Design and synthesis of new 1,3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmc.2009.06.056

A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one (7b) as a potent (IC₅₀ = 0.05 μM) and selective (selectivity index = 259) COX-2 inhibitor.

Full text of DOI:10.1016/j.bmc.2009.06.056

Bioorganic & Medicinal Chemistry 17 (2009) 5369–5373
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of new 1,3-benzthiazinan-4-one derivatives
as selective cyclooxygenase (COX-2) inhibitors
a
b
c
Afshin Zarghi a, , Tannaz Zebardast , Bahram Daraie , Mehdi Hedayati
*
a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran
b Department of Toxicology, Tarbiat Modarres University, Tehran, Iran
c Endocrine Research Center, Shahid Beheshti University (M.C), Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new group of 1, 3-benthiazinan-4-ones, possessing a methyl sulfonyl pharmacophore, were synthe-
sized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In
vitro COX-1/COX-2 inhibition studies identified 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-
Received 14 June 2009
Revised 24 June 2009
Accepted 25 June 2009
Available online 27 June 2009
benzthiazinan-4-one (7b) as a potent (IC50 = 0.05
l
M) and selective (selectivity index = 259) COX-2
inhibitor.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Benzthiazinan-4-ones
COX-2 inhibition
SAR
1. Introduction
Alzheimer’s10 diseases still continue to attract investigations on
development of COX-2 inhibitors. The majority of selective COX-
2 inhibitors belong to a class of diarylheterocycles that possess vic-
inal diaryl substitution attached to a mono or bicyclic central ring
system.11–18 In this regard, many classes of selective COX-2 inhib-
itors such as coxibs have been developed with desired selectivity.
The coxibs (e.g., celecoxib and rofecoxib, Fig. 1)11,12 for treating
pain and inflammation associated with arthritis have been shown
to be well tolerated and reduce GI side effects. The recent market
withdrawal of some coxibs such as rofecoxib and valdecoxib due
to their adverse cardiovascular side effects19 clearly delineates
the need to develop alternative structures with COX-2 inhibitory
activity. In addition, some studies have suggested that rofecoxib
adverse cardiac events may not be a class effect but rather an
intrinsic chemical property related to its metabolism.20 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 molecular modeling studies for 1,3-thiazolidine-4-
ones17 and 1,3-thiazinan-4-ones18 possessing a five or six mem-
bered central ring and methylsulfonyl COX-2 pharmacophore at
the para-position of C-2 phenyl ring in conjunction with different
substituents at the N-3 of the central ring. For example, 3-(4-fluo-
rophenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazolidine-4-one and
3-benzyl-2-(4-methyl sulfonylphenyl)-1,3-thiazinan-4-one (see
structures 1 and 2) exhibited highly selectivity for COX-2 inhibi-
tion. As a part of our ongoing program to design new types of selec-
tive COX-2 inhibitors, we now report the design, synthesis,
cyclooxygenase inhibitory and some molecular modeling studies
The non-steroidal anti-inflammatory drugs (NSAIDs) are among
the most commonly medications in the world. The mechanism of
action of these drugs is the inhibition of cyclooxygenase (COX) en-
zyme, which catalyzes the first step of the biosynthesis of PGG2
from arachidonic acid.1 A major factor limiting their use is gastro-
intestinal toxicity, ranging from ulcer to perforation and bleeding.2
COX isozymes exist at least in two isoforms, COX-1 and COX-2.3
The COX isoforms are heme containing enzymes that exhibit dis-
tinct expression roles in several physiological processes. The con-
stitutive COX-1 isozyme is found in platelets, kidneys, and the
gastrointestinal tract and is believed to be responsible for the
maintenance of physiological functions such as gastro protection
and vascular homeostasis.4 In contrast, the COX-2 enzyme is the
inducible isoform that is produced by various cell types upon expo-
sure to cytokines, mitogens, and endotoxins released during injury
and therefore molecules that inhibit its enzymatic activity would
be of therapeutic value.5,6 The gastrointestinal side effects associ-
ated with NSAIDs are due to the inhibition of gastroprotective
PGs synthesized through the COX-1 pathway.7 Thus, selective inhi-
bition of COX-2 over COX-1 is useful for the treatment of inflam-
mation and inflammation-associated disorders with reduced
gastrointestinal toxicities when compared with NSAIDs. Moreover,
recent studies indicating the place of COX-2 inhibitors in cancer
chemotherapy8 and neurological diseases such as Parkinson9 and
* 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.2009.06.056

5370
A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5369–5373
Me
SO2NH2
SO2Me
N
N
O
O
F3C
Rofecoxib
Celecoxib
SO2Me
SO2Me
R
R
N
N
O
O
S
S
1
(R=4-Fluorophenyl)
2 (R=Benzyl)
SO2Me
R
N
O
S
Designed compounds
Figure 1. Some representative examples of COXIBs (celecoxib and rofecoxib), 1,3-thiazolidine-4-one (1), 1,3-thiazinan-4-one (2) lead compounds and our 1,3-benz thiazinan-
4-one scaffolds.
