Synthesis and biological evaluation of methanesulfonamide analogues of rofecoxib: Replacement of methanesulfonyl by methanesulfonamido decreases cyclooxygenase-2 selectivity

Article abstract of DOI:10.1016/j.bmc.2006.10.023

A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl (MeSO₂) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO₂NH) moiety, and where the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and COX isozyme selectivity. Structure-activity relationship (SAR) studies showed that compounds having a neutral (H), or electronegative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2 selectivity indexes in the 3.1-39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective inhibitors of COX-2 (COX-1 IC₅₀ > 100 μM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.

Full text of DOI:10.1016/j.bmc.2006.10.023

Bioorganic & Medicinal Chemistry 15 (2007) 1056–1061
Synthesis and biological evaluation of methanesulfonamide
analogues of rofecoxib: Replacement of methanesulfonyl by
methanesulfonamido decreases cyclooxygenase-2 selectivity
Afshin Zarghi, P. N. Praveen Rao and Edward E. Knaus*
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta Edmonton, Alta., Canada T6G 2N8
Received 17 September 2006; accepted 11 October 2006
Available online 13 October 2006
Abstract—A new group of 3-(4-substituted-phenyl)-4-(4-methylsulfonamidophenyl)-2(5H)furanones in which the methylsulfonyl
(MeSO2) COX-2 pharmacophore present in rofecoxib was replaced by a methanesulfonamido (MeSO2NH) moiety, and where
the substituent at the para-position of the C-3 phenyl ring was simultaneously varied (H, F, Cl, Br, Me, OMe), were evaluated
to determine the combined effects of steric and electronic substituent properties upon COX-1 and COX-2 inhibitory potency and
COX isozyme selectivity. Structure–activity relationship (SAR) studies showed that compounds having a neutral (H), or electroneg-
ative halogen (F, Cl, Br), substituent at the para-position of the C-3 phenyl ring inhibited both COX-1 and COX-2 with COX-2
selectivity indexes in the 3.1–39.4 range. In contrast, compounds having an electron-donating Me or OMe substituent were selective
inhibitors of COX-2 (COX-1 IC50 > 100 lM). These SAR data indicate the 3-aryl-4-(4-methylsulfonamidophenyl)-2(5H)furanone
scaffold provides a suitable template to design COX inhibitors with variable COX-2 selectivity indexes.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
its withdrawal from the market, appear to be due to its
high COX-2 selectivity.3 A thorough in vitro assessment
of COX-2 selectivity, at drug concentrations that mimic
Identification of the selective cyclooxygenase-2 (COX-2)
inhibitory prototype ‘sulide’ compound NS-398 (1), and
the ‘coxib’ compound DuP 697 (2), served as the ratio-
nale for the original concept that a drug having a greater
selectivity for the proinflammatory inducible COX-2 iso-
zyme, relative to the cytoprotective constitutive COX-1
isozyme, would reduce the incidence of gastrointestinal
bleeding and renal toxicity (see structures in Fig. 1). Sub-
sequent drug discovery programs led to the clinical devel-
opment of the selective COX-2 inhibitors nimesulide (3),
celecoxib (4), and rofecoxib (5).1 Later it became evident
that rofecoxib may alter the balance in the cyclooxygen-
ase pathway resulting in a decrease in the level of the
vasodilatory and anti-aggregatory prostacyclin (PGI2),
in conjunction with a simultaneous increase in the level
of the prothrombotic thromboxane A2 (TxA2), that cul-
minated in increased incidences of an adverse cardiovas-
cular thrombotic event.2 The adverse cardiovascular
effects of rofecoxib associated with its use, that led to
NHSO2Me
MeO2S
O
R
Br
S
NO2
1, R = cyclohexyl
3, R = phenyl
F
2
H2NO2S
MeO2S
N
N
O
CF3
O
Me
Keywords: Cyclooxygenase inhibition; Rofecoxib analogues; Methane-
sulfonamido pharmacophore.
