Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives as cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2009.05.084

A group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activity relationships were

Full text of DOI:10.1016/j.bmc.2009.05.084

Bioorganic & Medicinal Chemistry 17 (2009) 5312–5317
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and biological evaluation of new 4-carboxyl quinoline derivatives
as cyclooxygenase-2 inhibitors
a
b
c
d
e
Afshin Zarghi a, , Razieh Ghodsi , Ebrahim Azizi , Bahram Daraie , Mehdi Hedayati , Orkideh G. Dadrass
*
a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran
b Department of Toxicology, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
c Department of Toxicology, Tarbiat Modarres University, Tehran, Iran
d Endocrine Research Center, Shahid Beheshti University (M.C), Tehran, Iran
e Department of Pharmaceutical Chemistry, School of Pharmacy, Azad University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A group of 4-carboxyl quinoline derivatives possessing a methylsulfonyl COX-2 pharmacophore at the
para position of the C-2 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro
COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-7
and C-8 quinoline ring. Among the 4-carboxyl quinolines, 7,8,9,10-tetrahydro-2-(4-(methyl sulfo-
nyl)phenyl)benzo[h]quinoline-4-carboxylic acid (9e) was identified as potent and high selective COX-2
Received 13 April 2009
Revised 3 May 2009
Accepted 5 May 2009
Available online 12 June 2009
inhibitor (COX-2 IC50 = 0.043
celecoxib (COX-2 IC50 = 0.060
binding site of COX-2 showed that the p-MeSO2 substituent on the C-2 phenyl ring is oriented in the
vicinity of the COX-2 secondary pocket (Arg513, Phe518 and Val523) and the carboxyl group can interact
with Arg120. The structure activity data acquired indicate that the presence of lipophilic substituents on
the C-7 and C-8 quinoline ring is important for COX-2 inhibitory activity.
l
l
M; selectivity index > 513) that was more potent than the reference drug
M; SI = 405). A molecular modeling study where 9e was docked in the
Keywords:
Cyclooxygenase-2 inhibition
4-Carboxyl quinolines
SAR
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
desired selectivity. The coxibs (e.g., celecoxib and rofecoxib,
Fig. 1)9,10 for treating pain and inflammation associated with
The clinical use of traditional nonsteroidal anti-inflammatory
drugs (NSAIDs) such as ibuprofen and naproxen for the treatment
of inflammation and pain is often accompanied by adverse gastro-
intestinal (GI) effects. Their anti-inflammatory activity is due to
inhibition of cyclooxygenases (COXs), which catalyze the biocon-
version of arachidonic acid to inflammatory prostaglandins
(PGs).1,2 COX is a membrane-bound heme protein which exists at
least in two isoforms, a constitutive form (COX-1) and an inducible
form (COX-2). The COX-1 enzyme is responsible for maintaining
homeostasis whereas COX-2 induces inflammatory conditions. Be-
cause COX-1 is involved in the maintenance of the GI tract, NSAIDs
which are inhibitors of both COX-1 and COX-2 have been found to
cause side effects associated with GI ulcers.3–5 Thus it was though
that more selective COX-2 inhibitors would have reduced side ef-
fects. Moreover, recent studies indicating the place of COX-2 inhib-
itors in cancer chemotherapy6 and neurological diseases such as
Parkinson7 and Alzheimer’s8 diseases still continues to attract
investigations on development of COX-2 inhibitors. Research at-
tempts in the discovery of selective COX-2 inhibitors have pro-
duced many classes of compounds such as coxibs possessing
arthritis have been shown to be well tolerated and reduced GI side
effects. All coxibs possess 1,2-diarylsubstitution on a central hetero
or carbocyclic ring system with a characteristic sulfonyl group on
one of the aryl rings that plays a crucial role on COX-2 selectivity.11
The recent market withdrawal of some coxibs such as rofecoxib
and valdecoxib due to their adverse cardiovascular side effects12,13
clearly delineates the need to explore and evaluate alternative
templates with COX-2 inhibitory activity. In addition, some 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.14 For this reason novel scaffolds with high selectivity
for COX-2 inhibition need to be found and evaluated for their anti-
inflammatory effects. Recently, we reported several investigations
describing the design, synthesis and a molecular modeling study
for a group of 2-phenyl-1H-indoles possessing a methylsulfonyl
COX-2 pharmacophore at the para-position of phenyl ring in con-
junction with an 1H-indole ring having different substituents at
C-5 position.15 For example, 5-methoxy-2-(4-(methylsulfonyl)
phenyl)-1H-indole (see structure 1 in Fig. 1) exhibited high selec-
tive COX-2 inhibition (COX-2 IC50 = 0.080 lM; SI = 291.2). On the
other hand, it is well known that the carboxyl group of NSAIDs
has a key role for binding to COX enzyme through interaction with
Arg120 of active site.16 Accordingly, we now describe the synthesis
* Corresponding author. Tel.: +98 21 8820096; fax: +98 21 88665341.
