Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2006.06.022

A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO₂NH, or N₃, COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen-Schmidt condensat

Full text of DOI:10.1016/j.bmc.2006.06.022

Bioorganic & Medicinal Chemistry 14 (2006) 7044–7050
Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones
possessing a methanesulfonamido or an azido pharmacophore as
cyclooxygenase-1/-2 inhibitors
Afshin Zarghi,a Tannaz Zebardast,a Farinaz Hakimion,a Farshad H. Shirazi,a
P. N. Praveen Raob and Edward E. Knausb,*
aDepartment of Pharmaceutical Chemistry and Toxicology, School of Pharmacy, Shaheed Beheshti University of Medical Sciences,
Tehran, Iran
bFaculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8
Received 19 April 2006; revised 7 June 2006; accepted 8 June 2006
Available online 22 June 2006
Abstract—A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO2NH, or N3, COX-2 pharmaco-
phore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen–Schmidt condensation
reaction. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-3 phenyl ring
(4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO2NH COX-2 pharmacophore,
(E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2
IC50 = 1.0 lM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC50 = 0.50 lM; SI > 200). The
corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N3 COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-
(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC50 = 22.2 lM; COX-2
IC50 = 0.3 lM; SI = 60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that
the p-MeSO2NH and N3 substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90,
Arg513, Phe518, and Val523). The structure–activity data acquired indicate that the propenone moiety constitutes a suitable scaffold
to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
of selective cyclooxygenase-2 (COX-2) inhibitors that
exhibited reduced gastrointestinal toxicity in the late
1990s4,5 proved to be short lived. The recent withdrawal
of diarylheterocyclic selective COX-2 inhibitors such as
rofecoxib and valdecoxib due to their adverse cardiovas-
cular side effects6,7 clearly delineates the need to explore
and evaluate new structural ring templates (scaffolds)
possessing COX inhibitory activity.
The clinical use of traditional nonsteroidal anti-inflam-
matory drugs (NSAIDs) such as aspirin and indometh-
acin for the treatment of inflammation and pain is
often accompanied by adverse gastrointestinal effects.
Their anti-inflammatory activity is due to inhibition of
cyclooxygenases (COXs), which catalyze the bioconver-
sion of arachidonic acid to inflammatory prostaglandins
(PGs).1,2 PGs that are produced via the inducible COX-2
isozyme are responsible for inflammation, pain, and
fever, whereas the constitutively expressed COX-1 isozy-
me produces PGs that exhibit beneficial cytoprotective
properties.3 The initial euphoria surrounding the launch
Recently, we reported several investigations describing
the design, synthesis, and anti-inflammatory properties
for a novel class of compounds possessing an acyclic tri-
aryl/diaryl olefin structural template.8–11 For example,
the acyclic 1-alkyl-1,2-diaryl (E)-olefin (see structure 1
in Fig. 1)11 possessing a trans-stilbenoid structure with
a 4-methylsulfonylphenyl COX-2 pharmacophore at
the C-1 position exhibited selective cyclooxygenase-2
(COX-2) inhibition, whereas the triphenyl acyclic
olefin (2) possessing either a methanesulfonamido
(MeSO2NH) or a linear azido (N3) pharmacophore at
Keywords: Cyclooxygenase inhibition; Propenone moiety; Azido
pharmacophore.
*
Corresponding author. Tel.: +1 780 492 5993; fax: +1 780 492
1217; e-mail: eknaus@pharmacy.ualberta.ca
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.06.022

A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
7045
was attached to the C-1 phenyl ring (7a–h).13 The sodi-
um hydroxide catalyzed condensation of an acetophe-
R1
MeO2S
none (5a–b) with
a para-substituted-benzaldehyde
H
(6a–d) afforded the 1,3-diphenylprop-2-en-1-ones
(7a–h) in moderate to high yield (45–80%) as illustrated
in Scheme 1. The acetophenone precursor 5a was
prepared by treating 4-aminoacetophenone with metha-
nesulfonyl chloride according to a previously reported
procedure.16 Diazotization of 4-aminoacetophenone
with sodium nitrite, followed by reaction of the diazoni-
um salt with sodium azide according to a previously
reported method,17 afforded the para-azido substituted
acetophenone (5b). 1H NMR spectrometry indicated
that the chalcone products 7a–h exist as the (E)-stereo-
isomers (JCH@CH = 15.4–15.6 Hz range).
