acid substituent can interact with Ser⁵³⁰. The structure activity data acquired indicate that the size and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity.

Full text of DOI:10.1016/j.bmc.2009.12.060

Bioorganic & Medicinal Chemistry 18 (2010) 1029–1033
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design, synthesis and biological evaluation of new 2,3-diarylquinoline
derivatives as selective cyclooxygenase-2 inhibitors
b
c
Razieh Ghodsi a, Afshin Zarghi a, , Bahram Daraei , Mehdi Hedayati
*
a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran
b Department of Toxicology, Tarbiat Modarres University, Tehran, Iran
c Research Institute for Endocrine Sciences, Shahid Beheshti University (M.C),Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new group of 2,3-diarylquinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the
para-position of the C-2 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In
vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on
the C-4 quinoline ring. Among the 2,3-diarylquinolines, 2-(4-(methylsulfonyl) phenyl)-3-phenylquino-
line-4-carboxylic acid (8) exhibited the highest potency and selectivity for COX-2 inhibitory activity
Received 1 December 2009
Revised 19 December 2009
Accepted 24 December 2009
Available online 4 January 2010
(COX-2 IC50 = 0.07
coxib (COX-2 IC50 = 0.06
l
M; selectivity index = 687.1) that was more selective than the reference drug cele-
Keywords:
l
M; selectivity index = 405). A molecular modeling study where 8 was docked
Cyclooxygenase-2 inhibition
2,3-Diarylquinolines
SAR
in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-2 phenyl
ring is oriented in the vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carbox-
ylic acid substituent can interact with Ser530. The structure activity data acquired indicate that the size
and nature of the C-4 quinoline substituent are important for COX-2 inhibitory activity.
Ó 2010 Published by Elsevier Ltd.
1. Introduction
system in conjunction with a characteristic sulfonyl group such as
a para-SO2NH2 or a para-SO2Me substituent on one of the phenyl
Non-steroidal anti-inflammatory drugs (NSAIDs) are competi-
tive inhibitors of cyclooxygenase (COX), the enzyme that mediates
the bioconversion of arachidonic acid to inflammatory prostaglan-
dins (PGs).1,2 COX is a membrane-bound heme protein which
exists at least in two different isoforms, a constitutive form
(COX-1) and an inducible form (COX-2). The COX-1 enzyme is con-
stitutively expressed and it is involved in the synthesis and supply
of the necessary arachidonic acid metabolites for maintaining of
gastric and renal functions as well as for an adequate vascular
homeostasis whereas COX-2 induces inflammatory conditions.3,4
The therapeutic anti-inflammatory action of NSAIDs is produced
by inhibition of COX-2, while the undesired side effects arise from
inhibition of COX-1 activity.5 Thus, it was though that more
selective COX-2 inhibitors would have reduced side effects. More-
over, recent studies indicating the place of COX-2 inhibitors in
cancer chemotherapy especially colon cancer6 and neurological
diseases such as Parkinson7 and Alzheimer’s8 diseases still contin-
ues to attract investigations on development of COX-2 inhibitors.
1,2-Diarylheterocycles, and other central ring pharmacophore
templates, have been extensively studied as the most important
selective COX-2 inhibitors. All these tricyclic molecules possess
1,2-diaryl substitution attached to a monocyclic or bicylclic central
rings which plays an important role on COX-2 selectivity.9 Cele-
coxib and rofecoxib are two well known selective COX-2 inhibitors
belong to COXIBs class.10,11 However, the recent market removal of
rofecoxib and some other COX-2 inhibitors due to their adverse
cardiovascular side effects12 clearly encourages the researchers to
explore and evaluate alternative templates with COX-2 inhibitory
activity. In addition, recent studies have suggested that rofecoxib’s
adverse cardiac events may not be a class effect but rather an
intrinsic chemical property related to its metabolism.13 For this
reason novel scaffolds with high selectivity for COX-2 inhibition
need to be found and evaluated for their biological activities.
