Synthesis and biological evaluation of 2-trifluoromethyl/sulfonamido-5,6-diaryl substituted imidazo[2,1-b]-1,3,4-thiadiazoles: A novel class of cyclooxygenase-2 inhibitors

Article abstract of DOI:10.1016/j.bmc.2007.09.038

A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives 15a-j have been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a-b and appropriately substituted α-bromo-1,2-(p-substituted)diaryl-1-ethanones 13a-h. Structures of these compounds were established by IR, ¹H NMR, ¹³C NMR, Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward COX-2 (80.6-49.4%) over COX-1 (30.6-8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory activity. These compounds also exhibited significant anti-inflammatory activity (70.09-42.32%), which is comparable to that of celecoxib in the carrageenan-induced rat paw edema method.

Full text of DOI:10.1016/j.bmc.2007.09.038

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 276–283
Synthesis and biological evaluation of 2-trifluoromethyl/
sulfonamido-5,6-diaryl substituted imidazo[2,1-b]-1,3,4-
thiadiazoles: A novel class of cyclooxygenase-2 inhibitors
b
b
b
Andanappa K. Gadad,a,b, Mahesh B. Palkar, K. Anand, Malleshappa N. Noolvi,
*
Thippeswamy S. Boreddyc and J. Wagwadec
aSchool of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, (St. Augustine), Champs Fleurs,
Mount Hope, Trinidad and Tobago, WI, USA
bDepartment of Medicinal Chemistry, J. N. Medical College, Belgaum, Karnataka 590 010, India
cPharmacology, College of Pharmacy, J. N. Medical College, Belgaum, Karnataka 590 010, India
Received 29 June 2007; revised 18 September 2007; accepted 19 September 2007
Available online 25 September 2007
Abstract—A series of 2-trifluoromethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole derivatives 15a–j have
been synthesized by the reaction of 2-amino-5-trifluoromethyl/sulfonamido-1,3,4-thiadiazoles 14a–b and appropriately substituted
a-bromo-1,2-(p-substituted)diaryl-1-ethanones 13a–h. Structures of these compounds were established by IR, 1H NMR, 13C NMR,
Mass, and HRMS data. The selected compounds were evaluated for their preliminary in vitro cyclooxygenase inhibitory activity
against COX-2 and COX-1enzymes using colorimetric method. The compounds tested showed selective inhibitory activity toward
COX-2 (80.6–49.4%) over COX-1 (30.6–8.6), amongst them compounds 15f and 15j showed appreciable COX-2 selective inhibitory
activity. These compounds also exhibited significant anti-inflammatory activity (70.09–42.32%), which is comparable to that of cele-
coxib in the carrageenan-induced rat paw edema method.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
tions in maintaining platelet aggregation and homeosta-
sis of the GI tract and the kidney.2 COX-2 is rapidly
induced in inflammatory cells in response to cytokines
such as tumor necrosis factor-a (TNF-a), interleukines,
growth factors, and so on. The PGs produced by COX-2
play an important role in inflammatory symptoms.3
COX-2 is also indicated in Cancer4 and Alzheimer’s dis-
eases.5 Recently a third full active isoform, COX-3, and
two partial isoforms, pCOX1a and b, in the cerebral
cortex and in human heart are reported.6,7
Prostaglandins (PGs) are active mediators of inflamma-
tory responses and also provide cytoprotection in the
stomach and intestine. The key enzyme of their biosyn-
thesis is prostaglandin H2 synthase (PGHS or cyclooxy-
genase, COX), which is a bifunctional enzyme exhibiting
both cyclooxygenase and peroxidase activities. The
cyclooxygenase component converts arachidonic acid
to a hydroperoxy endoperoxide (PGG2) and the perox-
idase component reduces the endoperoxide to the corre-
sponding alcohol (PGH2), the precursor of PGs,
thromboxanes, and prostacyclins.1 It is now well estab-
lished that three distinct COX isoforms exist: the consti-
tutive form COX-1 is expressed virtually in all tissues
and is involved in the regulation of physiological func-
Non-steroidal anti-inflammatory drugs (NSAIDs)
continue to be one of the more widely used groups of
therapeutic agents, which inhibit COX-1, COX-2, and
tromboxane synthase with a varying degree of selectiv-
ity. Researchers have recently focused on selective
COX-2 inhibitors which are believed to reduce inflam-
mation without influencing normal physiologic func-
tions of COX-1. The first COX-2 selective NSAID
approved by Food and Drug Administration (FDA)
was celecoxib8 (1), which was followed by introduction
of rofecoxib9 (2), valdecoxib10 (3), NS-39811 (4), DuP-
69712 (5), and SC-57666 (6). A common structural
Keywords: Cyclooxygenase; Anti-inflammatory activity; Imidazo[2,1-
b]-1,3,4-thiadiazoles; NSAIDs.
*
Corresponding author. Address: School of Pharmacy, Faculty of
Medical Sciences, The University of the West Indies, (St. Augustine),
Champs Fleurs, Mount Hope, Trinidad and Tobago, WI, USA.
Tel./fax: +1 868 662 1472; e-mail: akgadad@rediffmail.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.09.038

A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
277
backbone of most COX-2 selective inhibitors consists of
two aryl groups linked to adjacent atoms of a central
ring which can be homocyclic or heterocyclic, one of
the aryl groups is substituted in the para position with
either an aminosulfonyl (SO2NH2) or a methyl sulfonyl
(SO2CH3) group. There are also examples of potent
COX-2 inhibitors that possess cycloalkyl, alkoxy or
phenoxy moieties in the non-sulfonyl containing ‘aryl’
region.13–15 Some of the commonly found central rings
within this class of molecules are thiophene, pyrazole,
furanone, isoxazole, and cyclopentene as shown in
Figure 1.
b]thiazole moiety and also exhibits profound effect as
anti-arthritic and immuno-modulatory agent. The pres-
ently described compounds (15a–j) are bio-isosteric ana-
logs of imidazo[2,1-b]thiazole like L-766 112 (9).