R2
n-Hexyl
R1 = NHSO2Me, N3; R2 = n-alkyl
(2)
(1)
R1
R1
MeO2S
C
C
C
O
C
O
R2
R1 = 3,4-Disubstituted-phenyl
(3)
R1 = R2 = H, Me, F, OMe, SO2Me
(4)
3. Results and discussion
Figure 1. Some representative examples of novel acyclic structural
templates (scaffolds) that exhibit cyclooxygenase-1/2 inhibition.
A group of 1,3-diphenylprop-2-en-1-ones (7a–h), pos-
sessing either a para-methanesulfonamido (MeSO2NH),
or an azido (N3), substituent on the C-1 phenyl ring,
were synthesized. In this study, the substituents on the
C-3 phenyl ring were simultaneously varied (H, Me, F,
and OMe) to determine the combined effects of steric
and electronic 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 compounds to inhibit the COX-1
and COX-2 isozymes showed that the COX inhibition
was sensitive to the nature of both the C-1 and C-3
phenyl substituents. Our recent studies for a class of
acyclic triphenyl olefins have shown that potent and
selective COX-2 inhibition can be obtained by replacing
the traditional p-SO2Me COX-2 pharmacophore with a
p-MeSO2NH bioisostere.9 Accordingly, among the sub-
group of 1,3-diphenylprop-2-en-1-enes 7a–d possessing
a C-1 p-MeSO2NH COX-2 pharmacophore, compound
7a possessing an unsubstituted C-3 phenyl ring exhibited
equipotent and nonselective inhibition of the COX iso-
zymes (COX-2 IC50 = 3.0 lM; COX-1 IC50 = 3.2 lM)
as shown in Table 1. However, the introduction of a
C-3 p-Me substituent gave compound 7b that exhibited
good COX-2 inhibitory potency (COX-2 IC50 = 1.0 lM;
COX-1 IC50 > 100 lM) and selectivity (COX-2
the para-position of one of the phenyl rings showed
selective COX-2 inhibition with good in vivo anti-in-
flammatory activities.9 In addition, 1,3-diphenylprop-
2-yn-1-ones (3) possessing a central propynone moiety
display potent COX inhibition.12 It was also reported
that 1,3-diphenylprop-2-en-1-one regioisomers (4)
possessing a SO2Me COX-2 pharmacophore at the
para-position of one of the phenyl rings constitute a suit-
able template to design a new class of COX inhibitors.13
Some structurally related chalcones to treat inflamma-
tion have been described.14,15 Accordingly, we now
describe the synthesis and biological evaluation of a
group of acyclic 1,3-diphenylprop-2-en-1-ones (7a–h)
possessing either
a C-1 para-methanesulfonamido
(MeSO2NH), or a linear azido (N3), COX-2 pharmaco-
phore in conjunction with various substituents (H, Me,
F, and OMe) at the para-position of the C-3 phenyl ring.
2. Chemistry
A one-step Claisen–Schmidt condensation was used to
prepare the target 1,3-diphenylprop-2-en-1-ones in
which a methanesulfonamido, or an azido, substituent
R1
R2
R2
R1
a
+
H
C
O
Me
O
O
7a, R1 = NHSO2Me, R2 = H
7b, R1 = NHSO2Me, R2 = Me
7c, R1 = NHSO2Me, R2 = F
7d, R1 = NHSO2Me, R2 = OMe
7e, R1 = N3, R2 = H
6a. R2 = H
6b, R2 = Me
6c, R2 = F
5a, R1 = NHSO2Me
5b, R1 = N3
6d, R2 = OMe
7f, R1 = N3, R2 = Me
7g, R1 = N3, R2 = F
7h, R1 = N3, R2 = OMe
Scheme 1. Reagents and conditions: (a) NaOH, MeOH, 25 °C, 30 min to 2 h.

