Design, synthesis and biological evaluation of new (E)- and (Z)-1,2,3-triaryl-2-propen-1-ones as selective COX-2 inhibitors

Article abstract of DOI:10.1016/j.ejmech.2010.05.058

A group of (E)-and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure-activi

Full text of DOI:10.1016/j.ejmech.2010.05.058

European Journal of Medicinal Chemistry 45 (2010) 4013e4017
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and biological evaluation of new (E)- and
(Z)-1,2,3-triaryl-2-propen-1-ones as selective COX-2 inhibitors
*
Sara Arfaie, Afshin Zarghi
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, 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 (E)-and (Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2
pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective
COX-2 inhibitors. In vitro COX-1/COX-2 structureeactivity relationships were determined by varying the
substituents on the C-3 propenone moiety. Among the 1,2,3-triaryl-2-propen-1-ones, (Z)-1-(4-(meth-
ylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one (3b) showed the most potency and selectivity on COX-2
Received 27 January 2010
Received in revised form
23 May 2010
Accepted 26 May 2010
Available online 2 June 2010
inhibition (COX-2 IC50 ¼ 0.07 M; selectivity index ¼ 201). The Z-propenones were also found to be more
m
potent and selective than their E-isomers for COX-2 inhibitory activity. The structureeactivity data
acquired indicate that the geometry of propenone and also the type of substituents on the C-3 propenone
are important for COX-2 inhibitory activity.
Keywords:
Cyclooxygenase-2 inhibition
1,2,3-Triaryl-2-propen-1-ones
Synthesis
Ó 2010 Elsevier Masson SAS. All rights reserved.
Selectivity
1. Introduction
Because of their non-specific inhibition of both COX isoforms,
classical NSAIDs reduce the production of proinflammatory PGs at
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the
most widely used therapeutics. Through their anti-inflammatory,
anti-pyretic and analgesic activities, they represent a choice of
treatment in various inflammatory diseases such as arthritis,
rheumatisms as well as to relieve the pains of everyday life [1].
Despite the wide use of NSAIDs over the last century, their mech-
anism of action was not fully understood until 1971 when Vane
identified their molecular target, the COX enzyme [2]. In the early
1990s, a second isoform (COX-2) was discovered, distinct from the
first one, then renamed COX-1 [3]. COX-1 is expressed constitu-
tively in many tissues and PGs produced by COX-1 mediate the
“housekeeping” functions such as cytoprotection of gastric mucosa,
regulation of renal blood flow and platelet aggregation. In contrast,
COX-2 is not detected in most normal tissues, but its expression is
rapidly induced by stimuli such as proinflammatory cytokines,
lipopolysaccharides, mitogenes and oncogenes, growth factors,
hormones and disorders of water-electrolyte hemostasis, resulting
in increased synthesis of PGs in inflamed and neoplastic tissues.
Thus the inducible isozyme has been implicated in pathological
processes such as inflammation and various cancer types [4,5].
sites of injury (via COX-2 inhibition) but also the formation of
physiological PGs in the stomach and the kidney (via COX-1 inhi-
bition). These observations provided a rationale for the develop-
ment of COX-2 selective inhibitors that should retain the potent
anti-inflammatory and analgesic effects of classical NSAIDs with
less GI adverse effects [6]. In addition to role of COX-2 in rheuma-
toid arthritis and osteoarthritis, it is also implicated in colon cancer
and angiogenesis [7,8]. 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
therefore slow the progress of Alzheimer’s disease without causing
gastrointestinal damage [9]. Selective COX-2 inhibitors frequently
belong to a class of diarylheterocycles that possess vicinal diaryl
moieties attached to
a central heterocyclic ring scaffold in
conjunction with a COX-2 pharmacophore such as a para-SO2NH2,
or a para-SO2Me, substituent on one of the phenyl rings [10]. Cel-
ecoxib (1) and rofecoxib (2) are two typical selective COX-2 inhib-
itors in this class (COXIBs). However, the recent market withdrawal
of some COXIBs such as rofecoxib due to its adverse cardiovascular
side effects [11] clearly delineates the need to explore and evaluate
alternative templates with COX-2 inhibitory activity. For this
reason, several compounds possessing acyclic central systems have
also been designed and identified that exhibit COX-2 inhibitory
activity [12e16]. In this regard, compounds having an acyclic triaryl
olefinic structure (see structure 3 in Fig. 1) showed high potency
and selectivity on COX-2 inhibition. Recently, we also reported
Abbreviations: COX, Cyclooxygenase; NSAIDs, Nonsteroidal anti-inflammatory
drugs.