Recently, we reported several investigations describing the design,
synthesis and molecular modeling studies for a group of 2-phenyl-
4-carboxylquinolines possessing a methylsulfonyl COX-2 pharma-
cophore at the para-position of the C-2 phenyl ring in conjunction
with various substituents at C-7 and C-8 quinoline ring.14 In this
group, 2-(4-(methylsulfonyl) phenyl)quinoline-4-carboxylic acid
(see structure 2 in Fig. 1) having lipophilic substituents at C-7
and C-8 positions exhibited higher selectivity for COX-2 inhibition
than reference drug celecoxib. On the other hand, we recently
introduced a new class of 2,3-diaryl-1,3-benzthiazinan-4-ones
containing a bicyclic central ring as highly potent COX-2 inhibi-
tors.15 For example, 3-(p-fluorophenyl)-2-(4-methylsulfonylphe-
nyl)-1,3-benzthiazinane-4-one (see structure 1 in Fig. 1) showed
highly potency on COX-2 inhibition even more potent than
* Corresponding author. Tel.: +98 21 8820096; fax: +98 21 88665341.
E-mail address: azarghi@yahoo.com (A. Zarghi).
0968-0896/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2009.12.060

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R. Ghodsi et al. / Bioorg. Med. Chem. 18 (2010) 1029–1033
The ability of the 2,3-diarylquinolines 4–8 to inhibit the COX-1
SO2NH2
SO2Me
N
and COX-2 isozymes was determined using chemiluminescent en-
zyme assays (see enzyme inhibition data in Table 1.) according to
our previously reported method.21 In vitro COX-1/COX-2 inhibition
studies showed that all compounds 4–8 were selective inhibitors
of the COX-2 isozyme with IC50 values in the highly potent 0.07–
F3C
N
O
O
Me
0.13 lM range, and COX-2 selectivity indexes (SI) in the 78.5–
Celecoxib
Rofecoxib
687.1 range. The relative COX-2 potency, and COX-2 selectivity
profiles for the 2,3-diarylquinoline derivatives 4–8, with respect
to the C-4 substituent (X) was COOH > H > NH2 > Me > Ph. SAR data
(IC50 values) acquired by determination of the in vitro ability of the
title compounds to inhibit the COX-1 and COX-2 isozymes showed
that the COX inhibition is sensitive to the size and nature of substi-
tuent at the C-4 quinoline ring. These data showed that the type of
substituent attached to C-4 of quinoline ring affected both selectiv-
ity and potency for COX-2 inhibitory activity. Accordingly, com-
pound 6 having bulky group at the C-4 central ring showed less
selectivity and potency for COX-2 isozyme compared with com-
pounds 4 and 5 that can be explained by steric parameter. How-
ever, among the 2,3-diarylquinoline derivatives, compound 8
possessing a carboxylic acid attached to C-4 quinoline ring exhib-
ited the highest COX-2 inhibitory potency and selectivity (COX-2
O
COOH
F
N
S
N
SO2Me
SO2Me
1
2
X
N
IC50 = 0.07
lM; SI = 687.1) that was more selective than the refer-
ence drug celecoxib (COX-2 IC50 = 0.06
lM; SI = 405). However,
SO2Me
the replacement of carboxylic acid with amino group (7) decreased
the selectivity for COX-2 inhibition. This effect may be explained
by less ability of amino group for hydrogen binding interaction
compared with the carboxylic acid substituent. The binding inter-
actions of the most potent and selective COX-2 inhibitor
compound (8) within the COX-2 binding site were investigated.
The most stable enzyme–ligand complex of 2-(4-(methylsulfo-
Designed compounds
Figure 1. Some representative examples of COXIBs (celecoxib and rofecoxib), 2,3-
diaryl benzthiazinan-4-one (1), 4-carboxyl quinoline (2) lead compound and our
designed compounds.
celecoxib. As part of our ongoing program to design COX-2 inhibi-
tors, we now describe the synthesis and biological evaluation of a
group of 2,3-diarylquinoline derivatives possessing a methylsulfo-
nyl COX-2 pharmacophore at the para-position of the C-2 phenyl
ring in conjunction with various substituents at C-4 quinoline ring.
In these designed compounds we utilized quinoline ring instead of
benzthiazinan scaffold in our previously reported COX-2 inhibitors.
nyl)phenyl)-3-phenylquinoline-4-carboxylic acid possessing
a
MeSO2 COX-2 pharmacophore at para-position of C-2 phenyl ring
within the COX-2 binding site (Fig. 2) shows that the p-MeSO2-
phenyl moiety is oriented towards the COX-2 secondary pocket
(Arg513, Phe518 and Val523). One of the O-atoms of p-MeSO2 substi-
tuent forms a hydrogen binding interaction with amino group of
Arg513 (distance = 4.6 Å) whereas the other O-atom is about 2.9 Å
away from NH of Ser353. In addition, a hydrogen bonding interac-
tion can form between the nitrogen atom of quinoline ring and
NH of Arg120 (distance = 4.9 Å). Also, the distance between the
OH of carboxylic acid group of the quinoline ring is about 3 Å away
from C@O of Ala527 whereas the O-atom of C@O group is close to
NH of Ser530 (distance = 4.8 Å) which can explain the high potency
and selectivity of compound 8.