Therefore, in view of the above facts and in continuation
of our search for biologically active imidazo[2,1-b]-1,3,4-
thiadiazoles,24 in this paper, we report the synthesis and
preliminary biological evaluation of a novel class of 2-
trifluoromethyl/sulfonamide-5,6-diarylsubstituted imi-
dazo[2,1-b]1,3,4-thiadiazoles as COX-2 inhibitors.
Since their introduction, COX-2 specific inhibitors have
become rapidly growing segment of prescription drug
market, especially for osteoarthritis and rheumatoid
arthritis patients. However, recently there is a controversy
regarding hepatic toxicity of nimusulide and cardiovascu-
lar complications of rofecoxib. FDA has banned the use
of nimusulide in pediatric patients and rofecoxib in both
adults and childrens.16 In spite of these facts, there is a
growing need for the development of safer COX-2 selec-
tive inhibitors. During recent past several attempts have
been made to develop safer COX-2 selective inhibitors
containing fused heterocyclic ring system in place of a
regular central single heterocycle. Now several different
classes of COX-2 inhibitors have been reported, like 5,6-
diarylspiro heptenes17 (7) and 5,6-diarylsubstituted thiaz-
olotriazole derivatives (8).18 Recently, a novel series of
5,6-diarylimidazo[2,1-b]thiazole derivatives (9) have been
reported as potent, orally active, selective COX-2 inhibi-
tors19 indicating the increasing scope of alteration in the
central ring that may lead to development of newer, safer,
selective COX-2 inhibitors (see Fig. 2).
2. Chemistry
Synthesis of 1,2-(p-substituted)diaryl-1-ethanones 12a–h
was carried out by reacting appropriate phenyl acetic
acid 10a,b with various substituted aromatic hydrocar-
bons 11a–e. Further, 12a and 12b were oxidized to cor-
responding sulfoxides 12f and 12h. Subsequently, 12a–h
were subjected to bromination using liquid bromine in
chloroform to obtain a-bromo-1, 2-(p-substituted)dia-
ryl-1-ethanones 13a–h as shown in Scheme 1.25–27
The synthesis of 2-trifluoromethyl/sulfonamido-5,6-
diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazole deriva-
tives 15a–j was carried out by the condensation of 13a–h
with 2-amino-5-substituted-1,3,4-thiadiazole 14a,b under
reflux in dry ethanol (as depicted in Scheme 2). This reac-
tion28 proceeds via intermediate iminothiadiazole I,
which spontaneously undergoes ring closer to II under re-
flux temperature to afford the desired fused heterocycles
15a–j in good yields.
The substitution at 5th position of 2-amino-5-substituted-
1,3,4-thiadiazole is crucial in determining the course of its
reaction with substituted a-bromo-1,2-(p-substi-
tuted)diaryl-1-ethanone, such type of reactions has been
studied by deStevens et al.29 in case of 2-amino-5-substi-
tuted-1,3,4-thiadiazole derivatives and Therien et al.19
in case of 2-amino-5-substituted thiazole derivatives. Pyl
et al.30 have described the synthesis 5,6-unsubstituted dia-
ryl imidazo[2,1-b]-1,3,4-thiadiazole derivatives starting
Thiazole (sulfathiazole/cefixime),20 imidazo[2,1-b]thia-
zole and their bio-isosteric derivatives thiadiazole
(acetazolamide),21 imidazo[2,1-b]1,3,4-thiadiazole22 are
regarded as safer and better drug molecules that are found
to possess diversified biological activities like antibacte-
rial, diuretic, antifungal, leismaniacidal, antitubercular,
anticancer, anticonvulsant, etc. In addition, levamisole,23
a well-known anthelmintic drug, contains imidazo[2,1-
SO2Me
SO2NH2
SO2NH2
H3C
N
N
O
O
F3C
N
CH3
O
Celecoxib (1)
Valdecoxib (3)
Rofecoxib (2)
F
SO2Me
MeO2S
NH
O
Br
S
NO2
F
SO2Me
NS-398 (4)
SC-57666 (6)
DuP 697 (5)
Figure 1. Structures of some selective COX-2 NSAIDs characterized by diaryl carbocyclic or heterocyclic 5-membered ring (1–6).

278
A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
SO2Me
OCH3
SO2Me
F
N
N
N
S
N
SO2Me
R
F3C
N
S
(7)
(8)
L-766,112 (9)
R
R1
R1
N N
N N
S
N
N
F3C
H2NO2S
S
(15g-j)
(15a-f)
Figure 2. Structures of some selective COX-2 inhibitors containing a central fused heterocyclic ring system (7–9) and synthesized compounds (15a–f
and 15g–j).