* Corresponding author. Tel.: þ98 21 8820096; fax: þ98 21 88665341.
E-mail address: azarghi@yahoo.com (A. Zarghi).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.05.058

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S. Arfaie, A. Zarghi / European Journal of Medicinal Chemistry 45 (2010) 4013e4017
Fig. 1. Some representative examples of COXIBs (celecoxib and rofecoxib), Triarylolefines (3) and 1,3-diarylprop-2-en-1-ones (4) lead compounds and our designed scaffolds.
several investigations describing the design, synthesis, and COX
inhibitory activities of a novel class of compounds possessing an
acyclic 1,3-diarylprop-2-en-1-one structural template [17,18]. For
example, [(E)-1-(4-methylsulfonylphenyl)-3-(4-methylpheny) prop-
2-en-1-one] (see structure 4 in Fig. 1) identified as potent and
selective COX-2 inhibitor compared with reference drug cele-
coxib. Accordingly, we now describe the synthesis and biological
evaluation of a group of acyclic (E) and (Z)-1,2,3-triaryl-2-propen-
1-ones possessing a methylsulfonyl COX-2 pharmacophore at the
para position of the C-1 phenyl ring in conjunction with various
aryl substituents at C-3 propenone moiety. In these designed
compounds we utilized prop-2-en-1-one scaffold instead of olefin
moiety in 1,1,2-triaryl olefins. The choice of acyclic analogues,
which can exist as E- and Z-isomers, appeared particularly
fruitful for an investigation of geometrical effect of this series of
compounds on COX-2 inhibitory potency and selectivity.
the Z isomers [19]. Geometrical assignments of 1,2,3-triarylprop-2-
en-1-one isomers were carried out essentially on the basis of their
IR and UV data according to literature [20]. It is quite well estab-
lished that there is steric inhibition of the enone resonance in Z-
triarylprop-2-en-1-ones which results in the appearance of their
carbonyl absorption bands at relatively higher wavenumbers than
those in the E-isomers. For this reason, the E-isomers have higher
lmax than the Z isomers as well. The carbonyl absorption band
positions (
n
) and the lmax of the triarylprop-2-en-1-one isomers are
O
O
a
b
H3CS
H3CO2S
(1)
(2)
2. Chemistry
O
O
Ar
The target E- and Z-1,2,3-triarylprop-2-en-1-ones were
synthesized via Aldol condensation between 1-(4-(methylsulfonyl)
phenyl)-acetophenone and appropriate benzaldehyde as outlined
in Scheme 1. During Aldol condensation the products were
obtained in moderate to good yield (37e60%) as a mixture of E- and
Z-isomers. The E/Z ratio depends on the type of substituent at C-3
prop-2-en-1-one moiety. The crude products were crystallized in
methanol if possible, mainly to give the E-isomers. Crystals were
filtered and filtrates were purified by plate chromatography to give
Ar
H3CO2S
H3CO2S
E
Z
(3-9)
Scheme 1. Reagents and conditions: (a) Oxone, THF/H2O, 25 ꢀC (b) ArCHO, dry
benzene, AcOH, piperidine, reflux, 16e26 h.

S. Arfaie, A. Zarghi / European Journal of Medicinal Chemistry 45 (2010) 4013e4017
4015
shown in Table 1. The starting material 1-(4-(methylthio)phenyl)-
2-phenylethanone was prepared by reaction of phenyl-
acetylchloride and thioanisole in prescence of AlCl3 according to
a previously reported procedure [21]. Oxidation of 1 using oxone in
hydromethanol afforded (1-(4-(methylsulfonyl)phenyl)-acetophe-
none 2 [22].
relative to the methyl (5) and methoxy analogs (6), may be due to
the ability of the fluoro or hydroxyl substituent to participate in
a H-bonding interaction. In comparison, the presence of a hetero-
cyclic ring on the C-3 propenone (8a, 8b, 9) showed moderate to
good COX-2 inhibitory activity although it was not possible to
isolate the E- and Z-isomers of 9 and therefore the mixture was
evaluated. These results indicated that the geometry of propenone
and type of substituent at the C-3 of the propenone moiety are
important for COX-2 inhibition.