4
5
*
Figure 1. Structures of the selective cyclooxygenase-2 inhibitors NS-
398 (1), DuP 697 (2), nimesulide (3), celecoxib (4), and rofecoxib (5).
Corresponding author. Tel.: +1 780 492 5993; fax: +1 780 492
1217; e-mail: eknaus@pharmacy.ualberta.ca
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.10.023

A. Zarghi et al. / Bioorg. Med. Chem. 15 (2007) 1056–1061
1057
steady-state plasma levels produced at the therapeutic
dose, for a group of selective COX-2 inhibitors and
traditional non-steroidal anti-inflammatory drugs
(NSAIDs) has been reported. In this study, rofecoxib
was placed within a group of compounds having a
>50-fold COX-2 selectivity relative to celecoxib and
nimesulide which were placed within a group of com-
pounds having a 5- to 50-fold COX-2 selectivity.4
Scheme 1. Accordingly, reaction of 4-aminoacetophe-
none (6) with methanesulfonyl chloride in the presence
of triethylamine with dichloromethane as solvent affor-
ded 4-(methylsulfonamido)acetophenone (7, 70%). Bro-
mination of 7 using bromine in chloroform in the
presence of a catalytic quantity of AlCl3 furnished the
bromoacetyl derivative (8, 81%). Condensation of 8 with
a 4-substituted-phenylacetic acid (9a–f) in the presence
of triethylamine with acetonitrile as solvent yielded the
respective phenacyl phenylacetate product (10a–f,
78–84%). Cyclization of the esters (10a–f) using NaH
in DMSO gave the respective 4-(4-methylsulfonamid-
ophenyl)-3-(4-substituted-phenyl)-2(5H)furanone prod-
uct (11a–f, 31–42%).
The celecoxib SO2NH2 and rofecoxib SO2Me pharmaco-
phores are believed to induce COX-2 selectivity by
insertion into a secondary (2ꢁ) pocket that is present in
COX-2 but absent in COX-1. The oxygen and/or nitro-
gen atom in these pharmacophores undergo H-bonding
to arginine (Arg513) or the backbone amide NH of phen-
ylalanine (Phe518). Replacement of histidine (His513) in
COX-1 by arginine (Arg513) in COX-2 has been report-
ed to play a key role in the hydrogen-bond network of
the cyclooxygenase active site. Histidine (His90), gluta-
mine (Gln192), and tyrosine (Tyr355) control access of
ligands into the 2ꢁ COX-2 pocket.5 The interaction of
arginine (Arg513) with the bound ligand has been report-
ed to be a requirement for the time-dependent inhibition
of COX-2.6 It was therefore of interest to exploit the
presence of the arginine (Arg513) residue in the 2ꢁ-pock-
et of COX-2 by replacing the rofecoxib SO2Me pharma-
cophore by the nimesulide MeSO2NH pharmacophore
as a method to reduce the COX-2 selectivity of rofecoxib
that may reduce adverse cardiovascular effects. As part
of our ongoing program to acquire structure-function
relationship data for COX-2 inhibitors, we now describe
a group of rofecoxib analogues possessing a methylsulfo-
namido substituent at the para-position of the C-4 phen-
yl ring in conjunction with a variety of substituents (H,
F, Cl, Br, Me, OMe) at the para-position of the C-3
phenyl ring (11a–f).