2. Chemistry
The target 2,3-diarylquinoline derivatives 4–8 were synthesized
via the route outlined in Scheme 1. As illustrated in the scheme,
2-(4-(methylsulfonyl)phenyl)-1-phenylethanone16 3 was reacted
with 2-nitrobenzaldehyde in the presence of SnCl2 using
microwave irradiation to provide 2-(4-(methylsulfonyl)phenyl)-
3-phenylquinoline 4 (yield 10%).17 Reaction of 3 with 2-aminoace-
tophenone or 2-aminobenzophenone under acidic condition
through the well known Friedlander reaction gave quinolines 5
and 6 (yield: 10% and 76%, respectively).18 Treatment of 3 with
2-aminobenzonitrile and AlCl3 under argon atmosphere afforded
4-amino-2-(4-(methylsulfonyl)phenyl)-3-phenylquinoline 7 (yield
11%).19 The desired quinoline derivative 8 was prepared using
Pfitzinger reaction.20 Accordingly, 2-(4-(methylsulfonyl)phenyl)-
1-phenylethanone 3 was reacted with isatin in alkaline ethanol
to provide 8 (yield: 70%). The purity of all products was determined
by thin layer chromatography using several solvent systems of
different polarity. All compounds were pure and stable. The com-
pounds were characterized by 1H nuclear magnetic resonance,
infrared, mass spectrometry and CHN analysis.
4. Conclusions
This study indicates that (i) the bicyclic quinoline ring is a suit-
able scaffold (template) to design COX-1/-2 inhibitors, (ii) in this
class of compounds COX-1/-2 inhibition is sensitive to the size
and nature of the C-4 quinoline substituent, and (iii) 2-(4-(methyl-
sulfonyl)phenyl)-3-phenylquinoline-4-carboxylic acid (8) exhib-
ited high COX-2 inhibitory potency and selectivity.
5. Experimental section
All chemicals and solvents used in this study were purchased
from Merck AG and Aldrich Chemical. Melting points were deter-
mined with a Thomas–Hoover capillary apparatus. Infrared spectra
were acquired using a Perkin–Elmer Model 1420 spectrometer. A
Bruker FT-500 MHz instrument (Brucker Biosciences, USA) was
used to acquire 1HNMR spectra with TMS as internal standard.
Chloroform-D and DMSO-d6 were used as solvents. Coupling con-
stant (J) values are estimated in hertz (Hz) and spin multiples are
given as s (singlet), d (double), t (triplet), q (quartet), m (multiplet),
3. Results and discussion
A group of 2,3-diarylquinoline derivatives having different sub-
stituents at the C-4 quinoline ring were prepared to investigate the
effect of different substituents on COX-2 selectivity and potency.

R. Ghodsi et al. / Bioorg. Med. Chem. 18 (2010) 1029–1033
1031
COOH
N
SO2Me
8
N
SO2Me
4
e
a
O
d
3
NH2
SO2Me
b
c
CH3
N
SO2Me
7
N
SO2Me
5
N
SO2Me
6
Scheme 1. Reagents and conditions: (a) 2-nitrobenzaldehyde, SnCl2Á2H2O, MW (180 W), 10 min; (b) 2-aminoacetophenone, H2SO4, CH3COOH, reflux; (c) 2-aminobenzo-
phenone, H2SO4, CH3COOH, reflux; (d) 2-aminobenzonitrile, AlCl3, 1,2-dichloroethane, reflux; (e) isatin, KOH, EtOH, reflux.
Table 1
ionization was performed at an ionizing energy of 70 eV with a
source temperature of 250 °C. A 6410Agilent LC–MS triple quadru-
pole mass spectrometer (LC–MS) with an electrospray ionization
In vitro COX-1 and COX-2 enzyme inhibition assay data for 2,3-diarylquinoline
derivatives 4–8
(ESI) interface was also used for molecular weight measurement.