R
R
R
R1
(a)
(c)
+
R1
R1
Br
13a, R= H, R1= SCH3
13b, R= OCH3, R1= SCH3
13c, R= OCH3, R1= OCH3
13d, R= OCH3, R1= H
13e, R= H, R1= CH3
13f, R= H, R1= SO2CH3
13g, R= OCH3, R1= F
13h, R= OCH3, R1= SO2CH3
O
O
11a, R1= H
COOH
11b, R1=F
12a-e, g
10a, R = H
10b, R =OCH3
11c, R1= CH3
11d, R1= OCH3
11e, R1= SCH3
12a, R= H, R1= SCH3
12b, R= OCH3, R1= SCH3
12c, R= OCH3, R1= OCH3
12d, R= OCH3, R1= H
12e, R= H, R1= CH3
(c)
12g, R= OCH3, R1= F
R
R
(b)
R1
R1
O
O
12a, b
12f, h
12a, R= H, R1= SCH3
12b, R= OCH3, R1= SCH3
12f, R= H, R1= SO2CH3
12h, R= OCH3, R1= SO2CH3
Scheme 1. Reagents and conditions: (a) H3PO4, (CF3CO)2O, 25 ꢁC, 1 min; (b) H2O2/AcOH, 50–60 ꢁC, 3–4 h, in case of 12a and 12b; (c) Br2, CHCl3,
50 ꢁC, 0.5 h.
with 2-amino-5-substituted-1,3,4-thiadiazole with bulk-
ier (electron donating) group at 5th position.
matory activity for compounds 15a–d, f, g, i, and j
was also evaluated using carrageenan-induced rat paw
edema model by adopting the earlier reported method
of Winter et al.32
3. Biological evaluation
The synthesized compounds 15a–d, f, g, i, and j were
evaluated for their ability to inhibit COX-2 and COX-
1 by in vitro colorimetric COX (ovine) inhibitor assay
method,31 which utilizes the peroxidase component of
cyclooxygenase. The peroxidase activity is assayed col-
orimetrically by monitoring the appearance of oxidized
N,N,N0,N0-tetramethyl-p-phenylene diamine (TMPD)
during the reduction of PGG2 to PGH2, at 590 nm.
The IC50 values for 15f and 15j were calculated using
non-linear regression analysis. The in vivo anti-inflam-
4. Results and discussion
We have synthesized a series of 2-trifluoromethyl/sulfon-
amido-5,6-diarylsubstituted
imidazo[2,1-b]-1,3,4-thi-
adiazole derivatives by reacting 2-amino-5-substituted-
1,3,4-thiadiazole with an appropriately substituted
a-bromo-1,2-(p-substituted)diaryl-1-ethanone as illus-
trated in Scheme 2. Structures of the synthesized
compounds were established on the basis of IR, 1H
NMR, 13C NMR Mass, and HRMS data.

A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
279
R
N N
S
(a)
13a-h
+
R2
NH2
R1
Br
H
O
+
N N
14a, R2= CF3
14b, R2= SO2NH2
R2
S
NH
I
- HBr
R
4'
R
R1
5
R1
H
4
3
4''
- H2O
N N
6
N N
S
7a N
OH
R2
2
N
7
S
R2
1
15a-j
II
a: R= H, R1= SCH3, R2= CF3
b: R= OCH3, R1= SCH3, R2= CF3
c: R= OCH3, R1= OCH3, R2= CF3
d: R= OCH3, R1= H, R2= CF3
e: R= H, R1= CH3, R2= CF3
g: R= OCH3, R1= OCH3, R2= SO2NH2
h: R= OCH3, R1= H, R2= SO2NH2
i: R= OCH3, R1= F, R2= SO2NH2
j: R= OCH3, R1= SO2CH3, R2= SO2NH2
f: R= H, R1= SO2CH3, R2= CF3
Scheme 2. Reagents and conditions: (a) EtOH, P2O5, reflux, 12–14 h, Na2CO3.
In 1H NMR spectra the synthesized compounds showed
prominent signals for the aromatic protons between d
6.83 and 8.26 ppm. Compounds 15g–j showed a singlet
between d 8.63 and 8.8 ppm indicating the presence of
SO2NH2 group. The peaks appearing at around d
1.22, 1.96–2.03, 3.10, and 3.78–3.88 ppm confirm the
presence of CH3, SCH3, SO2CH3, and OCH3 groups,
respectively. In 13C NMR spectrum we have observed
most characteristic signals appeared at around d 14.9,
24.3, 46.3, 54.9–60.0, and 120.0 ppm, for SCH3, CH3,
SO2CH3, OCH3, and CF3, respectively. The signals ap-
peared at around d 107.0, 114.0, 143.0, 162.0 ppm for
C-5, C-6, C-7a, C-2 and carbons of aromatic rings at d
127.0–134.0 ppm, respectively. Electron Impact mass
spectra showed accurate molecular ion peaks at m/z
392.3, 421.9, 406.6, 375.5, 424.2, 415.9, 386.2, and
403.1 for compounds 15a–d and 15f–i, respectively.
OCH3 and F, showed moderate inhibitory activity to-
ward both COX-2 and COX-1, respectively, at 10 lM
concentration.
The structure–activity relationship (SAR) studies dem-
onstrated that the presence of OCH3, SCH3, SO2CH3,
and F groups at the 400-position of the 6-phenyl ring con-
tributes for selective COX-2 inhibitory activity and the
unsubstituted phenyl ring as in case of 15d (49.4%,
30.6%) was found to inhibit both COX-2 and COX-1.
However, we observed that replacement of SO2NH2
for CF3 group at second position did not alter the selec-
tivity and enzyme inhibitory activity to a greater extent.
The synthesized compounds were further assessed for
in vivo anti-inflammatory activity in carrageenan-in-
duced rat paw edema model. The results presented in
Table 1 show that compounds 15a (37.6%, 54.1%), 15b
(42.3%, 66.1%), 15c (38.0%, 48.7%), 15f (46.7%,
70.0%), 15i (43.4%, 51.72%), and 15j (54.2%, 61.2%)
exhibited good anti-inflammatory activity at the dose
of 10 mg/kg at 2 and 4 h, respectively, which is compa-
rable to celecoxib (48.3%, 64.8%).