7046
A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
Table 1. In vitro COX-1 and COX-2 enzyme inhibition assay data for
1,3-diphenylprop-2-en-1-one derivatives 7a–h
(COX-2 IC50 = 0.30 lM) than the reference drug rofecox-
ib (COX-2 IC50 = 0.50 lM). However, 7f showed COX-1
inhibition (COX-1 IC50 = 22.2 lM; COX-2 SI = 60) and
was not as selective as rofecoxib (COX-1 IC50 > 100 lM;
COX-2 SI > 200). Although 7g (R2 = F) exhibited both
COX-1 and COX-2 isozyme inhibition, it was a 2.5-fold
more potent inhibitor of COX-1. Incorporation of a C-3
p-OMe substituent resulted in a dramatic increase in
COX-1 inhibition with compound 7h (R2 = OMe) exhib-
iting potent and selective inhibition of the COX-1 isozyme
(COX-1 IC50 = 0.40 lM; COX-2 IC50 = 30.6 lM).
R1
R2
C
O
a
Compound R1
R2
IC50 (lM)
Selectivity
index (SI)b
COX-1 COX-2
7a
7b
NHSO2Me
H
3.0
>100
3.3
3.2
1.0
0.9
NHSO2Me Me
NHSO2Me
NHSO2Me OMe 1.0
>100
—
0.1
7c
7d
F
>100
10.0
3.4
The binding interactions of the most potent and selec-
tive COX-2 inhibitor compounds (7b and 7f) within
the COX-2 binding site were investigated. The most sta-
ble enzyme–ligand complex of the potent and selective
COX-2 inhibitor compound 7b [(E)-1-(4-methanesulfon-
amidophenyl)-3-(4-methylphenyl)prop-2-en-1-one] pos-
sessing a C-1 p-MeSO2NH COX-2 pharmacophore
within the COX-2 binding site (Fig. 2) shows that the
p-MeSO2NH-phenyl moiety is oriented toward the
COX-2 secondary pocket (Val523, Phe518, Ile517,
Arg513, Thr94, and His90). The methyl group of the
MeSO2NH moiety is involved in a hydrophobic binding
interaction with Phe518, Ile517, and Ala516 (distance
7e
N3
N3
N3
N3
H
>100
22.2
4.2
>29
60
7f
7g
Me
F
0.3
10.0
3.6
0.4
—
7h
Rofecoxib
OMe 0.4
>100
0.5
>200
a
Values are means of two determinations acquired using an ovine
COX-1/COX-2 assay kit (catalog no. 560101, Cayman Chemicals
Inc., Ann Arbor, MI, USA) 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).
˚
<5 A), whereas one of the O-atoms of the MeSO2 moi-
˚
ety is about 4.66 A away from NH2 of Arg513. The dis-
tance between the NH of MeSO2NH and NH2 of
SI > 100). In contrast, incorporation of a C-3 p-fluoro
substituent (7c, R2 = F) resulted in a dramatic loss in
COX-2 inhibition (COX-2 IC50 > 100 lM) with a gain
˚
Arg513 is about 5.72 A. In addition, a hydrogen bond-
ing interaction is observed between the NH of
in COX-1 inhibition
and potency
(COX-1
IC50 = 3.3 lM; Table 1). This loss of COX-2 inhibitory
activity for the fluoro compound 7c, relative to the
methyl analog 7b, may be due to the electronegativity
of the fluoro substituent and/or its ability to participate
in a H-bonding interaction. In comparison, the presence
of a C-3 p-MeO-phenyl substituent (7d, R2 = OMe) in-
creased COX-2 inhibition (COX-2 IC50 = 10 lM)
although 7d was not as potent and selective as 7b.