Microanalyses, determined for C, H, and N were within 0.4% of
theoretical values.
X
N
5.1. Synthesis of 2-(4-(methylsulfonyl)phenyl)-3-phenylquin-
oline (4)
SO2Me
Compound
X
IC50 (l
M)
Selectivity indexb (SI)
a
2-Nitrobenzaldehyde (0.3 g, 1.82 mmol) and 2-(4-(methylsulfo-
nyl)phenyl)-1-phenylethanone (0.5 g, 1.82 mmol) were uniformly
mixed with SnCl2, 2H2O (1.5 g, 4.35 mmol) the resulting mixture
was then irradiated with microwaves (MW) for 10 min while the
power was set on 180 W. The reaction mixture was cooled at room
temperature and treated with 10% NaHCO3 solution, and then ex-
tracted with ethyl acetate. The organic layer was washed with
brine, dried over Na2SO4, and evaporated to obtain the crude prod-
uct, which was further purified by plate chromatography using
chloroform as mobile phase. Yield: 10% (70 mg); white crystalline
COX-1
COX-2
4
5
6
7
H
Me
Ph
NH2
COOH
—
33.5
13.3
10.2
14.4
48.1
24.3
0.11
0.11
0.13
0.08
0.07
0.06
304.5
121.3
78.5
180.0
687.1
405
8
Celecoxib
a
Values are means of two determinations acquired using an ovine COX-1/COX-2
assay kit and the deviation from the mean is <10% of the mean value.
b
In vitro COX-2 selectivity index (COX-1 IC50/COX-2 IC50).
powder; mp: 135–136 °C; IR (KBr):
m
(cmÀ1) 1310, 1150 (SO2),
1HNMR (CDCl3): d (ppm) 3.02 (s, 3H, SO2Me), 7.21–7.24 (m, 2H,
phenyl H2 and H6), 7.32–7.34 (m, 3H, phenyl H3–H5), 7.61 (t, 1H,
quinoline H7, J = 7.5 Hz), 7.67 (d, 2H, 4-methylsulfonylphenyl H2
and br (broad). Low-resolution mass spectra were acquired with a
MAT CH5/DF (Finnigan) mass spectrometer that was coupled
online to a Data General DS 50 data system. Electron-impact

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R. Ghodsi et al. / Bioorg. Med. Chem. 18 (2010) 1029–1033
and 0.04 ml concentrated sulfuric acid in 5 ml of glacial acetic
acid was refluxed for 3 h, the reaction mixture was then cooled
and poured slowly with stirring into an ice-cold solution of
6 ml concentrated ammonium hydroxide in 15 ml of water. The
resultant suspension was allowed to stand in an ice bath until
the initially oily precipitate had hardened. The crude product
was collected, washed with water and recrystallized from ethanol
and washed with hexane. Yield: 76% (1.2 g); pale yellow crystal-
line powder; mp: 235–236 °C; IR (KBr):
m
(cmÀ1) 1310, 1155
(SO2), 1HNMR (CDCl3): d (ppm) 3.04 (s, 3H, SO2Me), 6.91–6.93
(m, 2H, 4-phenyquinoline H2 and H6), 7.05–7.09 (m, 3H, 4-phen-
ylquinoline H3–H5), 7.17–7.19 (m, 2H, 3-phenylquinoline H2 and
H6), 7.32–7.34 (m, 3H, 3-phenylquinoline H3–H5), 7.56 (t, 1H,
quinoline H6), 7.63–7.67 (m, 3H, 4-methylsulfonyl phenyl H2
and H6 and quinoline H5), 7.80–7.85 (m, 3H, 4-methylsulfonyl-
phenyl H3 and H5 and quinoline H7), 8.28 (d, 1H, quinoline H8,
J = 8.4 Hz); LC–MS (ESI) m/z : 436.2 (M+1) (100); Anal. Calcd for
C28H21NO2S: C, 69.88; H, 4.89; N, 4.53. Found: C, 69.62; H,
4.54; N, 4.32.