of a group of 1,3-benzthiazinan-4-one derivatives having a new
bicyclic central ring scaffold and different substituents at the N-3
in order to find the effect of these substituents on the inhibition
of COX-2 activity.
inhibit the COX-1 and COX-2 isozymes was determined using
chemiluminescent enzyme assays (see enzyme inhibition data in
Table 1.) according to our previously reported method.17 In vitro
COX-1/COX-2 inhibition studies showed that all compounds 7a–f
were selective inhibitors of the COX-2 isozyme with IC50 values
in the highly potent 0.05–0.12 lM range, and COX-2 selectivity in-
2. Chemistry
dexes (SI) in the 134.9–259.0 range. These data showed that the
nature and size of substituent attached to N-3 of 1,3-benzthiaz-
inan-4-one ring influenced both selectivity and potency for COX-
2 inhibitory activity. However, compound 7f showed less selectiv-
ity and potency for COX-2 isozyme compared with compound 7e
that may be explained by steric parameter. Our results indicated
that the introduction of suitable substituents such as F (7b) and
Me (7c) at the para-position of N-3 phenyl ring increased both
selectivity and potency for COX-2 inhibitory activity. According
to these results, 3-fluorophenyl-2-(4-methylsulfonyl phenyl)-1,3-
The target 1,3-benzthiazinan-4-one derivatives (7a–f) were
synthesized via the route outlined in Scheme 1. Accordingly, 4-
methylsulfonylbenzaldehyde (4) was treated with an appropriate
amine (5a–f) and thiosalicylic acid (6) in dry toluene in the pres-
ence of p-toluenesulfonic acid under reflux to give 2-(4-meth-
ylsulfonylphenyl)-3-substituted-1,3-benzthiazinan-4-one (7a–f,
33–73%).18 The purity of all products was determined by thin layer
chromatography using several solvent systems of different polar-
ity. All compounds were pure and stable. The compounds were
characterized by 1H nuclear magnetic resonance, infrared, mass
spectrometry and CHN analysis.
benzthiazinan-4-one 7b was the most potent (IC50 = 0.05
and selective (SI = 259), COX-2 inhibitor among the synthesized
compounds. It was more potent than celecoxib (IC50 = 0.06 M;
lM),
l
SI = 405) in terms of COX-2 inhibitory activity but showed less
selectivity. These data suggest that the compound 7b should inhi-
bit the biosynthesis of prostaglandins via the cyclooxgenase path-
way at sites of inflammation and be devoid of ulcerogenicity due to
the absence of COX-1 inhibition. The orientation of the highly po-
tent and selective COX-2 inhibitor, 3-fluorophenyl-2-(4-methylsul-
fonyl phenyl)-1,3-benzthiazinan-4-one 7b in the COX-2 active site
3. Results and discussion
A group of 1,3-benzthiazinan-4-one derivatives having different
substituents at the N-3 of central ring (7a–f) were prepared to
investigate the effect of different substituents on COX-2 selectivity
and potency. The ability of the 1,3-benzthiazinan-4-ones 7a–f to

A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5369–5373
5371
Trp387
Tyr385
Phe518
Ser353
Tyr348
Gly526
Val523
Ser530
Arg513
Val349
Ser353
Tyr355
Arg120
Figure 2. Compound 7b 3-(p-fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one docked in the active site of murine COX-2 isozyme. Hydrogen atoms of the
amino acid residues have been removed to improve clarity.