E-mail address: azarghi@yahoo.com (A. Zarghi).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.05.084

A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5312–5317
5313
Figure 1. Some representative examples of COXIBs (celecoxib and rofecoxib), NSAIDs (ibuprofen and naproxen), 2-phenyl-1H-indole lead compound and our quinoline
scaffolds.
and biological evaluation of a group of 4-carboxyl quinoline deriv-
atives possessing a methylsulfonyl COX-2 pharmacophore at the
para position of the C-2 phenyl ring in conjunction with various
substituents at C-7 and C-8 quinoline ring. In these designed com-
pounds we utilized certain feature from NSAIDs such as aryl car-
boxylic acid fragment in ibuprofen and naproxen, and quinoline
ring instead of 1H-indole ring in the our previously reported
COX-2 inhibitors.
with isatin 3 in alkaline ethanol to provide 4 (yield: 43%). The pur-
ity of all products was determined by thin layer chromatography
using several solvent systems of different polarity. All compounds
were pure and stable. The compounds were characterized by 1H
nuclear magnetic resonance, infrared, mass spectrometry and
CHN analysis.
3. Results and discussion
2. Chemistry
A group of 4-carboxyl quinolines (4, 9a–e), possessing a para-
methylsulfonyl substituent on the C-2 phenyl ring were synthe-
sized. In this study, the different substituents on the C-7 and C-8
quinoline ring were varied to determine the combined effects of
steric and lipophilic substituent properties upon COX-1 and
COX-2 inhibitory potency and selectivity. SAR data (IC50 values)
acquired by determination of the in vitro ability of the title com-
pounds to inhibit the COX-1 and COX-2 isozymes showed that
the COX inhibition was sensitive to the lipophilic nature of substit-
uents. As shown in Table 1, our results showed that the increase of
lipophilic properties of substituents on the C-7 and C-8 quinoline
ring increased COX-2 inhibitory potency and selectivity. The rela-
tive COX-2 potency, and COX-2 selectivity profiles for the 4-car-
boxyl quinoline derivatives, with respect to the C-7 and C-8
substituents was 9e > 9d > 9c > 9b > 9a > 4. Accordingly, com-
pound 9c showed less selectivity and potency for COX-2 isozyme
compared with compounds 9d that may be also explained by steric
A one-step Doebner reaction was used to prepare the target
2-(4-(methylsulfonyl)phenyl)-7,8-substituted-quinoline-4-carbox-
ylic acid derivatives 9a–e. As illustrated in Scheme 1, 4-(methyl-
thio) benzaldehyde 5, pyruvic acid 6 and an appropriate amine 7
were heated in ethanol to provide 4-carboxy quinolines 8a–e
(16–27%)17 and then oxidation of the methylthio substituent to a
methylsulfonyl substituent was carried out using OxoneÒ.18 How-
ever, the well known Doebner-type synthesis of quinolines did not
yield the expected 2-(4-(methylthio)phenyl)-quinoline-4-carbox-
ylic acid which is required for preparation of 2-(4-(methylsulfo-
nyl)phenyl)-quinoline-4-carboxylic acid 4. This result was
agreement to similar previously reported works19 in which aniline
was used as amine in Doebner reaction. Therefore, the desired
quinoline derivative 4 was prepared using Pfitzinger reaction.20
Accordingly, 4-(methylsulfonyl)acetophenone 221 was reacted

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A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5312–5317
O
COOH
O
O
a
N
MeO2S
N
H
2
3
4
SO2Me
O
COOH
O
H
OH
R2
NH 2
b
R2
N
R1
MeS
O
R1
5
6
7
SMe
8a, R1=Me; R 2=H
8b, R1=Me; R 2=Me
8c, R1=Phenyl; R 2=H
8d, R1&R2=Phenyl
COOH
N
8e, R1&R2 =Cyclohexyl
c
R2
R1
SO 2Me
9a, R1=Me; R2=H
9b, R1=Me; R2=Me
9c, R1=Phenyl; R2 =H
9d, R1&R 2=Phenyl
9e, R1&R 2=Cyclohexyl
Scheme 1. Reagents and conditions: (a) EtOH, 33% KOH, reflux, 48 h; (b) EtOH, reflux, 12 h; (c) oxone, THF/H2O, 25 °C, 12 h.