The results of in vitro COX enzyme inhibition assay
studies are summarized in Table 1. The results showed
that the compounds 15f and 15j exhibited effective inhi-
bition against COX-2 (73.6% and 80.6%), compared to
the inhibition of COX-1 (8.6% and 13.3%), indicating
that the SO2CH3 group is accountable for the diaryl het-
erocyclic inhibitors’ selective inhibition against COX-2.
Further, compounds 15f and 15j showed the IC50 values
4.79 and 3.24 lM against COX-2 and more than 50 lM
against COX-1, respectively (Celecoxib IC50 value is
0.04 and 13 lM against COX-2 and COX-1, respec-
tively). Compounds 15a (65.8%, 14.2%), 15b (63.2%,
10.5%), 15c (66.5%, 15.5%), and 15i (66.2%, 12.9%),
containing different functional groups like SCH3,
5. Conclusion
In the present paper, we report the synthesis, spectral
studies, and cyclooxygenase inhibition (COX-2 and
COX-1) and anti-inflammatory activity of a novel series
of imidazo-[2,1-b]-1,3,4-thiadiazoles. These fused het-
erocyclic compounds were prepared by the cyclodehy-
dration process between 2-amino-5-trifluoromethyl/

280
A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
Table 1. In vitro COX-1 and COX-2 enzyme inhibition data and in vivo anti-inflammatory activity data for compounds 15a–j
R
4'
R1
5
4
N
3
N
4''
6
7a N
R2
2
7
S
1
Compound
Structure
R1
% Inhibitiona,b
% Reduction in paw edemac,d
R
R2
COX-1 (10 lM)
COX-2 (10 lM)
2 h
4 h
15a
15b
H
SCH3
SCH3
OCH3
H
CF3
CF3
14.2
10.5
65.8
63.2
37.64 1.87
42.38 2.26
38.03 2.80
29.62 3.75
ND
54.16 3.50
66.16 2.87
48.78 5.75
42.32 4.96
ND
OCH3
OCH3
OCH3
H
15c
15d
CF3
CF3
15.5
30.6
NDe
8.6 (>50)f
28.1
ND
66.5
49.4
15e
15f
CH3
CF3
CF3
ND
H
SO2CH3
OCH3
H
73.6 (4.79)
58.9
ND
46.73 3.80
24.68 2.08
ND
70.09 4.65
37.05 3.72
ND
15g
15h
OCH3
OCH3
OCH3
OCH3
SO2NH2
SO2NH2
SO2NH2
SO2NH2
15i
15j
F
SO2CH3
12.9
13.3 (>50)
2.8 (13)
66.2
80.6 (3.24)
100 (0.04)
43.49 5.24
54.28 4.60
48.31 3.48
51.72 2.48
61.29 5.69
64.83 4.49
Celecoxib
a Values are acquired using in vitro ovine COX-1/COX-2 assay kit (Catalog No. 760 111, Cayman Chemicals Inc., Ann Arbor, MI).
b Experiments were carried out in duplicate and have less than 10% error.
c Values (Mean SE) are obtained using in vivo carrageenan-induced rat paw edema model, using six animal per group of male albino rats.
d Test compounds and celecoxib were administered orally at the dose of 10 mg/kg.
e Not determined.
f Values in bracket are IC50 in lM.
sulfonamido-1,3,4-thiadiazoles and a-bromo-1,2-(p-
substituted)diaryl-1-ethanones.
E-Merck Co and compounds visualized either by expo-
sure to UV or dipping in 10% aqueous potassium per-
manganate solution.
The preliminary in vitro and in vivo biological activities of
these novel series of 2-trifluoromethyl/sulfonamido-5,6-
diarylsubstituted imidazo[2,1-b]-1,3,4-thiadiazoles have
evidenced that 400-SO2CH3 substituted analogs 15f and
15j are more selective and active than 400-OCH3 (15c and
15g) and 400-SCH3 (15a and 15b) analogs. Furthermore,
replacement of the 400-SO2CH3 group with F as in case
of compound 15i also has shown moderate selectivity.
On the contrary, the replacement of CF3 by SO2NH2
group at second position showed no greater change in
selectivity and COX inhibitory activity. The possible
improvement of selective COX-2 inhibitory activity of
this basic imidazo[2,1-b]-1,3,4-thiadiazole structure
through modulation of ring substituents and/or addi-
tional functionation warrants further investigations. In
summary, we have identified a novel series of imi-
dazo[2,1-b]-1,3,4-thiadiazoles, which may develop into
the potential class of safer and selective COX-2 inhibitors.
Melting points were determined using open capillary
tube method and are uncorrected. Infra-red (IR) spectra
were recorded using KBr disk on a ThermoNicolet MX-
1
1 FTIR spectrometer; H NMR and 13C NMR spectra
were recorded on Bruker AMX-400 and 101 MHz,
respectively. Chemical shifts are reported in d ppm units
with respect to TMS as internal standard. Mass spectra
were recorded on Autospec Mass Spectrometer under
the electron impact at 70 eV.
6.1.1. General procedure for the synthesis of 1-(400-substi-
tuted)phenyl-2-(40-substituted)phenyl-1-ethanones (12a–e,g,
Scheme 1). To a mixture of phenyl acetic acid/p-substi-
tuted phenyl acetic acid (10a/b, 7.3 mmol), substituted
aromatic hydrocarbon (one of 11a–e, 8.8 mmol), and
88–93% orthophosphoric acid (8.8 mmol) was added tri-
fluoroacetic anhydride (29.5 mmol) rapidly with vigor-
ous stirring at 25 ꢁC. The mixture turned into a dark
colored solution with vigorous exothermic reaction.