1
3. Results and discussion
A group of E- and Z-1,2,3-triarylprop-2-en-1-ones (3e9), pos-
sessing a methylsulfonyl COX-2 pharmacophore at the para posi-
tion of the C-1 phenyl ring were synthesized and evaluated as
selective COX-2 inhibitors. In vitro COX-1/COX-2 structureeactivity
relationships were determined by varying the substituents on the
C-3 propenone moiety. As shown in Table 1, among the 1,2,3-tri-
4. Conclusions
This study indicates that (i) a new class of triaryl propenones can
be prepared via a simple Aldol condensation reaction, (ii) the
propenone moiety is a suitable scaffold (template) to design COX-
1/-2 inhibitors, (iii) in this class of compounds COX-1/-2 inhibition
is sensitive to the geometry of propenone and type of substituent at
the C-3 of the propenone moiety (iv) (Z)-1-(4-(methylsulfonyl)
phenyl)-2,3-diphenylprop-2-en-1-one (3b) showed the most
potency and selectivity on COX-2 inhibition.
aryl-2-propen-1-ones,
diphenylprop-2-en-1-one (3b) showed the most potency and
selectivity on COX-2 inhibition (COX-2 IC50 ¼ 0.07 M; selectivity
(Z)-1-(4-(methylsulfonyl)phenyl)-2,3-
m
index ¼ 201). The Z-propenones were also found to be more potent
and selective than the E-isomers for COX-2 inhibitory activity. Our
results showed that the size and nature of substituent at the para
position of the C-3 phenyl ring can affect the COX-2 inhibitory
potency and selectivity. Accordingly, among the 1,2,3-triaryl-2-
propen-1-one derivatives (3e7), compounds 3a, 3b and 4a, 4b
possessing an unsubstituted or small substituent phenyl ring
attached to C-3 of the propenone moiety exhibited higher COX-2
inhibitory potency and selectivity. However, the introduction of
a methyl or methoxy substituent gave compounds 5a, 5b or 6a, 6b
that exhibited low COX-2 inhibitory potency. In contrast, incorpo-
ration of a C-3 p-hydroxy phenyl substituent (7) resulted a single E
isomer with high COX-2 inhibitory potency and selectivity (COX-2
5. Experimental section
5.1. Chemistry
All chemicals and solvents used in this study were purchased
from Merck AG and Aldrich Chemical. Melting points were deter-
mined with a ThomaseHoover 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
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 a 6410Agilent LC-MS triple quadrupole mass spec-
trometer (LC-MS) with an electrospray ionization (ESI) interface.
Microanalyses, determined for C and H, were within ꢁ0.4% of
theoretical values.
IC50 ¼ 0.08 M; selectivity index ¼ 184.9). The increase of COX-2
m
inhibitory activity for the p-fluoro (4) or p-hydroxy (7) compounds,
Table 1
In vitro COX-1 and COX-2 enzyme inhibition assay data for (E)- and (Z)-1,2,3-triaryl-
2-propen-1-ones 3e9.
O
O
Ar
Ar
H3CO2S
H3CO2S
5.1.1. Preparation of (1): 1-(4-(methylthio)phenyl)-2-
phenylethanone (1)
Z
E
2
ml (15.13 mmol) phenylacetylchloride was added to
a suspension of 2.1 g (15.84 mmol) AlCl3 in 25 ml dichloromethane
under argon atmosphere. The temperature was kept at 0e5 ꢀC.
After 30 min, 1.5 ml (11.97 mmol) thioanisole was added drop wise
to the mixture. After 2 h, the temperature was let to approach the
room temperature and stirring continued overnight. Then the
reaction mixture was added to crushed ice and extracted with
dichloromethane. The organic phase was washed 3 times with
saturated NaHCO3 and dried with anhydrous Na2SO4 and concen-
trated in vacuo. The product was recrystallized in ethanol. Yield:
84%; mp: 96e97 ꢀC [21,22].