Table 1
It has been reported that replacement of His513 in COX-1 by
Arg513 in COX-2 plays a key role in the hydrogen-bond network
of the COX-2 binding site. Access of ligands to the secondary
In vitro COX-1 and COX-2 enzyme inhibition assay data for 4-carboxyl quinoline
derivatives 6a–f
COOH
R2
N
R1
SO2Me
a
Compound
R1
H
Me
Me
R2
IC50
COX-1
(lM)
Selectivity index (SI)b
COX-2
4
9a
9b
9c
9d
9e
Celecoxib
H
H
Me
H
13.4
14.2
14.5
14.7
17.6
22.1
24.3
0.091
0.086
0.075
0.071
0.054
0.043
0.060
147.2
165.1
193.3
207.0
325.9
513.9
405
phenyl
Phenyl
Cyclohexyl
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).
parameter. However, among the 4-carboxyl quinoline derivatives,
compound 9e possessing an unsaturated cyclohexyl ring attached
to C-7 and C-8 quinoline ring exhibited highest COX-2 inhibitory
potency and selectivity (COX-2 IC50 = 0.043
was more potent than the reference drug celecoxib (COX-2
IC50 = 0.060 M; SI = 405).
lM; SI > 513) that
Figure 2. Docking7,8,9,10-tetrahydro-2-(4-(methylsulfonyl)phenyl)benzo[h]quin-
oline-4-carboxylic acid (9e) in the active site of murine COX-2. Hydrogen atoms of the
amino acid residues have been removed to improve clarity.
l

A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5312–5317
5315
pocket of COX-2 and interaction of Arg513 with the bound drug is a
requirement for time-dependent inhibition of COX-2.22 The bind-
ing interactions of the most potent and selective COX-2 inhibitor
compound (9e) within the COX-2 binding site were investigated.
The most stable enzyme–ligand complex of 7,8,9,10-tetrahydro-
2-(4-(methylsulfonyl) phenyl) benzo[h] quinoline-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 sec-
ondary pocket (Val523, Phe518 and Arg513). One of the O-atoms
of p-MeSO2 substituent forms a hydrogen binding interaction with
amino group of Arg513 (distance = 3.9 Å) whereas the other
O-atom is about 5.1 Å away from NH2 of this amino acid. In
addition, a hydrogen bonding interaction may form between the
nitrogen atom of quinoline ring and NH of Ala527 (distance < 6 Å).
Also, the carboxylic group of the quinoline ring is very close to
amino group of Arg120 (distance < 5 Å) which can explain the high
potency of compound 9e. These observations together with exper-
imental results provide a good explanation for design of potent and
selective COX-2 inhibitors possessing 4-carboxyl quinoline
framework.