a
MeO2S
CHO
MeS
CHO
SO2Me
3
4
R
HS
COOH
N
4
+
+
H2N
R
b
O
S
5a, R=Phenyl
5b, R=4-F-phenyl
5c, R=4-Me-phenyl
5d, R=4-OMe-phenyl
5e, R=Benzyl
6
7a, R=Phenyl
5f, R=Phenethyl
7b, R=4-F-phenyl
7c, R=4-Me-phenyl
7d, R=4-OMe-phenyl
7e, R=Benzyl
7f, R=Phenethyl
Scheme 1. Reagents and conditions: (a) oxone, methanol/H2O, 2 h; (b) toluene, reflux, 48 h.
was examined by a docking experiment (Fig. 2).21 This molecular
modeling shows that it binds in the primary binding site such that
the C-2 para-SO2Me substituent inserts into the secondary pocket
present in COX-2 isozyme. One of the O-atoms of p-SO2Me forms
a hydrogen bonding interaction with the amino group of Arg513
(distance = 1.7 Å) whereas the other O-atom is close to the other
hydrogen of this amino acid (distance = 4.3 Å). The C@O of benz-
thiazinan-4-one ring is almost close to (distance = 5.8 Å) NH of
Val349. In addition, the phenyl moiety of the central ring is under-
going hydrophobic interactions with isopropyl group of Val349. It
was interesting to note that, the para-fluoro substituent of N-3
phenyl ring was forming a hydrogen bond with amide hydrogen
(NH) of Gly526 (distance = 5.4 Å). These observations together with
experimental results provide a good explanation for the potent and
selective inhibitory activity of 7b.
4. Conclusions
The results of this investigation indicate that (i) the 1,3-benz-
thiazinan-4-one moiety is a suitable scaffold (template) to design
COX-2 inhibitors, (ii) in this class of compounds COX-1/-2 inhibi-

5372
A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5369–5373
Table 1
5.2. Generalprocedureforpreparationof2-(4-methylsulfonylphenyl)-
3-substituted-1,3-benzthiazinan-4-one (7a–f)
In vitro COX-1/COX-2 enzyme inhibition assay data for 1,3-benzthiazinan-4-one
derivatives 7a–f
SO2Me
A mixture of 4-(methylsulfonyl)benzaldehyde 4 (20 mmol), an
appropriate amine 5a–f (30 mmol) and thiosalicylic acid
(30 mmol) 6 in 50 ml anhydrous toluene in the presence of p-tolu-
enesulfonic acid (100 mg) was refluxed for 48 h. After this time, the
solvent was removed in vacuo and the residue was extracted with
dichloromethane. The organic phase was washed with 2 M HCl, di-
lutes ammonium hydroxide and water and then dried (Na2SO4).
After removing the solvent, the solid product was recrystallized
in ethanol (yields: 33–73%). The physical and spectral data for
7a–f are listed below.
R
N
O
S
COX-2 SIb
a
Compound
R
IC50
COX-1
(l
M)
5.2.1. 2-(4-Methylsulfonylphenyl)-3-phenyl-1,3-benzthiazinan-
4-one (7a)
COX-2
7a
7b
7c
7d
7e
7f
Celecoxib
Phenyl
16.50
12.95
16.12
14.84
15.80
15.91
24.30
0.12
0.05
0.06
0.11
0.07
0.08
0.06
137.5
259.0
252.1
134.9
225.7
198.8
405
Yield, 33%; yellow crystalline powder, mp 218–219 °C; IR (KBr):
m
cmÀ1 1660 (C@O), 1310, 1150 (SO2); MS: m/z (%) 395.5 (M+,10),
4-F-phenyl
4-Me-phenyl
4-OMe-phenyl
Benzyl
340.0 (20), 310.0 (35), 221.0 (30), 175.0 (30), 136.0 (45), 106.1
(60), 91.1 (100); 1H NMR (DMSO-d6) d ppm 3.26 (s, 3H, SO2Me),
6.81 (s, 1H, CH), 6.87 (d, 1H, benzthiazinan H8, J = 7.9 Hz), 7.17–
7.47 (m, 5H, phenyl), 7.66 (m, 1H, benzthiazinan H6), 7.85 (m,
1H, benzthiazinan H7), 7.91 (d, 2H, 4-methylsulfonylphenyl H2
and H6, J = 7.8 Hz), 8.06 (d, 4-methylsulfonylphenyl H3 and H5,
J = 7.8 Hz), 8.33 (d, 1H, benzthiazinan H5, J = 7.8 Hz); Anal. Calcd
for C21H17NO3S2: C, 63.77; H, 4.33; N, 3.54. Found: C, 63.99; H,
4.61; N, 3.32.