3. Results and discussion
A group of rofecoxib analogues (11a–f) in which the
methylsulfonyl (MeSO2) COX-2 pharmacophore was re-
placed by a methanesulfonamido (MeSO2NH) moiety,
and where the substituent at the para-position of the
C-3 phenyl ring was simultaneously varied (H, F, Cl,
Br, Me, OMe), were evaluated to determine the com-
bined effects of steric and electronic substituent proper-
ties upon COX-1 and COX-2 inhibitory potency and
COX isozyme selectivity. SAR studies (IC50 values) to
determine the in vitro ability of the title compounds to
inhibit the COX-1 and COX-2 isozymes showed that
replacement of MeSO2 (rofecoxib) by MeSO2NH (11a)
reduced COX-2 potency and selectivity (see data in
Table 1). Compounds 11a–d having a neutral (H), or
electronegative (F, Cl, Br), R-substituent at the para-
position of the C-3 phenyl ring inhibited both COX-1
(IC50 values in the 10.0–35.5 lM range) and COX-2
(IC50 values in the 0.8–3.2 lM range) with COX-2 selec-
tivity indexes in the 3.1–39.4 range. In contrast, com-
pounds having an electron-donating R = Me (11e), or
R = OMe (11f), substituent were selective inhibitors of
COX-2 (COX-1 IC50 values >100 lM). Although the
chloro (11c, R = Cl), and methyl (11e, R = Me), com-
pounds were equipotent inhibitors of COX-2, the methyl
2. Chemistry
The target 3,4-diaryl-2(5H)furanones (11a–f) were syn-
thesized using the sequence of reactions illustrated in
H
H
Me
Me
N
R
H2N
N
b
a
S
S
O
O
+
O
O
O
O
O
C
C
C
Me
C
Me
8
9
7
O
OH
Br
6
H
N
c
C
Me
O
H
N
S
Me
O
9a-11a, R = H
9b-11b,R =F
9c-11c, R =Cl
9d-11d,R =Br
O
S
d
O
O
O
C
R
9e-11e,R = Me
9f-11f, R = OMe
O
O
O
R
10
11
Scheme 1. Reagents and conditions: (a) MeSO2Cl, NEt3, CH2Cl2, 0 ! 25 ꢁC, 3 h; (b) Br2, CHCl3, 0 ꢁC, 30 min; (c) NEt3, MeCN, 25 ꢁC, 30 min; and
(d) NaH, DMSO, 25 ꢁC, 4 h.

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A. Zarghi et al. / Bioorg. Med. Chem. 15 (2007) 1056–1061
Table 1. In vitro COX-1 and COX-2 enzyme inhibition data for 3,4-diaryl-2(5H)furanones 11a–f
H
Me
N
S
O
O
O
O
R
Selectivity index (SI)b
a
Compound
R
IC50 (lM)
COX-1
COX-2
11a
11b
H
31.6
10.0
1.7
3.2
18.5
3.1
F
Cl
11c
11d
31.5
35.5
0.8
3.2
39.4
11.1
Br
Me
OMe
11e
11f
>100
>100
>100
0.9
>111
>31
>200
31.5
0.5
Rofecoxib
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).
compound 11e was a selective inhibitor of COX-2 with a
selectivity index >111. Accordingly, 11e is a selective
inhibitor like rofecoxib, whereas 11c differs from rofec-
oxib since it inhibits both of the COX isozymes.
A molecular modeling (docking) study showed that the
selective COX-2 inhibitor 3-(4-methylphenyl)-4-(4-
methylsulfonamidophenyl)-2(5H)furanone (11e) binds
in the center of the primary binding site of the COX-
2 isozyme such that the NHSO2Me COX-2 pharmaco-
phore inserts into the COX-2 secondary pocket
(Val523, Arg513, Phe518, and His90) as illustrated in
Figure 2. One of the O-atoms of the NHSO2Me moiety
˚
is positioned about 5.16 A from the NH2 (guanidine
group) of Arg513. A hydrogen-bonding interaction
was observed between the other O-atom of the
NHSO2Me group and the NH of His90 (distance ꢀ
˚
3.17 A). In addition, the backbone C@O of Leu352 is
˚
located about 3.72 A from the NH of the NHSO2Me
group. The terminal Me of NHSO2Me is oriented to-
ward Ala516 and Gly519 within the COX-2 2ꢁ-pocket
(distance < 5 A). The C-3 4-methylphenyl moiety is ori-
˚
ented in a hydrophobic region at the apex of the COX-
2 channel where it is in close contact with Leu352,
˚
Trp387, Leu384, Gly526, and Tyr385 (distance < 5 A).