4-methylsulfonylphenyl H3 and H5, J = 8.4 Hz), 8.63 (d, 1H, quino-
line H5, J = 8.4 Hz), 13.77 (s, 1H, COOH); MS: m/z (%) 327.6 (M+,
100), 249.0 (80), 202.2 (30), 191.8 (20), 127.9 (10). Anal. Calcd
for C17H13NO4S: C, 62.37; H, 4.00; N, 4.28. Found: C, 62.42; H,
3.71; N, 4.39.
5.2. General procedure for preparation of 2-(4-
(methylthio)phenyl)-7,8-substituted-quinoline-4-carboxylic
acid (8a–e)
A solution of 4-(methylthio)benzaldehyde 5 (1.44 g, 9.45 mmol)
and pyrrovic acid 6 (1.26 g, 14.3 mmol) in ethanol (5 ml) was
heated for 15 min, then an appropriate amine 7 (9.45 mmol) was
added and the mixture was refluxed overnight. After cooling, the
produced precipitate was filtered and washed with ethanol, ben-
zene and hexane and recrystallized in methanol (yields: 16–27%).
The physical and spectral data for 8a–e are listed below.
5.2.1. 8-Methyl-2-(4-(methylthio)phenyl)quinoline-4-
carboxylic acid (8a)
Yield: 16%; cream crystalline powder; mp = 217–219 °C; IR
(KBr):
m
(cmÀ1) 3300–2400 (OH), 1700 (C@O); 1H NMR (DMSO-
d6): d ppm 2.52 (s, 3H, SCH3), 2.79 (s, 3H, CH3), 7.40 (d, 2H, 4-meth-
ylthiophenyl H3 and H5, J = 8.5 Hz), 7.51 (m, 1H, quinoline H6), 7.65
(d, 1H, quinoline H7, J = 6.9 Hz), 8.25 (d, 2H, 4-methylthiophenyl H2
and H6, J = 8.5 Hz), 8.38 (m, 2H, quinoline H3 and H5), 13.95 (s, 1H,
COOH); Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53.
Found: C, 69.62; H, 4.54; N, 4.32.
4. Conclusions
This study indicates that (i) the 4-carboxyl quinoline moiety is a
suitable scaffold (template) to design COX-1/-2 inhibitors, (ii) in
this class of compounds COX-1/-2 inhibition is sensitive to the lipo-
philic nature of the C-7 and C-8 quinoline substituents, and (iii)
7,8,9,10-tetrahydro-2-(4-(methylsulfonyl)phenyl)benzo[h] quino-
line-4-carboxylic acid (9e) exhibited high COX-2 inhibitory potency
and selectivity.
5.2.2. 7,8-Dimethyl-2-(4-(methylthio)phenyl)quinoline-4-
carboxylic acid (8b)
Yield: 27%; pale yellow crystalline powder; mp = 269–270 °C; IR
(KBr):
m
(cmÀ1) 3220–2360 (OH), 1700 (C@O); 1H NMR (DMSO-d6):
5. Experimental
d ppm 2.44 (s, 3H, C7–CH3), 2.51 (s, 3H, SCH3), 2.73 (s, 3H, C8–CH3),
7.38 (d, 2H, 4-methylthiophenyl H3 and H5, J = 8.5 Hz), 7.43 (d, 1H,
quinoline H6, J = 8.7 Hz), 8.23 (d, 2H, 4-methylthiophenyl H2 and
H6, J = 8.5 Hz), 8.30 (m, 2H, quinoline H3 and H5), 13.79 (s, 1H,
COOH); Anal. Calcd for C19H17NO2S: C, 70.56; H, 5.30; N, 4.33.
Found: C, 70.22; H, 5.66; N, 4.11.
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 1H NMR 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),
and br (broad). Low-resolution mass spectra were acquired with a
MAT CH5/DF (Finnigan) mass spectrometer that was coupled on-
line to a Data General DS 50 data system. Electron-impact ioniza-
tion was performed at an ionizing energy of 70 eV with a source
temperature of 250 °C. Microanalyses, determined for C and H,
were within 0.4% of theoretical values.