Compound
Ar
Geometry
IC50
(
m
M)a
Selectivity
index (SI)b
COX-
1
COX-
2
3a
3b
4a
4b
5a
5b
6a
Phenyl
Phenyl
E
Z
E
Z
E
Z
E
13.27
14.27
12.59
30.94
10.37
12.21
10.68
0.11
0.07
0.19
0.16
0.28
0.21
0.22
120.6
201
4-F-phenyl
4-F-phenyl
4-Methylphenyl
4-Methylphenyl
4-
Methoxyphenyl
4-
Methoxyphenyl
4-Hydroxyphenyl
2-Thienyl
66.2
193.4
37.0
58.1
48.5
6b
Z
18.38
0.21
87.5
5.1.2. Preparation of 1-(4-(methylsulfonyl)phenyl)-2-
phenylethanone (2)
7
8a
8b
9
E
E
Z
14.42
13.12
NDc
12.37
24.3
0.08
0.13
NDc
0.07
0.06
184.9
100.1
NDc
171.8
405
1g (4.13 mmol) of (1) was dissolved in 20 ml THF, and 6g OxoneÒ
in THF/water was added. The solution was stirred at room
temperature overnight. THF was evaporated and the residue was
extracted with chloroform. The organic phase was washed 3 times
with saturated NaHCO3 and dried with anhydrous Na2SO4 and
concentrated in vacuo. A white crystalline solid formed. Yield: 71%;
mp: 169e170 ꢀC [22].
2-Thienyl
4-Pyridyl
E & Z
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).
Not determined.
c

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S. Arfaie, A. Zarghi / European Journal of Medicinal Chemistry 45 (2010) 4013e4017
5.2. Preparation of (E)- and (Z)-1,2,3-triarylprop-2-en-1-ones
(3e9): General procedure
(m, 3H, 4-fluorophenyl H2 & H6 & ]CH), 7.38e7.43 (m, 3H, phenyl
H3eH5), 7.45e7.47 (m, 2H, phenyl H2 & H6), 7.98 (d, 2H, 4-meth-
ylsulfonylphenyl H2 & H6, J ¼ 8.5 Hz), 8.16 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.5 Hz); 13CNMR (CDCl3, 100 MHz):
Equimolar proportions of 1-(4-(methylsulfonyl)phenyl)-2-phe-
nylethanone and arylaldehydes were dissolved in anhydrous
benzene (usually 100 ml for each 50 mmol of reactants) and
refluxed in a DeaneStark assembly in the presence of catalytic
amounts of glacial AcOH and piperidine (2.8 and 1.0 ml, respec-
tively, for each 50 mmol of the reactants) for 12e24 h. After the
completion of the reaction, the mixtures were cooled and mixed
with equal proportions of water. The organic layers were separated,
washed twice with water, dried with anhydrous Na2SO4 and
concentrated in vacuo. The crude products were crystallized in
methanol if possible, mainly to give the E-isomers. Crystals were
filtered and filtrates were purified by plate chromatography to give
the Z isomers [20]. The yields of the reactions varied from 37 to 60%.
d
43.9, 115.1, 126.2, 127.5, 128.3, 128.8, 129.9, 130.6, 131.3, 132.6,
135.7, 140.9, 141.7, 144.8, 160.9, 197.5; LC-MS(ESI) m/z: 403 (M þ 23)
(100); Anal. Calcd. for C22H17O3SF: C, 69.46; H, 4.50. Found: C,
69.71; H, 4.68.