The ring O-atom of the central furanone ring is about
˚
4.32 A removed from the OH of Tyr355 at the mouth
Figure 2. 3-(4-Methylphenyl)-4-(4-methylsulfonamidophenyl)-2(5H)
uranone (11e) (ball and stick) docked in the binding site of murine
COX-2. Hydrogen atoms of the amino acid residues have been
removed to improve clarity.
of the COX-2 channel, and the distance between the
NH2 of Arg120 and the O-atom of the central fura-
˚
none ring is about 6.31 A. Interestingly, the furanone
C@O forms a hydrogen bond with the OH of Ser530
(distance = 3.53 A). These observations, together with
˚
4. Conclusions
the in vitro COX-2 inhibitor data, provide a rational
explanation for the high COX-2 selectivity and potency
exhibited by 3-(4-methylphenyl)-4-(4-methylsulfonamido-
phenyl)-2(5H)furanone (11e).
A group of 3-(4-substituted-phenyl)-4-(4-methylsulfon-
amidophenyl)-2(5H)furanones were synthesized to
determine their ability to inhibit the COX-1 and

A. Zarghi et al. / Bioorg. Med. Chem. 15 (2007) 1056–1061
1059
COX-2 isozymes. In vitro enzyme inhibition structure–
activity studies indicated that (i) replacement of the
MeSO2 pharmacophore in rofecoxib by a MeSO2NH
bioisostere provides a suitable scaffold (template) to
modulate the COX-2 selectivity index that is dependent
upon the specific substituent present at the para-position
of the C-3 phenyl ring, and (ii) compounds having a
neutral (H), or electronegative halogen (F, Cl, Br), substi-
tuent at the para-position of the C-3 phenyl ring inhibited
both COX-1 and COX-2. In contrast, compounds having
an electron-donating Me or MeO substituent at the same
position were selective inhibitors of COX-2.
solvent in vacuo gave a residue that was recrystallized
from EtOAc–hexane (1:2, v/v) to furnish 8 (3.2 g, 81%)
as white crystals; mp 189–191 ꢁC (lit.7 mp 190–191);
IR (film): 3380 (NH), 1705 (C@O), 1370, 1150 (SO2)
1
cmꢁ1; H NMR (CDCl3): d 3.24 (s, 3H, SO2CH3), 4.44
(s, 2H, CH2Br), 6.61 (s, 1H, NH), 7.51 (d, J = 8.2 Hz,
2H, phenyl H-3, H-5), 8.12 (d, J = 8.2 Hz, 2H, phenyl
H-2, H-6).
5.3. 4-Methylsulfonamidophenacyl phenylacetate (10a):
General procedure
4-Methylsulfamidophenacyl bromide
8
(582 mg,
2.0 mmol) was added to a solution of phenylacetic acid
9a (272 mg, 2.0 mmol) in acetonitrile (10 mL) containing
triethylamine (0.6 mL, 4.4 mmol) at 25 ꢁC with stirring.
The reaction was allowed to proceed for 1 h at 25 ꢁC
with stirring, the solvent was removed in vacuo, and
water (40 mL) was added to the residue. Extraction with
CH2Cl2 (3 · 50 mL). washing the combined organic
extracts with dilute hydrochloric acid, drying the organ-
ic fractions (Na2SO4), and removal of the solvent in vac-
uo gave a residue that was recrystallized from petroleum
ether–ethyl ether to afford 10a (560 mg, 81%) as white
needles; mp 118–119 ꢁC; IR (film): 3200 (NH), 1730,
1695 (C@O), 1375, 1150 (SO2) cmꢁ1; 1H NMR (CDCl3):
d 3.10 (s, 3H, SO2CH3), 3.83 (s, 2H, OCOCH2), 5.32 (s,
2H, OCH2CO), 7.0 (s, 1H, NH), 7.26 (d, J = 8.5 Hz, 2H,
4-methylsulfonamidophenyl H-3, H-5), 7.23–7.36 (m,
5H, phenyl), 7.88 (d, J = 8.5 Hz, 2H, 4-methylsulfon-
amidophenyl H-2, H-6).