5.2.3. 2-(4-(Methylthio)phenyl)-8-phenyl-quinoline-4-
carboxylic acid (8c)
Yield: 16%; yellow crystalline powder; mp = 259–260 °C; IR
(KBr):
m
(cmÀ1) 3345–2500 (OH), 1700 (C@O); 1H NMR (DMSO-
d6): d ppm 2.49 (s, 3H, SCH3), 7.34 (d, 2H, 4-methylthiophenyl H3
and H5, J = 8.4 Hz), 7.42 (t, 1H, quinoline H6, J = 7.4), 7.50 (d, 2H,
phenyl H2 and H6, J = 7.5 Hz), 7.72 (m, 3H, phenyl H3–H5), 7.82
(d, 1H, quinoline H7, J = 6.8, CH2), 8.10 (d, 2H, 4-methylthiophenyl
H2 and H6, J = 8.4 Hz), 8.42 (s, 1H, quinoline H3), 8.56 (d, 1H, quin-
oline H5, J = 8.2 Hz), 13.96 (s, 1H, COOH); Anal. Calcd for
C23H17NO2S: C, 74.37; H, 4.61; N, 3.77. Found: C, 74.65; H, 4.27;
N, 3.61.
5.1. Preparation of 2-(4-(methylsulfonyl)phenyl)-quinoline-4-
carboxylic acid (4)
A mixture of 0.37 g (2.5 mmol) of isatin 2, 10 ml of 33% potas-
sium hydroxide in diluted alcohol solution, and 0.5 g (2.5 mmol)
of 4-(methylsulfonyl) acetophenone 3 were stirred and heated un-
der reflux for 48 h. After evaporation of solvent, the residue was
acidified with acetic acid 10% and filtered. The precipitated product
was washed with acetic acid 10%, ethanol and hexane and crystal-
lized in methanol. Yield: 43%; cream crystalline powder;
5.2.4. 2-(4-(Methylthio)phenyl)benzo[h]quinoline-4-carboxylic
acid (8d)
Yield: 17%; orange crystalline powder; mp: 275–276 °C; IR
(KBr):
m
(cmÀ1) 3300–2800 (OH), 1700 (C@O), 1H NMR (DMSO-
d6): d ppm 2.54 (s, 3H, SCH3), 7.44 (d, 2H, 4-methylthiophenyl H3
and H5, J = 8.5 Hz), 7.76-7.79 (m, 2H, benzoquinoline H8 and H9),
7.99 (d, 1H, benzoquinoline H7, J = 9.2 Hz), 8.02 (d, 1H, benzoquin-
oline H6, J = 8.9 Hz), 8.37 (d, 2H, 4-methylthiophenyl H2 and H6,
J = 8.5 Hz), 8.47 (d, 1H, benzoquinoline H10, J = 9.1 Hz), 8.5 (s, 1H,
benzoquinoline H3), 9.34 (d, 1H, benzoquinoline H5, J = 9.2 Hz),
13.98 (s, 1H, COOH); Anal. Calcd for C21H15NO2S: C, 73.02; H,
4.38; N, 4.05. Found: C, 73.36; H, 4.71; N, 3.81.