5.4. Synthesis of 4-amino-2-(4-(methylsulfonyl)phenyl)-3-
phenylquinoline (7)
A solution of 2-(4-(methylsulfonyl)phenyl)-1-phenylethanone
(1 g, 3.72 mmol) in dry 1,2-dichloroethane (5 ml) was added drop-
wise to a suspension of AlCl3 (0.48 g, 3.72 mmol) and 2-aminoben-
zonitrile (0.43 g, 3.72 mmol) in dry 1,2-dichloroethane under argon
atmosphere. The temperature was kept at 0–5 °C for 30 min then
the reaction mixture was heated under reflux for 24 h. A mixture
of THF (40 ml) and cold water (20 ml) was added to the mixture
and then rendered basic (pH 8) and the mixture was stirred at
room temperature for 30 min. The organic solvents were evapo-
rated at reduced pressure, the produced oily liquid was purified
by column chromatography (hexane/ethyl acetate 1:1 v/v), the
product was recrystallized in methanol. Yield:11% (155 mg); pale
Figure 2. Docking 2-(4-(methylsulfonyl)phenyl)-3-phenylquinoline-4-carboxylic
acid (8) in the active site of murine COX-2. Hydrogen atoms of the amino acid
residues have been removed to improve clarity.
and H6, J = 8.5 Hz), 7.78 (t, 1H, quinoline H6, J = 8.3 Hz), 7.86 (d, 2H,
4-methylthiophenyl H3 and H5, J = 8.5 Hz), 7.91 (d, 1H, quinoline
H5, J = 8.1 Hz), 8.20 (d, 1H, quinoline H8, J = 8.1 Hz), 8.24 (s, 1H,
quinoline H4); MS m/z (%): 359.2 (M+, 15), 283.2 (70), 205.1 (10),
180.1 (60), 165.0 (75), 77.1 (100); Anal. Calcd for C22H17NO2S: C,
62.37; H, 4.00; N, 4.28. Found: C, 62.42; H, 3.71; N, 4.39.
yellow crystalline powder; mp: 256 °C; IR (KBr):
m
(cmÀ1) 3485,
3390 (NH2), 1300, 1145 (SO2); 1HNMR (DMSO-d6): d (ppm) 3.12
(s, 3H, SO2Me), 6.15 (s, 2H, NH2), 7.16 (d, 2H, phenyl H2 and H6,
J = 7.2 Hz), 7.28 (t, 1H, phenyl H4, J = 7.3 Hz), 7.33 (t, 2H, phenyl
H3 and H5, J = 7.4 Hz), 7.43–7.46 (m, 3H, 4-methyl sulfonylphenyl
H2 and H6 and quinoline H6), 7.63–7.68 (m, 3H, 4-methylsulfonyl-
phenyl H3 and H5 and quinoline H7), 7.80 (d, 1H, quinoline H5,
J = 8.4 Hz), 8.28 (d, 1H, quinoline H8, J = 8.4 Hz); LC–MS (ESI) m/z
: 375.8 (M+1) (100); Anal. Calcd for C22H18N2O2S: C, 69.88; H,
4.89; N, 4.53. Found: C, 69.62; H, 4.54; N, 4.32.
5.2. Synthesis of 4-methyl-2-(4-methylsulfonyl)phenyl)-3-
phenylquinoline (5)
A suspension of 2-aminoacetophenone (0.5 g, 3.70 mmol) and 2-
(4-(methylsulfonyl)phenyl)-1-phenylethanone (0.7 g, 2.55 mmol)
and 0.01 ml concentrated sulfuric acid in 5 ml of glacial acetic acid
was refluxed for 4 h, the reaction mixture was then cooled and
poured slowly with stirring into an ice-cold solution of 5 ml concen-
trated ammonium hydroxide in 15 ml of water. The resultant
suspension was allowed to stand in an ice bath until the initially oily
precipitate had hardened; the crude product was collected and then
purified by plate chromatography using chloroform–ethyl acetate
(95:5 v/v). Yield: 10% (95 mg); cream crystalline powder; mp:
5.5. Synthesis of 2-(4-(methylsulfonyl)phenyl)-3-phenylquin-
oline-4-carboxylic acid (8)
Isatin (0.7 g, 4.32 mmol) was added in 25 ml ethanol and
heated, then 14.2 mmol of 33% potassium hydroxide was added
to the solution and heated for 15 min. After this time, 2-(4-
(methyl sulfonylphenyl)-1-phenylethanone (1.3 g, 4.74 mmol)
was added and refluxed for 48 h. After evaporation of ethanol,
the precipitate was acidified with acetic acid 10% and washed
with ethanol and hexane. Yield: 70% (1.3 g); white crystalline
129–130 °C; IR (KBr):
m
(cmÀ1) 1310, 1160 (SO2), 1HNMR (CDCl3): d
(ppm) 2.57 (s, 3H, Me), 2.97 (s, 3H, SO2Me), 7.09–7.11 (m, 2H, phenyl
H2 and H6), 7.27–7.32 (m, 3H, phenyl H3–H5), 7.52 (d, 2H, 4-meth-
ylsulfonylphenyl H2 and H6, J = 8.2 Hz), 7.65 (t, 1H, quinoline H6,
J = 7.5 Hz), 7.64–7.67 (m, 3H, 4-methylsulfonylphenyl H3 and H5
and quinoline H7), 8.11 (d, 1H, quinoline H5, J = 8.4 Hz), 8.18 (d, 1H,
quinoline H8, J = 8.4 Hz); MS m/z (%): 373.2 (M+, 10), 372.1 (100),
293.2 (45), 278.2 (15), 145.7 (25), 78.9 (18); Anal. Calcd for
C23H19NO2S: C, 62.37; H, 4.00; N, 4.28. Found: C, 62.42; H, 3.71; N,
4.39.