Phenethyl
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).
tion is sensitive to the nature of the N-3 substituents, and (iii) 3-(p-
fluoropheny)-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-4-one
(7b) exhibited high COX-2 inhibitory potency and selectivity.
5.2.2. 3-(4-Fluorophenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzthiazinan-4-one (7b)
Yield, 55%;white crystalline powder, mp 221–223 °C; IR (KBr):
m
cmÀ1 1660 (C@O), 1310, 1145 (SO2); MS: m/z (%) 413.1 (M+, 20),
381.1 (40), 277.1 (100), 245.0 (80), 226.1 (20), 197.1 (40), 136.0
(50), 108.1 (30), 95.1 (30); 1H NMR (DMSO-d6) d ppm 3.05 (s, 3H,
SO2Me), 6.30 (s, 1H, CH), 7.18 (t, 2H, 4-fluorophenyl H3 and H5),
7.46 (dd, 2H, 4-fluorophenyl H2 and H6, JHH = 8.8 Hz, JHF = 4.7 Hz),
7.51 (d, 2H, 4-methylsulfonylphenyl H2 and H6, J = 8.3 Hz), 7.56
(d, 1H, benzthiazinan H8, J = 7.5 Hz), 7.65 (m, 1H, benzthiazinan
H6), 7.78 (m, 1H, benzthiazinan H7), 7.91 (d, 4-methyl sulfonylphe-
nyl H3 and H5, J = 8.3 Hz), 8.42 (d, 1H, benzthiazinan H5, J = 7.7 Hz);
Anal. Calcd for C21H16NO3S2F: C, 61.00; H, 3.90; N, 3.39. Found: C,
61.29; H, 4.21; N, 3.12.
5. Experimental
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 were estimated in hertz (Hz) and spin multiples
were given as s (singlet), d (double), t (triplet), q (quartet), m (mul-
tiplet), and br (broad). Low-resolution mass spectra were acquired
with a MAT CH5/DF (Finnigan) mass spectrometer that was cou-
pled 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, H
and N were within 0.4% of the theoretical values.
5.2.3. 3-(4-Methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzthiazinan-4-one (7c)
Yield, 71%; yellow crystalline powder, mp 250–251 °C; IR (KBr):
m
cmÀ1 1660 (C@O), 1300, 1145 (SO2); MS: m/z (%) 409.1 (M+, 5),
289.0 (90), 273.1 (30), 183.1 (100), 121.1 (40), 104.1 (20), 76.1
(30); 1H NMR (DMSO-d6) d ppm 2.14 (s, 3H, Me), 3.34 (s, 3H,
SO2Me), 5.26 (s, 1H, CH), 6.95 (d, 2H, 4-methylphenyl H3 and H5,
J = 7.1 Hz), 7.18 (d, 1H, benzthiazinan H8, J = 7.5 Hz), 7.31 (d, 2H,
4-methylphenyl H2 and H6, J = 7.1 Hz), 7.36 (d, 2H, 4-methylsulfo-
nylphenyl H2 and H6, J = 8.3 Hz), 7.44 (m, 1H, benzthiazinan H6),
7.50 (m, 1H, benzthiazinan H7), 7.76 (d, 4-methyl sulfonylphenyl
H3 and H5, J = 8.3 Hz), 8.36 (d, 1H, benzthiazinan H5, J = 7.7 Hz);
Anal. Calcd for C22H19NO3S2: C, 64.52; H, 4.68; N, 3.42. Found: C,
64.19; H, 4.31; N, 3.58.