mp = 320 °C; IR (KBr):
m
(cmÀ1) 3360–2700 (OH), 1710 (C@O),
1310,1160 (SO2); 1H NMR (DMSO-d6): d ppm 3.26 (s, 3H, SO2Me),
7.72 (t, 1H, quinoline H6), 7.86 (t, 1H, quinoline H7), 8.07 (d, 2H,
4-methylsulfonyl phenyl H2 and H6, J = 8.4 Hz), 8.16 (d, 1H,
quinoline H8, J = 8.3 Hz), 8.50 (s, 1H, quinoline H3), 8.52 (d, 2H,

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A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5312–5317
5.2.5. 7,8,9,10-Tetrahydro-2-(4-(methylthio)phenyl)benzo
[h]quinoline-4-carboxylic acid (8e)
5.3.4. 2-(4-(Methylsulfonyl)phenyl)benzo[h]quinoline-4-
carboxylic acid (9d)
Yield: 27%; cream crystalline powder; mp = 249–251 °C; IR
Yield: 64%; yellow crystalline powder; mp: 270–271 °C; IR
(KBr):
m
(cmÀ1) 3320–2850 (OH), 1695 (C@O), 1H NMR (DMSO-
(KBr): m
(cmÀ1) 3330–2500 (OH), 1725 (C@O), 1310, 1150 (SO2);
d6): d ppm 1.79–1.86 (m, 4H, CH2), 2.5 (s, 3H, SCH3), 2.85 (m, 2H,
CH2), 3.28 (m, 2H, CH2), 7.31 (d, 1H, tetrahydrobenzoquinoline
H6, J = 8.8 Hz), 7.36–7.38 (d, 2H, 4-methylthiophenyl H3 and H5,
J = 8.5 Hz), 8.21 (d, 2H, 4-methylthiophenyl H2 and H6, J = 8.5 Hz),
8.27 (d, 1H, tetrahydrobenzoquinoline H5, J = 8.8 Hz), 8.31 (s, 1H,
tetrahydrobenzoquinoline H3), 13.78 (s, 1H, COOH); Anal. Calcd
for C21H19NO2S: C, 72.18; H, 5.48; N, 4.01. Found: C, 72.40; H,
5.75; N, 3.84.
1H NMR (DMSO-d6): d ppm 3.32 (s, 3H, SO2Me), 7.83–7.86 (m,
2H, benzoquinoline H8 and H9), 8.09 (d, 2H, benzoquinoline H7
and H10, J = 9.1 Hz), 8.15 (d, 2H, 4-methyltsulfonylphenyl H2 and
H6, J = 8.5 Hz), 8.55 (d, 1H, benzoquinoline H6, J = 9.2 Hz), 8.67 (s,
1H, benzoquinoline H3), 8.71 (d, 2H, 4-methylsulfonylphenyl H3
and H5, J = 8.5 Hz), 9.40 (d, 1H, benzoquinoline H5, J = 7.9 Hz),
14.05 (s, 1H, COOH); MS m/z (%): 377.8 (M+, 100), 298.9 (50),
253.8 (25), 242.0 (20), 152.0 (10); Anal. Calcd for C21H15NO4S: C,
66.83; H, 4.01; N, 3.71. Found: C, 66.56; H, 4.31; N, 3.82.
5.3. General procedure for preparation of 2-(4-
(methylsulfonyl)phenyl)-7,8-substituted-quinoline-4-
carboxylic acid (9a–e)
5.3.5. 7,8,9,10-Tetrahydro-2-(4-(methylsulfonyl)phenyl)benzo
[h]quinoline-4-carboxylic acid (9e)
Yield: 89%; cream crystalline powder; mp = 277–278 °C; IR
(KBr):
m
(cmÀ1) 3230–2670 (OH), 1715 (C@O), 1300, 1140 (SO2);
One gram of 2-(4-(methylthio)phenyl)-7,8-substituted quino-
line-4-carboxylic acid 8a–e dissolved in 10 ml of THF and 5 g ox-
one in THF/water (20 ml) was added. The mixture was stirred at
room temperature overnight. After evaporation of THF, the residue
was extracted with ethyl acetate and dried with sodium sulfate
and then evaporated, the product was recrystallized in ethanol
(yields: 40–89%). The physical and spectral data for 9a–e are listed
below.
1H NMR (DMSO-d6): d ppm 1.80–1.87 (m, 4H, CH2), 2.87 (m, 2H,
CH2), 3.25 (s, 3H, SO2 Me), 3.30 (m, 2H, CH2), 7.37 (d, 1H, tetra-
hydrobenzoquinoline H6, J = 8.8 Hz), 8.05 (d, 2H, 4-methylsulfonyl-
phenyl H2 and H6, J = 8.3 Hz), 8.32 (d, 1H, tetrahydrobenzoquino-
line H5, J = 8.7 Hz), 8.42 (s, 1H, tetrahydrobenzoquinoline H3)
8.51 (d, 2H, 4-methylsulfonylphenyl H3 and H5, J = 8.3 Hz), 13.77
(s, 1H, COOH); MS m/z (%): 382.1 (M+, 100), 366.9 (20), 302 (20),
287.5 (20), 229.2 (10); Anal. Calcd for C21H19NO4S: C, 66.12; H,
5.02; N, 3.67. Found: C, 66.42; H, 4.75; N, 3.54.