MeSO2NH and Nd of His90 at the entrance to the
˚
COX-2 secondary pocket (distance ꢀ 2.70 A). The
C@O of the central a,b-unsaturated-carbonyl moiety is
oriented toward the entrance to the COX-2 binding site
(Tyr355 and Arg120). The distance between the C@O
˚
and the OH of Tyr355 is about 5.12 A, whereas the dis-
tance between the C@O and NH2 of Arg120 is about
˚
6.15 A. The trans C@C olefinic bond, which is surround-
ed by Val349, Leu352, and Ala527, positions the C-3
4-tolyl substituent toward the apex of the COX-2 bind-
ing site (Phe205, Thr206, Tyr348, Phe381, Tyr385, and
Ser530). The C-3 p-methyl substituent is within van
der Waal’s contact range of Thr206, Tyr348, and
Tyr385 (distance <5 A). The distance between the centre
of the C-3 phenyl ring and the OH of Ser530 is about
˚
4.60 A. A similar investigation of the selective COX-2
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 pocket of COX-2 is controlled
by histidine (His90), glutamine (Gln192), and tyrosine
(Tyr355), and interaction of Arg513 with the bound drug
is a requirement for time-dependent inhibition of
COX-2.18 Recently we exploited, for the first time, the
amino acid Arg513 to design selective COX-2 inhibitors
having a dipolar azide (N3) pharmacophore that can
undergo an electrostatic (ion–ion) interaction with
Arg513 in the COX-2 secondary pocket.9,19,20 According-
ly, the subgroup of 1,3-diphenylprop-2-en-1-ones pos-
sessing a C-1 p-azido COX-2 pharmacophore (7e and
7f) exhibited good COX-2 inhibitory potency and selec-
tivity as shown in Table 1. For example, the chalcone
derivative 7e (R2 = H) exhibited moderate COX-2 inhibi-
tion (COX-2 IC50 = 3.4 lM) with no inhibition of COX-1
at 100 lM (COX-2 SI > 29). However, 7e was a less
potent inhibitor of the COX-2 isozyme compared to the
reference drug rofecoxib (COX-2 IC50 = 0.50 lM). Intro-
duction of a C-3 p-methyl substituent provided potent
COX-2 inhibition since compound 7f (R2 = Me) was a
1.6-fold more potent inhibitor of the COX-2 isozyme
˚
inhibitor compound 7f [(E)-1-(4-azidophenyl)-3-(4-
methylphenyl)prop-2-en-1-one] docked in the COX-2
active site (Fig. 3) shows that it binds in the primary
binding site such that the para-azido substituent on the
C-1 phenyl ring is oriented in the vicinity of the second-
ary pocket present in COX-2 (Val523, Phe518, Ile517,
Ala516, Arg513, Ser353, Thr94, and His90). The linear
dipolar azido substituent, as proposed, is involved in
an ion–ion (electrostatic) interaction with Arg513. The
distance between the terminal N-atom of the azido sub-
˚
stituent and the NH2 of Arg513 is about 5.71 A, whereas
the distance between the N2-atom of the azido substitu-
˚
ent and the NH of His90 is about 4.18 A. Interestingly,
the C@O of the central a,b-unsaturated-carbonyl moiety
is oriented toward the entrance of the COX-2 binding
site (Tyr355 and Arg120) similar to that observed for
the methanesulfonamido derivative (7b). The C@O par-

A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
7047
Figure 2. Docking (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) (ball and stick) in the active site of murine COX-2.
Hydrogen atoms of the amino acid residues have been removed to improve clarity.
Figure 3. Docking (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f) (ball and stick) in the active site of murine COX-2. Hydrogen
atoms of the amino acid residues have been removed to improve clarity.

7048
A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
ticipates in a weak hydrogen bonding interaction with
˚
nol, and the product was recrystallized from ethanol.