5. Experimental
Melting points were determined using a Thomas–Hoover
capillary melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded as films with NaCl
plates on a Nicolet 550 Series II Magna FT-IR spectrom-
eter. Nuclear magnetic resonance (1H NMR) spectra
were recorded on a Bruker AM-300 spectrometer in
which coupling constants (J) were estimated in Hz. Ele-
mental analyses, performed for C, H, and N (Micro-
analytical Laboratory, Department of Chemistry, Uni-
versity of Alberta), were within 0.4% of theoretical
values. Silica-gel column chromatography was per-
formed using Merck silica gel 60 ASTM (70-230 mesh).
All reagents were purchased from Aldrich Chemical
Company (Milwaukee, WI), which were used without
further purification.
5.1. 4-(Methylsulfonamido)acetophenone (7)
Compounds 10b–f were prepared using a similar proce-
dure to that described above for 10a except that 9b–f
were used in place of 9a. The physical and spectral data
of 10b–f are listed below.
Methanesulfonyl chloride (1.8 mL, 24 mmol) was added
dropwise with vigorous stirring to a solution of
4-aminoacetophenone (6, 2.72 g, 20.0 mmol) and trieth-
ylamine (4.2 mL, 30 mmol) in CH2Cl2 (150 mL) at 0 ꢁC,
the cooling bath was removed, and the reaction was al-
lowed to proceed for 3 h at 25 ꢁC. Water (150 mL) was
added, the organic layer was separated and washed with
an aqueous NaHCO3 solution, and the organic fraction
was dried (Na2SO4). Removal of the solvent in vacuo
gave a residue that was recrystallized from petroleum
ether–ethyl ether to afford 7 (3.0 g, 70%) as white crys-
tals; mp 150–152 ꢁC (lit.7, mp 156.5–158.5 ꢁC); IR (film):
5.4. 4-Methylsulfonamidophenacyl 4-fluorophenylacetate
(10b)
Compound 10b was obtained as white needles in 81%
yield; mp 123 ꢁC; IR (film): 3240 (NH), 1725, 1685
1
(C@O), 1340, 1150 (SO2) cmꢁ1; H NMR (CDCl3): d
3.11 (s, 3H, SO2CH3), 3.81 (s, 2H, OCOCH2), 5.32 (s,
2H, OCH2CO), 6.86 (s, 1H, NH), 7.05 (d, JHCCF = 8.4
of d, JHCCH = 8.4 Hz, 2H, 4-fluorophenyl H-3, H-5),
7.25 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-
3, H-5), 7.32 (d, JHCCF = 8.4 Hz of d, JHCCH = 5.4 Hz,
2H, 4-fluorophenyl H-2, H-6), 7.90 (d, J = 8.4 Hz, 2H,
4-methylsulfonamidophenyl H-2, H-6).
3285 (NH), 1680 (C@O), 1335, 1150 (SO2) cmꢁ1 1H
;
NMR (CDCl3): d 2.60 (s, 3H, CH3CO), 3.11 (s, 3H,
SO2CH3), 6.75 (s, 1H, NH), 7.26 (d, J = 8.4 Hz, 2H,
phenyl H-3, H-5), 7.98 (d, J = 8.4 Hz, 2H, phenyl H-2,
H-6).
5.5. 4-Methylsulfonamidophenacyl 4-chlorophenylacetate
(10c)
5.2. 4-Methylsulfamidophenacyl bromide (8)
A catalytic amount of AlCl3 (10 mg), and then a solu-
tion of bromine (0.5 mL, 12.5 mmol) in CHCl3 (5 mL),
was added to a solution of 7 (3.0 g, 14.1 mmol) in CHCl3
(100 mL) at 0 ꢁC with vigorous stirring. The reaction
was allowed to proceed for 30 min with stirring prior
to addition of water (100 mL). The aqueous and organic
layers were separated, the aqueous fraction was extract-
ed with CHCl3 (2 · 30 mL), the two organic fractions
were combined, and dried (Na2SO4). Removal of the
Compound 10c was obtained as white needles in 79%
yield; mp 158–159 ꢁC; IR (film): 3325 (NH), 1730,
1705 (C@O), 1375, 1150 (SO2) cmꢁ1; 1H NMR (CDCl3):
d 3.12 (s, 3H, SO2CH3), 3.80 (s, 2H, OCOCH2), 5.34
(s, 2H, OCH2CO), 6.86 (s, 1H, NH), 7.25 (d, J =
8.4 Hz, 2H, 4-methylsulfonamidophenyl H-3, H-5),
7.33 (d, J = 8.2 Hz, 2H, 4-chlorophenyl H-2, H-6), 7.49
(d, J = 8.2 Hz, 2H, 4-chlorophenyl H-3, H-5), 7.98 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-2, H-6).