The reaction mixture was stirred for 1 min at the same
temperature and poured into ice-cold water (50 mL)
with stirring. Then it was washed with cold hexane
(2· 10 mL) to obtain 12a–e, g as solid.
6. Experimental
6.1. Chemistry protocols
All research chemicals were purchased from Sigma–Al-
drich or Lancaster Co., and used as such for the reac-
tions. Solvents except LR grade were dried and
purified according to the literature when necessary.
Reactions were monitored by thin-layer chromatogra-
phy (TLC) on pre-coated silica gel GF254 plates from
6.1.2. General procedure for the synthesis of 1-(400-
methylsulfonyl)phenyl-2-(40-substituted)phenyl-1-ethanon-
es (12f,h). Thirty percent of hydrogen peroxide solution
(3.5 mL, 29.41 mmol) was slowly added to a mixture of
1-(400-methylsulfanyl)phenyl-2-(40-substituted)phenyl-1-

A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
281
ethanones (12a/b, 8.0 mmol) in glacial acetic acid
(12 mL). The reaction mixture was heated at 50 ꢁC for
3–4 h. The cooled mass was poured over ice water and
extracted with dichloromethane. The combined organic
layer was washed with water, dried, and evaporated.
The crude solid was triturated with dichloromethane–
petroleum ether mixture to get 12f,h as light yellow/
brown solid.
6.2.2. 2-Trifluoromethyl-5-(40-methoxyphenyl)-6-(400-(meth-
ylthio)phenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15b). This
was obtained by reacting 2-amino-5-trifluoromethyl-
1,3,4-thiadiazole (14a,1.69 g) and a-bromo-1-(400-(meth-
ylthio)phenyl)-2-(40-methoxy)phenyl-1-ethanone (13b,
3.51 g) as described in the general procedure and iso-
lated as cream colored crystals. Yield: 2.56 g (60.90%);
mp 142–144 ꢁC; IR (KBr) mmax 3129, 2964, 2841, 1609,
1519, 1495, 1328, 1193, 1146, 745 cmꢀ1 1H NMR
;
6.1.3. General procedure for the synthesis of a-bromo-1-
(400-substituted)phenyl-2-(40-substituted)phenyl-1-ethanones
(13a–h). To a solution of 12a–h (200 mmol) in chloro-
form (30 mL) kept at 50 ꢁC was added dropwise bro-
mine (220 mmol) with stirring. After being stirred at
50 ꢁC for 0.5 h, the mixture was washed successively
with aqueous 10% sodium thiosulfate solution and
water.
(CDCl3) d 8.12 (d, J = 8.8 Hz, 2H, aryl-H), 8.08 (d,
J = 8.4 Hz, 2H, aryl-H), 7.82 (d, J = 8.9 Hz, 2H, aryl-
H), 7.80 (d, J = 8.8 Hz, 2H, aryl-H), 3.78 (s, 3H, 40-
OCH3), 1.96 (s, 3H, 400-SCH3) ppm; 13C NMR (CDCl3)
d 163.7, 159.1, 143.1, 136.4, 129.5, 128.5, 127.7, 126.8,
126.3, 123.2, 120.0, 114.5, 58.5, 14.9 ppm; EI-MS m/z
(relative intensity) 421 (M+, 40%), 391 (77%), 350
(54%), 288 (12%), 270 (24%), 242 (67%), 169 (100%),
148 (41%), 120 (20%); HRMS (EI) m/z calcd for
C19H14F3N3OS2: 421.4592; found: 421.4584.
The solvent was removed in vacuo to obtain the title
compounds (13a–h) either as oil/solid mass/crystalline
compounds.
6.2.3. 2-Trifluoromethyl-5-(40-methoxyphenyl)-6-(400-meth-
oxyphenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15c). This was
obtained by reacting 2-amino-5-trifluoromethyl-1,3,4-
thiadiazole (14a, 1.69 g) and a-bromo-1-(400-methoxy)-
phenyl-2-(40-methoxy)phenyl-1-ethanone (13c, 3.35 g)
as described in the general procedure and isolated as white
crystals. Yield: 2.32 g (57.35%); mp 110–112 ꢁC; IR (KBr)
mmax 3104, 2969, 2814, 1597, 1442, 1339, 1256, 1169,
6.2. General procedure for the synthesis of 2-trifluorom-
ethyl/sulfonamido-5,6-diarylsubstituted imidazo[2,1-b]-
1,3,4-thiadiazole (15a–j, Scheme 2)
A mixture of 2-amino-5-substituted-1,3,4-thiadiazole
(one of 14a–b, 10 mmol) and an appropriate a-bromo-
1-(400-substituted)phenyl-2-(40-substituted)phenyl-1-eth-
anone (one of 13a–h, 10 mmol) in dry ethanol (150 mL)
was heated to reflux on a water bath for 6–8 h, phospho-
rus pentoxide (3 mmol) was added, and refluxing was
continued for another 4–6 h. The reaction mixture was
cooled overnight at room temperature. Excess of solvent
was removed under reduced pressure and the solid
hydrobromide separated was filtered, washed with cold
ethanol, and dried. Neutralization of hydrobromide
salts with cold aqueous solution of Na2CO3 yielded
the corresponding free bases (15a–j), which were purified
by recrystallization from dry ethanol. Further, the com-
pounds were purified by column chromatography using
200–400 mesh silica gel and eluted either with ethyl ace-
tate/hexane (2:8) or chloroform/hexane (1:9) as mobile
phase.