5.1. Preparation of 4-(methylsulfonyl)benzaldehyde (4)
One milliliter of 2-(4-(methylthio)benzaldehyde dissolved in
5 ml of methanol and 5 g oxone in methanol/water (10 ml) was
added. The mixture was stirred at room temperature for 2 h. After
evaporation of methanol, the residue was extracted with ethyl ace-
tate and dried with sodium sulfate and then evaporated. The ob-
tained product was purified by column chromatography using
chloroform/methanol (95:5 v/v) as mobile phase. Yield, 21%; yel-
5.2.4. 3-(4-Methoxyphenyl)-2-(4-methylsulfonylphenyl)-1,3-
benzthiazinan-4-one (7d)
low crystalline powder; IR (KBr):
m
cmÀ1 2850, 2750 (C–H),
1660(C@O), 1360, 1120 (SO2); MS: m/z (%) 184.1 (M+, 10), 169.1
(30), 122.2 (75), 105.1 (90), 77.1 (100); 1H NMR(CDCl3): d ppm
3.15 (S, 3H, SO2Me), 8.14 (d, 2H, 4-methylsulfonylphenyl H2 and
H6, J = 8.4 Hz), 8.19 (d, 2H, 4-methylsulfonylphenyl H3 and H5,
J = 8.4 Hz), 10.19 (s, 1H, CH); Anal. Calcd for C8H8O3S: C, 52.16;
H, 4.38. Found: C, 52.42; H, 4.60.
Yield, 47%; brown crystalline powder, mp 203–205 °C; IR (KBr):
m
cmÀ1 1660 (C@O), 1300, 1150 (SO2); MS: m/z (%) 425.1 (M+, 5),
367.5 (10), 289.2 (100), 274.2 (90), 195.2 (60), 167.2 (50), 139.1
(40), 92.1 (30), 77.1 (50); 1H NMR (DMSO-d6) d ppm 3.07 (s, 3H,
SO2Me), 3.85 (s, 3H, OMe), 5.96 (s, 1H, CH), 6.96 (d, 2H, 4-methoxy-
phenyl H3 and H5, J = 7.0 Hz), 7.28 (d, 2H, 4-methoxyphenyl H2 and

A. Zarghi et al. / Bioorg. Med. Chem. 17 (2009) 5369–5373
5373
H6, J = 7.0 Hz), 7.36 (d, 2H, 4-methylsulfonylphenyl H2 and H6,
7. In vitro cyclooxygenase (COX) inhibition assays
J = 8.4 Hz), 7.77–7.80 (m, 2H, benzthiazinan H6 and H8), 7.87 (m,
1H, benzthiazinan H7), 7.93 (d, 4-methylsulfonyl phenyl H3 and
H5, J = 8.4 Hz), 8.42 (d, 1H, benzthiazinan H5, J = 7.8 Hz); Anal.
Calcd for C22H19NO4S2: C, 62.10; H, 4.50; N, 3.29. Found: C,
62.45; H, 4.81; N, 3.34.
The assay was performed using an enzyme chemiluminescent kit
(catalog number 760101, Cayman chemical, MI, USA) according to
our previously reported method.17 The Cayman chemical chemilu-
minescent 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 andthesubstratearachidonicacid. Arachidonate-induced
luminescence was shown to be an index of real-time catalytic activ-
ity 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.
5.2.5. 3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-benzthiazinan-
4-one (7e)
Yield, 39%, yellow crystalline powder, mp 210–211 °C; IR (KBr):
m
cmÀ1 1695 (C@O), 1300, 1140 (SO2); MS: m/z (%) 409.1 (M+, 10),
377.1 (50), 272.1 (60), 193.1 (40), 152.1 (70), 136.1 (80), 105.1 (40),
91.1 (100); 1H NMR (DMSO-d6) d ppm 3.23 (s, 3H, SO2Me), 3.96 (d,
1H, CH2, J = 15.2 Hz), 5.63 (s, 1H, CH), 5.92 (d, 1H, CH2, J = 15.2 Hz),
7.12 (d, 1H, benzthiazinan H8, J = 7.7 Hz), 7.26–7.31 (m, 5H, phe-
nyl), 7.32–7.34 (m, 2H, benzthiazinan H6 and H7), 7.37 (d, 2H, 4-
methylsulfonylphenyl H2 and H6, J = 7.9 Hz), 7.41 (d, 4-meth-
ylsulfonylphenyl H3 and H5, J = 7.9 Hz), 8.28 (d, 1H, benzthiazinan
H5, J = 7.9 Hz); Anal. Calcd for C22H19NO3S2: C, 64.52; H, 4.68; N,
3.42. Found: C, 62.85; H, 4.96; N, 3.64.
Acknowledgements
We are grateful to Research deputy of Shahid Beheshti Univer-
sity (M.C) for financial support of this research.