5.3.1. 8-Methyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-
carboxylic acid (9a)
Yield: 69%; cream crystalline powder; mp = 262 °C; IR (KBr):
m
6. Molecular modeling (docking) studies
(cmÀ1) 3370–2480 (OH), 1690 (C@O), 1300, 1150 (SO2); 1H NMR
(DMSO-d6): d ppm 2.80 (s, 3H, CH3), 3.26 (s, 3H, SO2Me), 7.58 (t,
1H, quinoline H6), 7.71 (d, 1H, quinoline H7, J = 6.8 Hz), 8.07 (d,
2H, 4-methylsulfonylphenyl H2 and H6, J = 8.5 Hz), 8.43 (d, 1H,
quinoline H5, J = 8.5 Hz), 8.49 (s, 1H, quinoline H3), 8.54 (d, 2H, 4-
methylsulfonyl phenyl H3 and H5, J = 8.5 Hz), 13.96 (s, 1H, COOH);
MS: m/z (%) 341.6 (M+, 100), 261.9 (30), 217.0 (20); Anal. Calcd for
C18H15NO4S: C, 63.33; H, 4.43; N, 4.10. Found: C, 63.62; H, 4.70; N,
4.31.
Docking studies were performed using AUTODOCK software Ver-
sion 3.0.5. The coordinates of the X-ray crystal structure of the
selective COX-2 inhibitor SC-558 bound to the murine COX-2 en-
zyme 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 Å. 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
greater than 7.5 Å from the docking box were removed for effi-
ciency. These docked structures were very similar to the mini-
mized structures obtained initially. The quality of the docked
structures was evaluated by measuring the intermolecular energy
of the ligand–enzyme assembly.23,24
5.3.2. 7,8-Dimethyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-
carboxylic acid (9b)
Yield: 83%; cream crystalline powder; mp = 266–267 °C; IR
(KBr):
m
(cmÀ1) 3220–2370 (OH), 1700 (C@O), 1300, 1140 (SO2);
1H NMR (DMSO-d6): d ppm 2.76 (s, 3H, quinoline, C7–CH3), 3.26
(s, 6H, SO2Me and C8–CH3), 7.51 (d, 1H, quinoline H6, J = 8.7 Hz),
8.06 (d, 2H, 4-methylsulfonylphenyl H2 and H6, J = 8.5 Hz), 8.33
(d, 1H, quinoline H5, J = 8.8 Hz), 8.42 (s, 1H, quinoline H3), 8.53
(d, 2H, 4-methylsulfonyl phenyl H3 and H5, J = 8.5 Hz), 13.95 (s,
1H, COOH); MS: m/z (%) 355.7 (M+, 100), 277.1 (20), 230.9 (20);
Anal. Calcd for C19H17NO4S: C, 64.21; H, 4.82; N, 3.94. Found: C,
64.52; H, 4.50; N, 4.21.
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.25
5.3.3. 2-(4-(Methylsulfonyl)phenyl)-8-phenyl-quinoline-4-
carboxylic acid (9c)
Yield: 40%; yellow crystalline powder; mp = 272–273 °C; IR
(KBr):
Acknowledgment
m
(cmÀ1) 3250–2380 (OH), 1680 (C@O), 1300, 1140 (SO2),
1H NMR (DMSO-d6): d ppm 3.23 (s, 3H, SO2Me), 7.43–7.50 (m,
3H, phenyl H3–H5), 7.72 (d, 2H, phenyl H2 and H6, J = 7.5 Hz),
7.78 (t, 1H, quinoline H6), 7.88 (d, 1H, quinoline H7, J = 7.1 Hz),
8.01 (d, 2H, 4-methylsulfonylphenyl H2 and H6, J = 8.4 Hz), 8.39
(d, 2H, 4-methylsulfonylphenyl H3 and H5, J = 8.4 Hz), 8.45 (s, 1H,
quinoline H3), 8.61 (d, 1H, quinoline H5, J = 8.4 Hz), 14.08 (s, 1H,
COOH); MS m/z (%): 403.3 (M+, 100), 323.1 (60), 278.1(20), 201.9
(10), 139.3 (10), 83.5 (20); Anal. Calcd for C23H17NO4S: C, 68.47;
H, 4.25; N, 3.47. Found: C, 68.66; H, 4.30; N, 3.21.