5.2.5. (E)-1-(4-(Methylsulfonyl)phenyl)-2-phenyl-3-p-tolylprop-2-
en-1-one (5a)
White powder; mp 168e170 ꢀC; UV (lmax): 324 nm; IR (KBr
disk):
500 MHz):
y
(cmꢂ1) 1642 (C]O), 1300, 1150 (SO2); 1HNMR (CDCl3,
d
2.34 (s, 3H, CH3), 3.13 (s, 3H, SO2CH3), 7.01 (d, 2H, 4-
methylphenyl H3 & H5, J ¼ 8.2 Hz), 7.05(d, 2H, 4-methylphenyl H2 &
H6, J ¼ 8.2 Hz), 7.29 (m, 2H, phenyl H2 & H6), 7.34 (s, 1H, ]CH),
7.42e7.44 (m, 3H, phenyl H3eH5), 7.97 (d, 2H, 4-methyl-
sulfonylphenyl H2 & H6, J ¼ 8.4 Hz), 8.06 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.4 Hz); 13CNMR (CDCl3, 100 MHz):
5.2.1. (E)-1-(4-(Methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-
one (3a)
Pale yellow powder; mp 166e167 ꢀC; UV (lmax): 314 nm; IR (KBr
d 23.9, 44.0, 126.3, 126.6, 127.9, 128.5, 128.9, 129.3, 130.9, 131.9,
disk):
y
(cmꢂ1) 1651 (C]O), 1315, 1150 (SO2);1HNMR (CDCl3,
132.5, 135.7, 137.5, 140.8, 142.9, 144.5, 194.9; LC-MS(ESI) m/z: 377
(M þ 1), 399 (M þ 23); Anal. Calcd. for C23H20O3S: C, 73.38; H, 5.35.
Found: C, 73.67; H, 5.08.
500 MHz):
d
3.13 (s, 3H, SO2CH3), 7.13 (d, 2H, 3-phenyl H2 & H6,
J ¼ 7.5 Hz), 7.24 (t, 2H, 2-phenyl H2 & H6, J ¼ 7.5 Hz), 7.29e7.31 (m,
3H, 3-phenyl H3eH5), 7.35 (s, 1H, ]CH), 7.41e7.43 (m, 3H, 2-phenyl
H3eH5), 7.99 (d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.3 Hz),
8.06 (d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.3 Hz); 13CNMR
5.2.6. (Z)-1-(4-(Methylsulfonyl)phenyl)-2-phenyl-3-p-tolylprop-2-
en-1-one (5b)
(CDCl3, 100 MHz):
d
43.8, 126.1, 126.6, 128.1, 128.3, 128.6, 128.9,
Yellow powder; mp 116.5e118 ꢀC; UV (lmax): 288 nm; IR (KBr
129.5, 131.2, 132.6, 135, 135.9, 142.1, 142.8, 144.7, 195.5; LC-MS (ESI)
m/z: 385 (M þ 23) (100); Anal. Calcd. for C22H18O3S: C, 72.90; H,
5.01. Found: C, 72.72; H, 5.21.
disk):
500 MHz):
y
(cmꢂ1) 1664 (C]O), 1315, 1145 (SO2);1HNMR (CDCl3,
d
2.30 (s, 3H, CH3), 3.06 (s, 3H, SO2CH3), 7.04 (d, 2H, 4-
methylphenyl H3 & H5, J ¼ 8.0 Hz), 7.18 (d, 2H, 4-methylphenyl H2 &
H6, J ¼ 8.0 Hz), 7.37 (s, 1H, ]CH), 7.37e7.42 (m, 3H, phenyl H3eH5),
7.46e7.48 (m, 2H, phenyl H2 & H6), 7.96 (d, 2H, 4-methyl-
sulfonylphenyl H2 & H6, J ¼ 8.5 Hz), 8.17 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.5 Hz); 13CNMR (CDCl3, 100 MHz):
5.2.2. (Z)-1-(4-(Methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-
one (3b)
White powder; mp 122e124 ꢀC; UV (lmax): 283 nm; IR (KBr
disk):
y
(cmꢂ1) 1661 (C]O), 1310, 1145 (SO2); 1H NMR (CDCl3,
d 22.9, 44.1, 126.1, 126.5, 127.7, 128.3, 128.8, 129.2, 130.6, 131.5, 132.5,
500 MHz):
d
3.05 (s, 3H, SO2CH3), 7.23e7.25 (m, 3H, 3-phenyl
135.5, 137.1, 139.7, 142.8, 144.4, 196.7; LC-MS(ESI) m/z: 377 (M þ 1),
399 (M þ 23); Anal. Calcd. for C23H20O3S: C, 73.38; H, 5.35. Found:
C, 73.57; H, 5.16.