References and notes
5.2.6. 2-(4-Methylsulfonylphenyl)-3-phenethyl-1,3-benzthiazinan-4-
one (7f)
1. Otta, J. C.; Smith, W. L. J. Lipid Mediators Cell Signalling 1995, 12, 139.
2. Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Ann. Rev. Pharmacol. Toxicol. 1998, 38,
9704.
3. Xie, W. L.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.; Simmons, D. L. Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 2692.
Yield, 73%, white crystalline powder, mp 217–219 °C; IR (KBr):
m
cmÀ1 1665 (C@O), 1300, 1140 (SO2); MS: m/z (%) 423.1 (M+, 5),
391.1 (90), 376.1 (30), 312.1(90), 193.1 (40), 152.1 (70), 136.1
(80), 105.1 (40), 91.1 (100); 1H NMR (DMSO-d6) d ppm 3.07 (s,
3H, SO2Me), 3.10 (m, 2H, CH2), 3.50 (m, 1H, CH2), 4.45 (m, 1H,
CH2), 5.64 (s, 1H, CH), 7.24–7.33 (m, 6H, phenyl and benzthiazinan
H8), 7.41 (d, 2H, 4-methylsulfonyl phenyl H2 and H6, J = 8.4 Hz),
7.71–7.76 (m, 2H, benzthiazinan H6 and H7), 7.88 (d, 4-meth-
ylsulfonylphenyl H3 and H5, J = 8.4 Hz), 8.39 (d, 1H, benzthiazinan
H5, J = 7.9 Hz); Anal. Calcd for C23H21NO3S2: C, 65.22; H, 5.00; N,
3.31. Found: C, 64.95; H, 4.76; N, 3.60.
4. Laneuville, O.; Breuer, D. K.; DeWitt, D. L.; Hla, T.; Funk, C. D.; Smith, W. L. J.
Pharmacol. Exp. Ther. 1994, 271, 927.
5. Herschman, H. R. Biochem. Biophys. Acta 1996, 1299, 125.
6. Kanaoka, S.; Takai, T.; Yoshida, K. Adv. Clin. Chem. 2007, 43, 59.
7. Eberhart, C. E.; DuBois, R. N. Gasteroenterology 1995, 109, 285.
8. Kawamori, T.; Rao, C. V.; Seibert, K.; Reddy, B. S. Cancer Res. 1998, 58, 409.
9. Yasojima, K.; Tourtellotte, W. E.; McGeer, E. G.; McGeer, P. L. Neurology 2001,
57, 952.
10. Nivsarkar, M.; Banerjee, A.; Padh, H. Pharmacol. Rep. 2008, 60, 692.
11. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
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.
Satisfactory analysis for C, H, N was obtained for all the com-
pounds within 0.4% of the theoretical values.
12. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charlson, 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’Neil,
G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
Therien, M.; Vikers, 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.
13. Riendeau, D.; Percival, M. D.; Brideau, C.; Dube, C. S.; Ethier, D.; Falgueyret, J. P.;
Friesen, R. W.; Gordon, R.; Greig, G.; Guay, J.; Girard, Y.; Prasit, P.; Zamboni, R.;
Rodger, I. W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan, C. C. J.
Pharmacol. Exp. Ther. 2002, 296, 558.
14. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J.
L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J. Med. Chem. 2000, 43, 775.
15. Zarghi, A.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem. 2007, 15, 1056.
16. Zarghi, A.; Rao, P. N. P.; Knaus, E. E. J. Pharm. Pharm. Sci. 2007, 10, 159.
17. Zarghi, A.; Najafnia, L.; Daraee, B.; Dadrass, O. G.; Hedayati, M. Bioorg. Med.
Chem. Lett. 2007, 17, 5634.
18. Zebardast, T.; Zarghi, A.; Daraie, B.; Hedayati, M.; Dadrass, O. G. Bioorg. Med.
Chem. Lett. 2009, 19, 3162.
19. Dogné, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem. 2005, 48, 2251.
20. 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.
21. 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. Molecular modeling (docking) studies
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 (1cÂ2) 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.21