We are grateful to Research deputy of Shahid Beheshti Univer-
sity (M.C.) for financial support of this research.
References and notes
1. Vane, J. R. Nat. New Biol. 1971, 231, 232.
2. Vane, J. R.; Botting, R. M. Inflamm. Res. 1998, 47, S78.
3. Perini, R.; Fiorucci, R.; Wallace, J. L. Can. J. Gastroenterol. 2004, 18, 229.
4. Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Ann. Rev. Pharmacol. Toxicol. 1998, 38,
9704.

A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5312–5317
5317
5. Radi, Z. A.; Khan, N. K. Exp. Toxicol. Pathol. 2006, 58, 163.
14. Mason, R. P.; Walter, M. F.; McNulty, H. P.; Lockwood, S. F.; Byun, J.; Day, C. A.;
Jacob, R. F. J. Cardivasc. Pharmacol. 2006, 47, S7.
15. Zarghi, A.; Tahghighi, A.; Soleimani, Z.; Daraei, B.; Dadrass, O. G.; Hedayati, M.
Sci. Pharm. 2008, 76, 361.
16. Llorens, O.; Perez, J. J.; Palomer, A.; Mauleon, D. J. Mol. Graphics Modell. 2002, 20,
359.
17. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1989, 32, 396.
18. Zarghi, A.; Arfaee, S.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem. 2006, 14,
2600.
19. Anreichikov, Y. S.; Gein, V. L.; Anikina, I. N. Zh. Org. Khim. 1988, 24, 875.
20. Mueller, G. P.; Stobaugh, R. E. J. Am. Chem. Soc. 1950, 72, 1598.
21. Therien, M.; Gauthier, J. Y.; Leblanc, Y.; Leger, S.; Perrier, H.; Prasit, P.; Wang, Z.
Synthesis 2001, 12, 1778.
22. Garavito, R. M.; DeWitt, D. L. Biochim. Biophys. Acta 1999, 1441, 278.
23. 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.
24. 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.
6. Aparicio Gallego, G.; Diaz Prado, S.; Jimenez Fonceca, P.; Garcia Campelo, R.;
Cassinello Epinosa, J.; Anton Aparicio, L. M. Clin. Trans. Oncol. 2007, 9, 3305.
7. Van Gool, W. A.; Aisen, P. S.; Eikelenboom, P. J. Neurol. 2003, 250, 788.
8. Aisen, P. S.; Schafer, K. A.; Grundman, M.; Pfeiffer, E.; Sano, M.; Davis, K. I.;
Farlow, M. R.; Jin, S.; Thomas, R. G.; Thal, L. J. JAMA 2003, 289, 2819.
9. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt,
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J.
Med. Chem. 1997, 40, 1347.
10. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson, S.; Cromlish, W.; Ethier,
D.; Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.;
Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill,
G. P.; Quellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
Therien, M.; Vickers, P.; Wong, E.; Xu, L. J.; Young, R. N.; Zamboni, R.; Boyce, S.;
Rupniak, N.; Forrest, M.; Visco, D.; Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9,
1773.
11. Dannhardt, G.; Kiefer, W. Eur. J. Med. Chem. 2001, 36, 109.
12. Dogné, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem. 2005, 48, 2251.
13. Solomon, D. H. Arthritis Rheum. 2005, 52, 1968.
25. Zarghi, A.; Najafnia, L.; Daraee, B.; Dadrass, O. G.; Hedayati, M. Bioorg. Med.
Chem. Lett. 2007, 17, 5634.