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A. Zarghi et al. / Bioorg. Med. Chem. 15 (2007) 1056–1061
5.6. 4-Methylsulfonamidophenacyl 4-bromophenylacetate
(10d)
10.15 (s, 1H, NH). Anal. Calcd for C17H15NO4SÆ1/
5H2O: C, 61.32; H, 4.66; N, 4.21. Found: C, 60.97;
H, 4.52; N, 4.10.
Compound 10d was obtained as white needles in 78%
yield; mp 160–161 ꢁC; IR (film): 3315 (NH), 1750,
1710 (C@O), 1375, 1155 (SO2) cmꢁ1; 1H NMR (CDCl3):
d 3.13 (s, 3H, SO2CH3), 3.78 (s, 2H, OCOCH2), 5.34
(s, 2H, OCH2CO), 6.86 (s, 1H, NH), 7.23 (d, J =
8.4 Hz, 2H, 4-methylsulfonamidophenyl H-3, H-5),
7.47 (d, J = 8.3 Hz, 2H, 4-bromophenyl H-2, H-6),
7.51 (d, J = 8.3 Hz, 2H, 4-bromophenyl H-3, H-5),
7.98 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl
H-2, H-6).
5.10. 3-(4-Fluorophenyl)-4-(4-methylsulfonamidophenyl)-
2(5H)furanone (11b)
Compound 11b was obtained as a yellow solid in 31%
yield; mp 92–93 ꢁC; IR (film) 3330 (NH), 1730 (furanone
1
CO), 1375, 1155 (SO2) cmꢁ1; H NMR (DMSO-d6): d
3.07 (s, 3H, SO2CH3), 5.35 (s, 2H, CH2), 7.16 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-3, H-5),
7.23–7.50 (m, 6H total, 4-fluorophenyl hydrogens,
4-methylsulfonamidophenyl H-2, H-6), 10.18 (s, 1H,
NH). Anal. Calcd for C17H14FNO4SÆ 2/3H2O: C,
56.82; H, 4.30; N, 3.90. Found: C, 56.85; H, 4.41; N,
3.54.
5.7. 4-Methylsulfonamidophenacyl 4-methylphenylacetate
(10e)
Compound 10e was obtained as white needles in 82%
yield; mp 158–159 ꢁC; IR (film): 3325 (NH), 1740,
1705 (C@O), 1365, 1165 (SO2) cmꢁ1; 1H NMR (CDCl3):
d 2.35 (s, 3H, CH3), 3.10 (s, 3H, SO2CH3), 3.79 (s, 2H,
OCOCH2), 5.31 (s, 2H, OCH2CO), 6.83 (s, 1H, NH),
7.18 (d, J = 7.8 Hz, 2H, 4-methylphenyl H-3, H-5),
7.21 (d, 2H, J = 7.8 Hz, 4-methylphenyl H-2, H-6),
7.26 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl
H-3, H-5), 7.89 (d, J = 8.4 Hz, 2H, 4-methylsulfonamido-
phenyl H-2, H-6).