H3eH5), 7.28e7.30 (m, 3H, 3-phenyl H2 & H6 & ]CH), 7.38e7.43 (m,
3H, 2-phenyl H3eH5), 7.49 (d, 2H, 2-phenyl H2 & H6, J ¼ 7.1 Hz), 7.96
(d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.3 Hz), 8.16e8.18 (d,
2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.3 Hz); 13CNMR (CDCl3,
5.2.7. (E)-3-(4-Methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-2-
phenylprop-2-en-1-one (6a)
100 MHz): d 43.6, 126.0, 126.5, 128.0, 128.2, 128.5, 128.8, 129.5, 131.1,
132.4, 134.8, 135.7, 140.9, 142.7, 144.6, 197.5; LC-MS (ESI) m/z: 385
(M þ 23) (100); Anal. Calcd. for C22H18O3S: C, 72.90; H, 5.01. Found:
C, 72.76; H, 5.30.
Pale yellow powder; mp 200e202 ꢀC; UV (lmax): 344 nm; IR
(KBr disk):
500 MHz):
y
(cmꢂ1) 1652 (C]O), 1295, 1155 (SO2); 1HNMR (CDCl3,
3.13 (s, 3H, SO2CH3), 3.81 (s, 3H, OCH3), 6.75 (d, 2H, 4-
d
methoxyphenyl H3 & H5, J ¼ 8.9 Hz), 7.06 (d, 2H, 4-methoxyphenyl
H2 & H6, J ¼ 8.9 Hz), 7.29e7.31 (m,2H, phenyl H2 & H6), 7.34 (s,1H, ]
CH), 7.42e7.45 (m, 3H, phenyl H3-H5), 7.94 (d, 2H, 4-methyl-
sulfonylphenyl H2 & H6, J ¼ 8.3 Hz), 8.05 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.3 Hz); 13CNMR (CDCl3, 100 MHz):
5.2.3. (E)-3-(4-Fluorophenyl)-1-(4-(methylsulfonyl)phenyl)-2-
phenylprop-2-en-1-one (4a)
White powder; mp 171e173 ꢀC; UV (lmax): 315 nm; IR (KBr
disk):
500 MHz):
y
(cmꢂ1) 1653 (C]O), 1310, 1160 (SO2); 1HNMR (CDCl3,
d
3.13 (s, 3H, SO2CH3), 6.92 (t, 2H, 4-fluorophenyl H3
&
d 44.2, 55.6,114.5,126.5,127.4,127.8,128.2,128.6,129.0,130.9,131.6,
H5, J ¼ 8.6 Hz), 7.12(dd, 2H, 4-fluorophenyl H2 & H6, JHH ¼ 8.7 Hz,
JHF ¼ 5.5 Hz), 7.27e7.29 (m, 2H, phenyl H2 & H6), 7.32 (s, 1H, ]CH),
7.41e7.44 (m, 3H, phenyl H3eH5), 7.97 (d, 2H, 4-methyl-
sulfonylphenyl H2 & H6, J ¼ 8.2 Hz), 8.05 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.2 Hz); 13CNMR (CDCl3, 100 MHz):
135.8, 140.8, 142.7, 144.4, 159.7, 196.9; LC-MS(ESI) m/z: 393 (M þ 1),
415 (M þ 23); Anal. Calcd. for C23H20O4S: C, 70.39; H, 5.14. Found: C,
70.67; H, 5.36.
5.2.8. (Z)-3-(4-Methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-2-
phenylprop-2-en-1-one (6b)
d
43.9, 115.7, 126.5, 127.8, 128.6, 129.2, 129.9, 130.8, 131.4, 132.6,
135.9, 141.2, 142.9, 144.9, 162.1, 195.8; LC-MS(ESI) m/z: 403 (M þ 23)
(100); Anal. Calcd. for C22H17O3SF: C, 69.46; H, 4.50. Found: C,
69.77; H, 4.30.