The physical and spectral data for 7a–h are listed below.
the OH of Tyr355 (distance ꢀ 4.08 A). The distance
˚
between the C@O and NH2 of Arg120 is about 6.24 A.
The trans C@C olefinic bond, which is surrounded by
Leu352 and Ala527, positions the C-3 4-tolyl substituent
toward the apex of the COX-2 binding site (Phe205,
Thr206, Tyr348, Phe381, Tyr385, and Ser530). The
C-3 p-methyl substituent on the C-3 phenyl ring is with-
in van der Waal’s contact range of Thr206, Phe381 and
6.1. (E)-1-(4-Methanesulfonamidophenyl)-3-phenylprop-
2-en-1-one (7a)
Yield, 51%; pale yellow crystals; mp 169–170 °C; IR
(KBr): 3200 (NH), 1670 (C@O), 1120, 1340 (SO2) cmÀ1
;
1H NMR (DMSO-d6): d 3.05 (s, 3H, SO2CH3), 7.25–
7.36 (m, 5H, phenyl H-3, H-4, H-5 and 4-methanesul-
fonamidophenyl H-3, H-5), 7.45–7.60 (m, 2H, phenyl
H-2, H-6), 7.71 (d, J = 15.6 Hz, 1H, COCH@CH),
7.90 (d, J = 15.6 Hz, 1H, COCH@CH), 8.14 (d,
J = 8.0 Hz, 2H, 4-methanesulfonamidophenyl H-2,
H-6), 10.36 (s, 1H, NH); MS: m/z (%): 301.1 (M+, 20),
222.2 (20), 194.2 (25), 131 (65), 103.1 (100), 91 (40),
77.2 (65). Anal. Calcd for C16H15NO3S: C, 63.77; H,
5.02; N, 4.65. Found: C, 63.47; H, 5.25; N, 4.38.
˚
Tyr385 (distance <5 A). Accordingly, this computation-
al study shows that the p-N3 substituent present in 7f
interacts within the COX-2 secondary pocket where it
acts as a suitable COX-2 pharmacophore.
4. Conclusions
This study indicates that (i) a new class of acyclic (E)-1,3-
diphenylprop-2-en-1-ones can be prepared via a simple
one-step stereoselective Claisen–Schmidt condensation,
(ii) the propenone moiety is a suitable scaffold (template)
to design COX-1/-2 inhibitors, (iii) in this chalcone class
of compounds (7), the p-MeSO2NH and N3 moieties
proved to be suitable COX-2 pharmacophores, (iv)
COX-1/-2 inhibition is sensitive to the nature of the
C-3 phenyl substituents, and (v) (E)-1-(4-azidophenyl)-
3-(4-methylphenyl)prop-2-en-1-one (7e) exhibited good
COX-2 inhibitory potency and selectivity.
6.2. (E)-1-(4-Methanesulfonamidophenyl)-3-(4-methyl-
phenyl)prop-2-en-1-one (7b)
Yield, 45%; pale yellow crystals; mp 194–196 °C; IR
(KBr): 3200 (NH), 1680 (C@O), 1120, 1320 (SO2) cmÀ1
;
1H NMR (DMSO-d6): d 2.49 (s, 3H, CH3), 3.05 (s, 3H,
SO2CH3), 7.27 (d, J = 8.1 Hz, 2H, 4-methylphenyl H-3,
H-5), 7.32 (d, J = 8.0 Hz, 1H, 4-methanesulfonamido-
phenyl H-3, H-5), 7.65 (d, J = 8.1 Hz, 2H, 4-methylphe-
nyl H-2, H-6), 7.70 (d, J = 15.6 Hz, 1H, COCH@CH),
7.80 (d, J = 15.6 Hz, 1H, COCH@CH), 8.10 (d,
J = 8.0 Hz, 2H, 4-methanesulfonamidophenyl H-2,
H-6), 10.05 (s, 1H, NH); MS: m/z (%): 315.1 (M+, 40),
300 (85), 236 (100), 221.2 (35), 208.2 (75), 165.0 (50),
119.1 (55), 91 (95), 77.2 (30). Anal. Calcd for
C17H17NO3S: C, 64.74; H, 5.43; N, 4.44. Found: C,
64.45; H, 5.32; N, 4.18.