5.11. 3-(4-Chlorophenyl)-4-(4-methylsulfonamidophenyl)-
2(5H)furanone (11c)
Compound 11c was obtained as a yellow solid in 42%
yield; mp 108–110 ꢁC; IR (film) 3305 (NH), 1750 (fura-
1
none CO), 1320, 1155 (SO2) cmꢁ1; H NMR (DMSO-
d6): 3.07 (s, 3H, SO2CH3), 5.35 (s, 2H, CH2), 7.16 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-3, H-5),
7.31 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl
H-2, H-6), 7.36 (d, 2H, J = 7.5 Hz, 4-chlorophenyl H-
3, H-5), 7.51 (d, J = 7.5 Hz, 2H, 4-chlorophenyl H-2,
H-6), 10.19 (s, 1H, NH). Anal. Calcd for C17H14-
ClNO4S: C, 56.12; H, 3.88; N, 3.85. Found: C, 56.40;
H, 4.17; N, 3.68.
5.8. 4-Methylsulfonamidophenacyl 4-methoxyphenylace-
tate (10f)
Compound 10f was obtained as white needles in 84%
yield; mp 151–152 ꢁC; IR (film): 3310 (NH), 1740,
1710 (C@O), 1365, 1155 (SO2) cmꢁ1; 1H NMR (CDCl3):
d 3.03 (s, 3H, SO2CH3), 3.69 (s, 2H, OCOCH2), 3.73 (s,
3H, OCH3), 5.22 (s, 2H, OCH2CO), 6.62 (s, 1H, NH),
6.80 (d, J = 8.4 Hz, 2H, 4-methoxyphenyl H-3, H-5),
7.16 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl
H-3, H-5), 7.19 (d, 2H, J = 8.4 Hz, 4-methoxyphenyl
H-2, H-6), 7.89 (d, J = 8.4 Hz, 2H, 4-methylsulfonamido-
phenyl H-2, H-6).
5.12. 3-(4-Bromophenyl)-4-(4-methylsulfonamidophenyl)-
2(5H)furanone (11d)
Compound 11d was obtained as a yellow solid in 36%
yield; mp 115–116 ꢁC; IR (film) 3300 (NH), 1745 (fura-
1
none CO), 1315, 1150 (SO2) cmꢁ1; H NMR (DMSO-
d6): 3.08 (s, 3H, SO2CH3), 5.35 (s, 2H, CH2), 7.17 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-3, H-5),
7.31 (d, J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl
H-2, H-6), 7.35 (d, 2H, J = 7.5 Hz, 4-bromophenyl H-
2, H-6), 7.62 (d, J = 7.5 Hz, 2H, bromophenyl H-3, H-
5), 10.19 (s, 1H, NH). Anal. Calcd for C17H14BrNO4S
Æ1/2 H2O: C, 48.93; H, 3.52; N, 3.36. Found: C, 48.55;
H, 3.14; N, 3.11.
5.9. 4-(4-Methylsulfonamidophenyl)-3-phenyl-2(5H)fura-
none (11a): General procedure
A solution of 10a (517 mg, 1.5 mmol) in dimethylsulf-
oxide (5 mL) was added dropwise to a stirred suspen-
sion of sodium hydride (100 mg, 4.2 mmol) in
dimethylsulfoxide (2 mL) at 25 ꢁC. The reaction was al-
lowed to proceed for 4 h at 25 ꢁC prior to pouring into
water (20 mL). Extraction with ethyl acetate
(3 · 25 mL), washing the combined ethyl acetate ex-
tracts with water, drying the organic fraction
(Na2SO4), and removal of the solvent in vacuo afforded
a residue. Purification of this residue by silica-gel col-
umn chromatography using ethyl acetate:hexane (1:1,
v/v) as eluent furnished 11a (201 mg, 41%) as yellow
needles; mp 206–207 ꢁC; IR (film) 3255 (NH), 1735
5.13. 3-(4-Methylphenyl)-4-(4-methylsulfonamidophenyl)-
2(5H)furanone (11e)
Compound 11e was obtained as yellow needles in 42%
yield; mp 199–200 ꢁC; IR (film) 3250 (NH), 1740 (fura-
1
none CO), 1340, 1150 (SO2) cmꢁ1; H NMR (DMSO-
d6): 2.34 (s, 3H, CH3), 3.06 (s, 3H, SO2CH3), 5.33 (s,
2H, CH2), 7.13–7.16 (m, 4H, 4-methylsulfonamidophe-
nyl H-3, H-5; 4-methylphenyl H-3, H-5), 7.22 (d,
J = 8.8 Hz, 2H, 4-methylphenyl H-2, H-6), 7.35 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-2, H-6),
10.1 (s, 1H, NH). Anal. Calcd for C18H17NO4SÆ1/2
H2O: C, 61.35; H, 5.10; N, 3.97. Found: C, 61.25; H,
4.74; N, 3.75.