Yellow powder; mp 136e137 ꢀC; UV (lmax): 299 nm; IR (KBr
disk):
500 MHz):
y
(cmꢂ1) 1666 (C]O), 1315, 1150 (SO2);1HNMR (CDCl3,
d
3.06 (s, 3H, SO2CH3), 3.78 (s, 3H, OCH3), 6.76 (d, 2H, 4-
methoxyphenyl H3 & H5, J ¼ 8.8 Hz), 7.23 (d, 2H, 4-methoxyphenyl
5.2.4. (Z)-3-(4-Fluorophenyl)-1-(4-(methylsulfonyl)phenyl)-2-
H2 & H6, J ¼ 8.8 Hz), 7.28 (s, 1H, ]CH), 7.35 (m,1H, phenyl H4),
phenylprop-2-en-1-one (4b)
7.38e7.41 (m, 2H, phenyl H3 & H5), 7.42e7.46 (m, 2H, phenyl H2 &
Yellow oil liquid; UV (lmax): 281 nm; IR (CHCl3):
y
(cmꢂ1) 1676
3.07 (s, 3H,
H6), 7.97 (d, 2H, 4-methylsulfonylphenyl H2 & H6, J ¼ 8.5 Hz), 8.18
(C]O), 1325, 1160 (SO2);1HNMR (CDCl3, 500 MHz):
d
(d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.5 Hz); 13CNMR
SO2CH3), 6.94(t, 2H, 4-fluorophenyl H3 & H5, J ¼ 8.6 Hz), 7.26e7.30
(CDCl3, 100 MHz): d 44.3, 55.5, 114.3, 126.2, 127.1, 127.6, 128.0, 128.4,

S. Arfaie, A. Zarghi / European Journal of Medicinal Chemistry 45 (2010) 4013e4017
4017
128.8, 130.6, 131.3, 135.7, 138.9, 142.6, 144.3, 159.6, 195.8; LC-MS
(ESI) m/z: 393 (M þ 1), 415 (M þ 23); Anal. Calcd. for C23H20O4S: C,
70.39; H, 5.14. Found: C, 70.64; H, 4.95.
methylsulfonylphenyl H2 & H6, J ¼ 8.3 Hz), 8.02 (d, 2H, 4-methyl-
sulfonylphenyl H2 & H6, J ¼ 8.3 Hz), 8.05 (d, 2H, 4-methyl-
sulfonylphenyl H3
&
H5,
J
¼
8.3 Hz), 8.15 (d, 2H, 4-
methylsulfonylphenyl H3 & H5, J ¼ 8.3 Hz), 8.50 (d, 4H, pyridine H2
5.2.9. (E)-3-(4-Hydroxyphenyl)-1-(4-(methylsulfonyl)phenyl)-2-
phenylprop-2-en-1-one (7)
& H6, J ¼ 3.9 Hz); LC-MS m/z: 364 (M þ 1) (100).
Pale yellow powder; mp 181e183 ꢀC; UV (lmax): 342 nm; IR (KBr
5.3. In vitro cyclooxygenase (COX) inhibition assays
disk):
y
(cmꢂ1) 3600e3200 (OH), 1620 (C]O), 1305, 1150 (SO2);
1HNMR (CDCl3, 500 MHz):
d
3.14 (s, 1H, SO2CH3), 5.34 (s, 1H, OH),
The assay was performed using an enzyme chemiluminescent
kit (Cayman chemical, MI, USA) according to our previously
reported method [23]. The Cayman chemical chemiluminescent
COX (ovine) inhibitor screening assay utilizes the heme-catalyzed
hydroperoxidase activity of ovine cyclooxygenases to generate
luminescence in the presence of a cyclic naphthalene hydrazide
and the substrate arachidonic acid. Arachidonate-induced lumi-
nescence was shown to be an index of real-time catalytic activity
and demonstrated the turnover inactivation of the enzyme. Inhi-
bition of COX activity, measured by luminescence, by a variety of
selective and nonselective inhibitors showed potencies similar to
those observed with other in vitro and whole cell methods.
6.68 (d, 2H, 4-hydroxyphenyl H3 & H5, J ¼ 8.7 Hz), 7.01 (d, 2H, 4-
hydroxyphenyl H2 & H6, J ¼ 8.7 Hz), 7.29e7.31 (m, 2H, phenyl H2 &
H6), 7.33 (s, 1H, ]CH), 7.41e7.45 (m, 3H, phenyl H3eH5), 7.94 (d, 2H,
4-methylsulfonylphenyl H2 & H6, J ¼ 8.4 Hz), 8.05 (d, 2H, 4-meth-
ylsulfonylphenyl H3 & H5, J ¼ 8.4 Hz); 13CNMR (CDCl3, 100 MHz):
d
44.1, 116.1, 126.4, 127.7, 127.9, 128.1, 128.8, 129.1, 131.1, 132.4, 135.9,
140.7, 142.9, 144.6, 158.4, 196.1; LC-MS m/z:379 (M þ 1), 401
(M þ 23); Anal. Calcd. for C23H20O4S: C, 70.39; H, 5.14. Found: C,
70.71; H, 5.43.