1
755 cmꢀ1; H NMR (CDCl3) d 8.01 (d, J = 8.8 Hz, 2H,
aryl-H), 7.98 (d, J = 8.8 Hz, 2H, aryl-H), 7.17 (d,
J = 8.5 Hz, 2H, aryl-H), 6.85 (d, J = 8.6 Hz, 2H, aryl-
H), 3.88 (s, 3H, 40-OCH3), 3.85 (s, 3H, 400-OCH3) ppm;
13C NMR (CDCl3) d 164.5, 159.7, 145.0, 135.3, 129.7,
129.2, 128.8, 127.5, 125.4, 123.6, 120.9, 114.8, 56.5,
57.1 ppm; EI-MS m/z (relative intensity) 406 (M+, 45%),
365 (20%), 316 (33%), 276 (14%), 239 (45%), 193 (60%),
165 (62%), 148 (35%), 121 (100%), 104 (77%); HRMS
(EI) m/z calcd for C19H14F3N3O2S: 405.3936; found:
405.3931.
6.2.4. 2-Trifluoromethyl-5-(40-methoxyphenyl)-6-pheny-
limidazo[2,1-b]-1,3,4-thiadiazole (15d). This was ob-
tained by reacting 2-amino-5-trifluoromethyl-1,3,
4-thiadiazole (14a, 1.69 g) and a-bromo-1-phenyl-2-(40-
methoxy)phenyl-1-ethanone (13d, 3.05 g) as described
in the general procedure and isolated as yellow crystals.
Yield: 2.38 g (63.50%); mp 138–140 ꢁC; IR (KBr) mmax
3045, 2932, 2823, 1604, 1519, 1418, 1292, 1251, 1175,
6.2.1. 2-Trifluoromethyl-5-phenyl-6-(400-(methylthio)phenyl)-
imidazo[2,1-b]-1,3,4-thiadiazole (15a). This was obtained
by reacting 2-amino-5-trifluoromethyl-1,3,4-thiadiazole
(14a, 1.69 g) and a-bromo-1-(400-(methylthio)phenyl)-2-
phenyl-1-ethanone (13a, 3.21 g) as described in the gen-
eral procedure and isolated as dark yellow crystals.
Yield: 2.83 g (72.5%); mp 162–164 ꢁC; IR (KBr) mmax
3133, 2925, 2832, 1595, 1514, 1409, 1287, 1156,
736 cmꢀ1 1H NMR (CDCl3) d 7.58 (d, J = 8.8 Hz,
;
2H, aryl-H), 7.45 (d, J = 8.1 Hz, 2H, aryl-H), 7.25–
7.18 (m, 3H, aryl-H), 6.85 (d, J = 8.8 Hz, 2H, aryl-H),
3.82 (s, 3H, 40-OCH3) ppm; 13C NMR (CDCl3) d
163.6, 161.9, 144.2, 137.8, 129.6, 129.4, 129.1, 126.3,
122.0, 120.9, 114.4, 55.6 ppm; EI-MS m/z (relative inten-
sity) 375 (M+, 100%), 279(61%), 237 (32%), 190 (59%),
177 (40%), 147 (20%), 133 (90%), 103 (55%); HRMS
(EI) m/z calcd for C18H12F3N3OS: 375.0653; found:
375.0650.
746 cmꢀ1 1H NMR (CDCl3) d 8.02 (d, J = 8.8 Hz,
;
2H, aryl-H), 7.98 (d, J = 8.4 Hz, 2H, aryl-H), 7.65–
7.26 (m, 3H, aryl-H), 6.95 (d, J = 8.5 Hz, 2H, aryl-H),
2.03 (s, 3H, 400-SCH3) ppm; 13C NMR (CDCl3) d
163.0, 160.3, 141.2, 136.4, 129.6, 129.5, 129.3, 128.8,
126.3, 122.0, 120.9, 114.4, 14.9 ppm; EI-MS m/z (relative
intensity) 392 (M+, 100%), 345 (40%), 284 (13%), 239
(22%), 213 (67%), 170 (40%), 150 (20%), 101 (55%);
HRMS (EI) m/z calcd for C18H12F3N3S2: 391.4332;
found: 391.4328.
6.2.5. 2-Trifluoromethyl-5-phenyl-6-p-tolylimidazo[2,1-b]-
1,3,4-thiadiazole (15e). This was obtained by reacting 2-
amino-5-trifluoromethyl-1,3,4-thiadiazole (14a, 1.69 g)
and a-bromo-1-p-tolyl-2-phenyl-1-ethanone (13e, 2.89 g)

282
A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
as described in the general procedure and isolated as
dark yellow crystals. Yield: 1.66 g (46.52%); mp 178–
180 ꢁC; IR (KBr) mmax 3050, 2936, 2845, 1609, 1510,
142.8, 131.6, 130.2, 129.8, 129.3, 129.1, 126.9, 114.8,
56.0 ppm; EI-MS m/z (relative intensity) 386 (M+,
63%), 375 (68%), 306 (31%), 279 (34%), 248 (27%),
213 (33%), 177 (52%), 147 (60%), 133 (100%), 103
(64%); HRMS (EI) m/z calcd for C17H14N4O3S2:
386.0507; found: 386.0504.
1414, 1275, 1156, 748 cmꢀ1 1H NMR (CDCl3) d
;
7.51–7.45 (m, 5H, aryl-H), 7.09 (d, J = 8.1 Hz, 2H,
aryl-H), 6.93 (d, J = 8.2 Hz, 2H, aryl-H), 1.22 (s, 3H,
40-CH3) ppm; 13C NMR (CDCl3) d 163.0, 158.9,
142.1, 133.2, 130.1, 129.5, 128.8, 127.5, 121.5, 119.8,
115.2, 24.3 ppm.