5. Experimental
All chemicals and solvents used in this study were
purchased from Merck AG and Aldrich Chemical.
Melting points were determined with a Thomas–Hoover
capillary apparatus. Infrared spectra were acquired
using a Perkin-Elmer Model 550 SE spectrometer. Com-
pounds 7e and 7h have been described in a previous
study.21 A Bruker AM-300 NMR spectrometer was used
6.3. (E)-3-(4-Fluorophenyl)-1-(4-methanesulfonamidophe-
nyl)prop-2-en-1-one (7c)
1
to acquire H NMR spectra with TMS as internal stan-
dard. Coupling constant (J) values are estimated in hertz
(Hz) and spin multiples are given as s (singlet), d (dou-
ble), 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 online to a Data General DS 50 data
system. Electron-impact ionization 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.
Yield, 52%; pale yellow crystals; mp 192–195 °C; IR
(KBr): 3240 (NH), 1680 (C@O), 1140, 1300 (SO2) cmÀ1
;
1H NMR (DMSO-d6): d 3.10 (s, 3H, SO2CH3), 7.28 (d,
J = 8.1 Hz, 2H, 4-fluorophenyl H-2, H-6), 77.35 (d,
J = 8.5 Hz, 1H, 4-methanesulfonamidophenyl H-3,
H-5), 7.72 (d, J = 15.5 Hz, 1H, COCH@CH), 7.94 (dd,
JHH = 8.1 Hz, JHF = 5.5 Hz, 2H, 4-fluorophenyl H-3,
H-5), 7.88 (d, J = 15.5 Hz, 1H, COCH@CH), 8.15 (d,
J = 8.5 Hz, 2H, 4-methanesulfonamidophenyl H-2,
H-6), 10.35 (s, 1H, NH); MS: m/z (%): 319 (M+, 15),
240.2 (20), 183 (10), 149.0 (65), 121.1 (60), 101.0 (100),
91.2 (45). Anal. Calcd for C16H14FNO3S: C, 60.18; H,
4.42; N, 4.39. Found: C, 59.95; H, 4.65; N, 4.66.
6. General procedure for the synthesis of (E)-1,3-diphe-
nylprop-2-en-1-ones (7a–h)
6.4. (E)-1-(4-Methanesulfonamidophenyl)-3-(4-methoxy-
phenyl)prop-2-en-1-one (7d)
A 4-substituted-acetophenone (5a or 5b, 1 mmol) and a
4-substituted-benzaldehyde (6a–d, 1 mmol) were dis-
solved in a minimum amount of methanol (3–5 mL).
A NaOH pellet (100 mg, 2.5 mmol) was then added to
this solution, and the reaction was allowed to proceed
with stirring at 25 °C for a period of 30 min to 2 h prior
to neutralization with 2N HCl (2–3 mL). The solid prod-
uct 7 was collected on a filter, washed with cold metha-
Yield, 44%; pale yellow crystals; mp 132–135 °C; IR
(KBr): 3200 (NH), 1670 (C@O), 1120, 1300 (SO2) cmÀ1
;
1H NMR (DMSO-d6): d 3.12 (s, 3H, SO2CH3), 3.81 (s,
3H, OCH3), 7.00 (d, J = 8.5 Hz, 2H, 4-methoxyphenyl
H-3, H-5), 7.27 (d, J = 8.5 Hz, 2H, 4-methanesulfon-
amidophenyl H-3, H-5), 7.31 (d, J = 8.5 Hz, 2H,

A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
7049
4-methoxyphenyl H-2, H-6), 7.68 (d, J = 15.4 Hz, 1H,
COCH@CH), 7.77 (d, J = 15.4 Hz, 1H, COCH@CH),
7.92 (d, J = 8.5 Hz, 2H, 4-methanesulfonamidophenyl
H-2, H-6), 10.32 (s, 1H, NH); MS: m/z (%): 331.2
(M+, 10), 213.2 (30), 198.1 (100), 119.2 (65), 106 (60),
91.2 (60), 77.2 (95). Anal. Calcd for C17H17NO4S: C,
61.61; H, 5.17; N, 4.23. Found: C, 61.35; H, 5.45; N,
4.55.