(furanone CO), 1330, 1155 (SO2) cmꢁ1 1H NMR
;
(DMSO-d6): d 3.06 (s, 3H, SO2CH3), 5.36 (s, 2H,
CH2), 7.14 (d, J = 8.4 Hz, 2H, 4-methylsulfonamid-
ophenyl H-3, H-5), 7.28–7.48 (m, 7H total, 4-methyl-
sulfonamidophenyl H-2, H-6; phenyl hydrogens),

A. Zarghi et al. / Bioorg. Med. Chem. 15 (2007) 1056–1061
1061
5.14. 3-(4-Methoxyphenyl)-4-(4-methylsulfonamidophe-
nyl)-2(5H)furanone (11f)
Arbor, MI, USA) according to our previously reported
method.9
Compound 11f was obtained as a yellow solid in 39%
yield; mp 123–124 ꢁC; IR (film) 3250 (NH), 1750
Acknowledgment
(furanone CO), 1335, 1150 (SO2) cmꢁ1
;
1H NMR
(DMSO-d6): d 3.06 (s, 3H, SO2CH3), 3.78 (s, 3H,
OCH3), 5.31 (s, 2H, CH2), 7.01 (d, J = 8.7 Hz, 2H,
4-methoxyphenyl H-3, H-5), 7.15 (d, J = 8.4 Hz, 2H,
4-methylsulfonamidophenyl H-3, H-5), 7.31 (d,
J = 8.4 Hz, 2H, 4-methylsulfonamidophenyl H-2, H-
6), 7.37 (d, 2H, J = 8.7 Hz, 4-methoxy phenyl H-2,
H-6), 10.14 (s, 1H, NH). Anal. Calcd for C18H17-
NO5S: C, 60.15; H, 4.77; N, 3.90. Found: C, 60.51;
H, 4.46; N, 3.98.
We are grateful to the Canadian Institutes of Health
Research (CIHR) (MOP-14712) for financial support
of this research.
References and notes
1. Borne, R. F. In Foye’s Principles of Medicinal Chemistry,
5th ed., Williams, D. A.; Lemke, T. L., Eds; Lippincott,
Williams & Wilkins: Philadelphia, 2002; Chapter 32, pp
751–90.
2. Charlier, C.; Michaux, C. Eur. J. Med. Chem. 2003, 38, 645.
3. Dogne, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem.
2005, 48, 2251.
4. Warner, T. D.; Giuliano, F.; Vojnovic, I.; Bukasa, A.;
Mitchell, J. A.; Vane, J. R. Proc. Natl. Acad. Sci. U.S.A.
1999, 96, 7563.
5. Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.;
Browner, M. F. Nat. Struct. Biol. 1996, 3, 927.
6. Lorens, O.; Perez, J. J.; Palomer, A.; Mauleon, D. Biochim.
Biophys. Acta 1999, 278, 1441.
7. Uloth, R. H.; Kirk, J. R.; Gould, W. A.; Larsen, A. A.
J. Med. Chem. 1966, 9, 88.
6. Molecular modeling (docking) study
The docking experiment was performed using Insight II
software Version 2000.1 (Accelrys Inc.) running on a Sil-
icon Graphics Octane 2 R1400A workstation according
to a previously reported method.8
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 an enzyme immunoassay (EIA) kit
(catalog number 560101, Cayman Chemical, Ann
8. Praveen Rao, P. N.; Chen, Q.-H.; Knaus, E. E. J. Med.
Chem. 2006, 49, 1668.
9. Uddin, M. J.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med.
Chem. 2004, 12, 5929.