6.2.9. 2-Sulfonamido-5-(40-methoxyphenyl)-6-(400-fluor-
ophenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15i). This was
obtained by reacting 2-amino-5-sulfonamido-1,3,4-thi-
adiazole (14b,1.80 g) and a-bromo-1-(400-fluorophenyl)-
2-(40-methoxyphenyl)-1-ethanone (13g, 3.23 g) as de-
scribed in the general procedure and isolated as white
fluffy crystals. Yield: 2.08 g (51.69%); mp 186–188 ꢁC;
IR (KBr) mmax 3447, 3030, 2920, 2845, 1615, 1586,
6.2.6. 2-Trifluoromethyl-5-phenyl-6-(400-(methylsulfonyl)-
phenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15f). This was
obtained by reacting 2-amino-5-trifluoromethyl-1,3,4-
thiadiazole (14a, 1.69 g) and a-bromo-1-(400-(meth-
ylsulfonyl)phenyl)-2-phenyl-1-ethanone (13f, 3.53 g) as
described in the general procedure and isolated as white
crystals. Yield: 2.88 g (68.28%); mp 146–148 ꢁC; IR
(KBr) mmax 3019, 2922, 2832, 1592, 1492, 1402, 1296,
1433, 1225, 1187, 834 cmꢀ1 1H NMR (DMSO-d6) d
;
8.8 (s, 2H, SO2NH2), 7.93 (d, J = 8.5 Hz, 2H, aryl-H),
7.77 (d, J = 8.5 Hz, 2H, aryl-H), 7.59 (d, J = 8.8 Hz,
2H, aryl-H), 7.53 (d, J = 8.8 Hz, 2H, aryl-H), 3.8 (s,
3H, 40-OCH3) ppm; 13C NMR (DMSO-d6) d 162.9,
158.2, 147.1, 134.3, 131.0, 129.5, 128.7, 127.1, 124.8,
121.0, 113.7, 57.6 ppm; EI-MS m/z (relative intensity)
403 (M+ꢀ1, 20%) 316 (32%), 288 (23%), 241 (26%),
212 (100%), 169 (80%), 148 (37%), 105 (25%); HRMS
(EI) m/z calcd for C17H13FN4O3S2: 404.0413; found:
404.0409.
1149, 743 cmꢀ1
; d 8.26 (d,
1H NMR (CDCl3)
J = 8.4 Hz, 2H, aryl-H), 8.21 (d, J = 8.5 Hz, 2H, aryl-
H), 7.67 (d, J = 8.8 Hz, 2H, aryl-H), 7.45-7.25 (m, 3H,
aryl-H), 3.15 (s, 3H, 400-SO2CH3) ppm; 13C NMR
(CDCl3) d 166.6, 147.2, 138.8, 136.3, 132.8, 129.5,
129.1, 128.8, 126.7, 121.1, 112.5, 46.3 ppm; EI-MS m/z
(relative intensity) 424 (M+, 100%), 392 (83%), 345
(55%), 316 (18%), 259 (35%), 240 (47%), 208 (40%),
166 (35%), 152 (20%), 105 (15%); HRMS (EI) m/z calcd
for C18H12F3N3O2S2: 423.7320; found: 423.7313.
6.2.10. 2-Sulfonamido-5-(40-methoxyphenyl)-6-(400-(meth-
ylsulfonyl)phenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15j).
This was obtained by reacting 2-amino-5-sulfonamido-
1,3,4-thiadiazole (14b, 1.80 g) and a-bromo-1-(400-(meth-
ylsulfonyl)phenyl)-2-(40-methoxyphenyl)-1-ethanone
(13h, 3.84 g) as described in the general procedure and
isolated as white crystals. Yield: 2.46 g (53.17%); mp
160–162 ꢁC; IR (KBr) mmax 3452, 3080, 2961, 2873,
6.2.7. 2-Sulfonamido-5-(40-methoxyphenyl)-6-(400-meth-
oxyphenyl)imidazo[2,1-b]-1,3,4-thiadiazole (15g). This
was obtained by reacting 2-amino-5-sulfonamido-1,3,4-
thiadiazole (14b, 1.80 g) and a-bromo-1-(400-methoxy)-
phenyl-2-(40-methoxy)phenyl-1-ethanone (13c, 3.35 g) as
described in the general procedure and isolated as white
crystals. Yield: 1.66 g (39.90%); mp 298–300 ꢁC; IR
(KBr) mmax 3397, 3164, 2932, 2831, 1610, 1493, 1352,
1622, 1575, 1489, 1402, 1256, 1152, 861 cmꢀ1 1H
;
1
NMR (DMSO-d6) d 8.71 (s, 2H, SO2NH2), 8.26 (d,
J = 8.3 Hz, 2H, aryl-H), 8.07 (d, J = 8.3 Hz, 2H, aryl-
H), 7.53 (d, J = 8.5 Hz, 2H, aryl-H), 7.23 (d,
J = 8.5 Hz, 2H, aryl-H), 3.81 (s, 3H, 40-OCH3), 3.08 (s,
3H, 400-SO2CH3) ppm; 13C NMR (DMSO-d6) d 163.0,
159.4, 144.5, 135.3, 132.8, 130.6, 130.1, 127.9, 127.3,
126.2, 121.7, 114.3, 56.5, 46.4 ppm.