4-azidophenyl H-2, H-6); MS: m/z (%): 279.1 (M+, 10),
253.2 (100), 238.1 (40), 207 (35), 120 (100), 91.2 (50).
Anal. Calcd for C16H13N3O2: C, 68.81; H, 4.69; N,
15.05. Found: C, 68.55; H, 4.85; N, 15.26.
6.9. Molecular modeling (docking) studies
Docking experiments were performed using Insight II
Software Version 2000.1 (Accelrys Inc.) running on a
6.5. (E)-1-(4-Azidophenyl)-3-phenylprop-2-en-1-one (7e)
Silicon Graphics Octane
2 R14000A workstation
according to a previously reported method.22
Yield, 72%; pale yellow crystals; mp 115–116 °C; IR
(KBr): 2080 (N3), 1670 (C@O) cmÀ1; 1H NMR (CDCl3):
d 7.13 (d, J = 8.5 Hz, 2H, 4-azidophenyl H-3, H-5),
7.42–7.44 (m, 3H, phenyl H-3, H-4, H-5), 7.52 (d,
J = 15.6 Hz, 1H, COCH@CH), 7.64–7.66 (m, 2H, phen-
yl H-2, H-6), 7.82 (d, J = 15.6 Hz, 1H, COCH@CH),
8.05 (d, J = 8.5 Hz, 2H, 4-azidophenyl H-2, H-6); MS:
m/z (%): 249.1 (M+, 10), 222.2 (80), 194.2 (25), 120.1
(100), 103 (25), 91 (45), 77.2 (35). Anal. Calcd for
C15H11N3O: C, 72.28; H, 4.45; N, 16.86. Found: C,
72.55; H, 4.86; N, 16.95.
6.10. 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 an enzyme immuno assay (EIA) kit
(catalog number 560101, Cayman Chemical, Ann
Arbor, MI, USA) according to our previously reported
method.22
Acknowledgment
6.6. (E)-1-(4-Azidophenyl)-3-(4-methylphenyl)prop-2-en-
1-one (7f)
We are grateful to the Canadian Institutes of Health
Research (CIHR) (MOP-14712) for financial support
of this research.
Yield, 60%; pale yellow crystals; mp 128 °C; IR (KBr):
2080 (N3), 1670 (C@O) cmÀ1; 1H NMR (CDCl3): d 2.40
(s, 3H, CH3), 7.13 (d, J = 8.5 Hz, 2H, 4-azidophenyl
H-3, H-5), 7.22 (d, J = 7.9 Hz, 2H, 4-methylphenyl H-3,
H-5), 7.48 (d, J = 15.6 Hz, 1H, COCH@CH), 7.55
(d, J = 7.9 Hz, 2H, 4-methylphenyl H-2, H-6), 7.80
(d, J = 15.6 Hz, 1H, COCH@CH), 8.05 (d, J = 8.5 Hz,
2H, 4-azidophenyl H-2, H-6); MS: m/z (%): 263.2
(M+, 5), 237 (100), 221.1 (35), 145 (30), 120 (100), 91
(45). Anal. Calcd for C16H13N3O: C, 72.99; H, 4.98; N,
15.96. Found: C, 73.25; H, 5.12; N, 16.10.
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. Gastroen-
terol. 2004, 18, 229.
4. 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.
5. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson,
S.; Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutch-
inson, 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.