5.2.10. (E)-1-(4-(Methylsulfonyl)phenyl)-2-phenyl-3-(thiophen-2-
yl)prop-2-en-1-one (8a)
Cream powder; mp 195.5e197 ꢀC; UV (lmax): 345 nm; IR (KBr
Acknowledgements
disk):
500 MHz):
y
(cmꢂ1) 1644 (C]O), 1310, 1145 (SO2); 1HNMR (CDCl3,
d
3.15 (s, 3H, -SO2CH3), 7.01 (dd, 1H, thiophene H4,
We are grateful to Research deputy of Shahid Behesti University
of Medical Sciences (SBMU) for financial support of this research.
J ¼ 5.1 Hz), 7.18 (d, 1H, thiophene H5, J ¼ 3.48 Hz), 7.35e7.38 (m, 3H,
thiophene H3 & phenyl H2 & H6), 7.53e7.55 (m, 3H, phenyl H3eH5),
7.64 (s, 1H, ]CH), 7.94 (d, 2H, 4-methylsulfonylphenyl H2 & H6,
J ¼ 8.4 Hz), 8.08 (d, 2H, 4-methylsulfonylphenyl H3 & H5, J ¼ 8.4 Hz);
References
13CNMR (CDCl3, 100 MHz):
d 44.2, 126.4, 127.2, 127.9, 128.2, 128.6,
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128.9, 130.6, 130.9, 131.9, 132.4, 137.4, 141.5, 142.8, 144.6, 196.5; LC-
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Yellow powder; mp 144 ꢀC; UV (lmax): 312 nm; IR (KBr disk):
y
(cmꢂ1) 1662 (C]O), 1310, 1150 (SO2); 1HNMR (CDCl3, 500 MHz):
d
3.08 (s, 3H, SO2CH3), 6.96 (dd, 1H, thiophene H4, J ¼ 5.0 Hz), 7.10
(d, 1H, thiophene H5, J ¼ 3.45 Hz), 7.24 (d, 1H, thiophene H3,
J ¼ 5.0 Hz), 7.36e7.39 (m, 1H, phenyl H4), 7.40e7.42 (m, 3H, phenyl
H3 & H5 & ]CH), 7.42e7.46 (m, 2H, phenyl H2 & H6), 8.01 (d, 2H, 4-
methylsulfonylphenyl H2 & H6, J ¼ 8.5 Hz), 8.23 (d, 2H, 4-methyl-
sulfonylphenyl H3 & H5, J ¼ 8.5 Hz); 13CNMR (CDCl3, 100 MHz):
d
44.3, 126.2, 127.0, 127.6, 128.0, 128.4, 128.7, 130.2, 130.6, 131.0,
132.2, 137.2, 141.2, 142.6, 144.3, 197.6; LC-MS(ESI) m/z: 369 (M þ 1),
391 (M þ 23); Anal. Calcd. for C20H16O3S2: C, 65.19; H, 4.38. Found:
C, 64.88; H, 4.60.
5.2.12. (E & Z)-1-(4-(Methylsulfonyl)phenyl)-2-phenyl-3-(pyridin-
4-yl)prop-2-en-1-one (9)
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Two isomers (E/Z ratio: 3:1) were obtained. cream powder; mp
58e60 ꢀC; UV (lmax): 284 nm; IR (KBr disk): (cmꢂ1) 1658 (C]O),
y
1300, 1150 (SO2);1HNMR (CDCl3, 500 MHz):
d 3.07 (s, 3H, SO2CH3),
3.12 (s, 3H, SO2CH3), 6.98 (d, 2H, phenyl H2 & H6, J ¼ 5.6 Hz), 7.17 (d,
2H, phenyl H2 & H6, J ¼ 5.6 Hz), 7.19 (s, 1H, ]CH), 7.21 (s, 1H, ]CH),
7.27e7.49 (m, 10H, phenyl H3eH5, pyridine H3 & H5), 8.00 (d, 2H, 4-
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