1255, 1176, 833 cmꢀ1; H NMR (DMSO-d6) d 8.63 (s,
2H, SO2NH2), 7.52 (d, J = 8.9 Hz, 2H, aryl-H), 7.46
(d, J = 8.8 Hz, 2H, aryl-H), 6.94 (d, J = 8.8 Hz, 2H,
aryl-H), 6.83 (d, J = 8.8 Hz, 2H, aryl-H), 3.86 (s, 3H,
40-OCH3), 3.82 (s, 3H, 400-OCH3) ppm; 13C NMR
(DMSO-d6) d 163.0, 159.8, 141.0, 134.3, 130.2, 128.2,
127.3, 122.3, 119.2, 113.7, 55.7, 55.2 ppm; EI-MS m/z
(relative intensity) 416 (M+, 80%) 386 (50%), 336
(26%), 278 (21%), 203 (34%), 177 (44%), 160 (51%),
133 (100%), 103 (60%); HRMS (EI) m/z calcd for
C18H16N4O4S2: 416.2740; found: 416.2735.
6.3. Biological evaluation
6.3.1. In vitro cylcooxygenase inhibition studies. The se-
lected compounds listed in Table 1 were tested for their
ability to inhibit in vitro COX-1 and COX-2 using a col-
orimetric COX (ovine) inhibitor screening kit (Catalog
No. 760 111, Cayman Chemicals Inc., Ann Arbor, MI,
USA) using the previously established method.31
6.2.8. 2-Sulfonamido-5-(40-methoxyphenyl)-6-phenylimi-
dazo[2,1-b]-1,3,4-thiadiazole (15h). This was obtained
by reacting 2-amino-5-sulfonamido-1,3,4-thiadiazole
(14 b, 1.80 g) and a-bromo-1-phenyl-2-(40-methoxy)-
phenyl-1-ethanone (13d, 3.05 g) as described in the gen-
eral procedure and isolated as light yellow crystals.
Yield: 2.65 g (68.91%); mp 302–304 ꢁC; IR (KBr) mmax
3402, 3069, 2959, 2820, 1604, 1554, 1496, 1413, 1349,
6.3.2. In vivo anti-inflammatory activity. The preliminary
in vivo anti-inflammatory activity was evaluated using
carrageenan-induced rat paw edema assay model of
inflammation by adopting the method of Winter
et al.32 for the selected compounds listed in Table 1.
Male albino rats (170–220 g) were fasted with free access
to water at least 12 h prior to experiments and divided
randomly into nine groups of six each. Control group
received 1 mL of vehicle (0.5% methyl cellulose and
1
1109, 918 cmꢀ1; H NMR (DMSO-d6) d 8.71 (s, 2H,
SO2NH2), 8.08–7.83 (m, 3H, aryl-H), 7.52 (d,
J = 8.0 Hz, 2H, aryl-H), 7.50 (d, J = 8.0 Hz, 2H, aryl-
H), 6.92 (d, J = 8.5 Hz, 2H, aryl-H), 3.78 (s, 3H, 40-
OCH3) ppm; 13C NMR (DMSO-d6) d 164.3, 159.3,

A. K. Gadad et al. / Bioorg. Med. Chem. 16 (2008) 276–283
283
Li, C. S.; Riendeau, D.; Visco, D.; Wang, Z.; Webb, J.;
Xu, L. J.; Prasit, P. Bioorg. Med. Chem. Lett. 1999, 9,
2207.
0.025% Tween 20), standard group received 10 mg/kg of
celecoxib, and test groups received 10 mg/kg of synthe-
sized compounds. The rats were dosed orally, 1 h later,
a subplantar injection of 0.05 mL of 1% solution of car-
rageenan in 0.9% sterile solution was administered to the
left hind foot pad of each animal. The paw edema vol-
ume was measured with a digital plethysmometer
(Ugo-Basile, Italy) at 0, 2, 4 h after carrageenan injec-
tion. Paw edema volume was compared with vehicle
control group and percent reduction was calculated as
1 ꢀ (edema volume in the drug treated group/edema
volume in the control group) · 100.
15. Lau, C. K.; Brideau, C.; Chan, C. C.; Charleson, S.;
Cromlish, W. A.; Ethier, D.; Gauthier, J. Y.; Gordon, R.;
Guay, J.; Kargman, S.; Li, C. S.; Prasit, P.; Riendeau, D.;
Therien, M.; Visco, D. M.; Xu, L. Bioorg. Med. Chem.
Lett. 1999, 9, 3187.
16. Mahajan, A.; Sharma, R. JAPI 2005, 53, 200.
17. Huang, H. C.; Li, J. J.; Garlan, D. J.; Chamberlain, T. S.;
Reinhard, E. J.; Manning, R. E. J. Med. Chem. 1996, 29,
253.
18. Roy, P.; Leblanc, Y.; Ball, R. G.; Brideau, C.; Chan, C.
C.; Chauret, N.; Gauthier, J. Y.; Gordon, R.; Greig, G.;
Gauy, J.; Kargman, S.; Lau, C. K.; O’Neill, G.; Silva, J.;
Therien, M.; Van Staden, C.; Wong, E.; Xu, L.; Prasit, P.
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Acknowledgments
19. (a) Therien, M.; Brideau, C.; Chan, C. C.; Cromlish, W.
A.; Gauthier, J. Y.; Gordon, R.; Greig, G.; Kargman, S.;
Lau, C. K.; Leblanc, Y.; Li, C. S.; O’Neill, G. P.;
Riendeau, D.; Roy, P.; Wang, Z.; Xu, L.; Prasit, P. Bioorg.
Med. Chem. Lett. 1997, 7, 47; (b) Bender, P. E.; Hill, D.
T.; Offen, P. H.; Razgaitis, M.; Lavanchy, P.; Stringer, O.
D.; Sutton, B. M.; Griswold, D. E.; DiMatrino, M.; Walz,
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1169.
We express our sincere thanks to Shri. Prabhakar B.
Kore, Chairman, K.L.E. Society, and Dr. F.V. Manvi,
Principal, College of Pharmacy, J. N. Medical College,
Belgaum (India), for providing the necessary facilities.
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