6.7. (E)-1-(4-Azidophenyl)-3-(4-fluorophenyl)prop-2-en-1-
one (7g)
Yield, 70%; pale yellow crystals; mp 138–139 °C; IR
(KBr): 2120 (N3), 1670 (C@O)cmÀ1; 1H NMR (CDCl3):
d 7.12 (d, J = 8.4 Hz, 2H, 4-fluorophenyl H-2, H-6), 7.13
(d, J = 8.5 Hz, 2H, 4-azidophenyl H-3, H-5), 7.43 (d,
J = 15.5 Hz, 1H, COCH@CH), 7.94 (dd, JHH = 8.4 Hz,
JHF = 5.5 Hz, 2H, 4-fluorophenyl H-3, H-5), 7.78 (d,
J = 15.5 Hz, 1H, COCH@CH), 8.05 (d, J = 8.5 Hz,
2H, 4-azidophenyl H-2, H-6); MS: m/z (%): 267.2
(M+, 5), 200.9 (80), 165.9 (45), 116.9 (100), 94 (35).
Anal. Calcd for C15H10FN3O: C, 67.41; H, 3.77; N,
15.72. Found: C, 67.35; H, 3.95; N, 15.55.
´
6. Dogne, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem.
2005, 48, 2251.
7. Solomon, D. H. Arthritis Rheum. 2005, 52, 1968.
8. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. Lett. 2004, 14, 1953.
6.8. (E)-1-(4-Azidophenyl)-3-(4-methoxyphenyl)prop-2-
ene-1-one (7h)
Yield, 71%; yellow crystals; mp 121–122 °C; IR (KBr):
9. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. 2005, 13, 417.
2100 (N3), 1670 (C@O) cmÀ1 1H NMR (CDCl3): d
;
3.86 (s, 3H, OCH3), 6.94 (d, J = 8.4 Hz, 2H, 4-methoxy-
phenyl H-3, H-5), 7.12 (d, J = 8.5 Hz, 2H, 4-azidophenyl
H-3, H-5), 7.39 (d, J = 15.6 Hz, 1H, COCH@CH), 7.61
(d, J = 8.4 Hz, 2H, 4-methoxyphenyl H-2, H-6), 7.79 (d,
J = 15.6 Hz, 1H, COCH@CH), 7.80 (d, J = 8.5 Hz, 2H,
10. Uddin, M. J.; Rao, P. N. P.; McDonald, R.; Knaus, E. E.
J. Med. Chem. 2004, 47, 6108.
11. Uddin, M. J.; Rao, P. N. P.; Rahim, M. A.; McDonald,
R.; Knaus, E. E. Bioorg. Med. Chem. Lett. 2004, 14,
4911.

7050
A. Zarghi et al. / Bioorg. Med. Chem. 14 (2006) 7044–7050
12. Rao, P. N. P.; Chen, Q. H.; Knaus, E. E. Bioorg. Med.
Chem. Lett. 2005, 15, 4842.
18. Garavito, R. M.; DeWitt, D. L. Biochim. Biophys. Acta
1999, 1441, 278.
13. Zarghi, A.; Arfaee, S.; Rao, P. N. P.; Knaus, E. E. Bioorg.
Med. Chem. 2006, 14, 2600.
19. Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. J. Med. Chem.
2001, 44, 3039.
14. Potter, G. A.; Butler, P. C.; Wanogho, E. US Patent
6,787,672 B2, September 7, 2004.
20. Rao, P. N. P.; Uddin, M. J.; Knaus, E. E. J. Med. Chem.
2004, 47, 3972.
15. Hall, C. M.; Glenn, E. M. US Patent 4,279,930, July 21,
1981.
16. Lisa, R.; Marisca, A. J. J. Org. Chem. 1987, 52, 4377.
17. Kym, P. R.; Carlson, K. E.; Katzenellenbogen, J. A.
J. Med. Chem. 1993, 36, 1111.
21. Pomerantseva, L. L.; Smirnova, G. A.; Oleinik, A. V. Tr.
Khim. Tekhnol. 1972, 1, 14; . Chem. Abstr. 1973, 78,
159099w.
22. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. 2004, 12, 5929.