powder; mp: 310–311 °C; IR (KBr):
m
(cmÀ1) 3100–2700 (OH),
1730 (C@O), 1320, 1155 (SO2); 1HNMR (DMSO-d6): d (ppm) 3.21
(s, 3H, SO2Me), 7.25–7.29 (m, 2H, phenyl H2 and H6), 7.31–7.36
(m, 3H, phenyl H3–H5), 7.59 (d, 2H, 4-methylsulfonylphenyl H2
and H6, J = 8.4 Hz), 7.78–7.81 (m, 3H, 4-methylsulfonylphenyl H3
and H5 and quinoline H7), 7.91–7.94 (m, 2H, quinoline H6 and
H8), 8.18 (d, 1H, quinoline H5, J = 8.3 Hz), 13.93 (s, 1H, COOH);
LC–MS (ESI) m/z : 404.2 (M+1), 425.1 (M+23); Anal. Calcd for
C23H17NO4S: C, 69.88; H, 4.89; N, 4.53. Found: C, 69.62; H, 4.54;
N, 4.32.
5.3. Synthesis of 3,4-diphenyl-2-(4-methylsulfonyl)phenyl)-
quinoline (6)
A solution of 2-aminobenzophenone 0.72 g, 3.65 mmol) and 2-
(4-(methylsulfonyl)phenyl)-1-phenyl ethanone (1 g, 3.65 mmol)

R. Ghodsi et al. / Bioorg. Med. Chem. 18 (2010) 1029–1033
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13. Mason, R. P.; Walter, M. F.; McNulty, H. P.; Lockwood, S. F.; Byun, J.; Day, C. A.;
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Docking studies were performed using Autodock software ver-
sion 3.0.5. The coordinates of the X-ray crystal structure of the selec-
tive COX-2inhibitorSC-558bound tothemurineCOX-2enzymewas
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 Å. The energy minimized li-
gands 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 ri-
gid protein. Protein residues with atoms greater than 7.5 Å from the
docking box were removed for efficiency. 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.22,23
7. 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 (Cayman Chemical, Ann Ar-
bor, MI, USA) according to our previously reported method.21
17. Chaudhuri, M. K.; Hussain, S. J. Chem. Sci. 2006, 118, 199.
18. Fehnel, E. A. J. Org. Chem. 1965, 31, 2899.
19. Camps, P.; Gomez, E.; Munz-Torrero, D.; Arno, M. Tetrahedron: Asymmetry
2001, 12, 2909.
Acknowledgment
20. Mueller, G. P.; Stobaugh, R. E. J. Am. Chem. Soc. 1950, 72, 1598.
21. Zarghi, A.; Najafnia, L.; Daraee, B.; Dadrass, O. G.; Hedayati, M. Bioorg. Med.
Chem. Lett. 2007, 17, 5634.
22. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart, W. E.; Belew, R. K.;
Olson, A. J. Comput. Chem. 1998, 19, 1639.
23. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.;
Pak, J. Y.; Gildehaus, D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson, P.
C.; Stallings, W. C. Nature 1996, 384, 644.
We are grateful to Research deputy of Shahid Beheshti Univer-
sity (M.C.) for financial support of this research.
References and notes
1. Smith, W. L.; DeWitt, D. L. Adv. Immunol. 1996, 62, 167.