1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, biological evaluation and molecular modeling studies

Article abstract of DOI:10.1016/j.bmc.2013.04.074

A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO ₂NH₂ attached to one aryl ring and various substituents (H, F, Cl, CH₃ or OCH

Full text of DOI:10.1016/j.bmc.2013.04.074

Accepted Manuscript
1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, bio‐
logical evaluation and molecular modeling studies
Jatinder Kaur, Atul Bhardwaj, Sai Kiran Sharma, Frank Wuest
PII:
S0968-0896(13)00413-6
DOI:
http://dx.doi.org/10.1016/j.bmc.2013.04.074
BMC 10814
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
14 February 2013
17 April 2013
25 April 2013
Please cite this article as: Kaur, J., Bhardwaj, A., Sharma, S.K., Wuest, F., 1,4-Diaryl-substituted triazoles as
cyclooxygenase-2 inhibitors: Synthesis, biological evaluation and molecular modeling studies, Bioorganic &
Medicinal Chemistry (2013), doi: http://dx.doi.org/10.1016/j.bmc.2013.04.074
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GRAPHICALABSTRACT
1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, biological
evaluation and molecular modeling studies
Jatinder Kaur, Atul Bhardwaj, Sai Kiran Sharma and Frank Wuest*
Keywords: Cyclooxygenase; COX-2 Inhibition; 1,4-diaryl-substituted triazoles; Click chemistry;
Molecular modeling.
*Corresponding author: Tel.: +1 780 989 8150; fax: +1 780 432 8483.
E-mail address: wuest@ualberta.ca (Frank Wuest)
1

1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis,
biological evaluation and molecular modeling studies
Jatinder Kaur, Atul Bhardwaj, Sai Kiran Sharma and Frank Wuest*
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2
___________________________________________________________________________________
Abstract − A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by
introducing the cyclooxygenase-2 (COX-2) pharmacophore SO2NH2 attached to one aryl ring and
various substituents (H, F, Cl, CH3 or OCH3) attached to the other aryl ring. The effects of size and
flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by
increasing the size of an alkyl linker chain [(-CH2)n, where n = 0, 1, 2]. In vitro COX-1/COX-2
inhibition studies showed that all compounds (14–18, 21-25 and 28–32) are more potent inhibitors of
COX-2 isozyme (IC50 = 0.17–28.0 µM range) compared to COX-1 isozyme (IC50 = 21.0 – >100 µM
range). Within the group of 1, 4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-
yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and
selectivity (COX-1: IC50 = >100 µM, COX-2: IC50 = 0.17 µM, SI > 588). Molecular docking studies
using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical
support for the obtained experimental biological structure–activity relationship data. Results of
molecular docking studies revealed that COX-2 pharmacophore SO2NH2 in compound 30 is positioned
in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO2NH2 group being
hydrogen bonded to Q192 (N----O=C = 2.85 Å), and one of the oxygen atoms of SO2NH2 group
forming a hydrogen bond to H90 (S=O----N = 2.38 Å).
2

1. Introduction
Over the last 100 years, nonsteroidal anti-inflammatory drugs (NSAIDs) were among the most
prominent and frequently used drugs in medicine for the treatment of pain, fever, inflammation and
arthritis-associated disorders. The main therapeutic mechanism of NSAIDs action involves inhibition
of cyclooxygenase-mediated biosynthesis of prostaglandins (PGs). Cyclooxygenase (prostaglandin
endoperoxide synthase or COX) enzyme exists in at least two closely related isoforms1-4 viz. COX-1
and COX-2. COX-1 is consecutively expressed in most tissues. COX-1 is involved in homeostasis of
cytoprotective PGs in the gastrointestinal tract, homeostasis of proaggregatory thromboxane A2
(TXA2) in blood platelets5 and in overall vascular homeostasis.6 In contrast, inducible COX-2 isoform
is absent in most organs and tissues, except for brain, kidney, pancreas, uterus, ovary, and
macrophages. However, upon inflammatory or carcinogenic stimulation, COX-2 expression levels are
elevated, and COX-2 is responsible for the production of inflammatory PGs.7-9 Moreover, high levels
of COX-2 were also found in various human cancers like gastric, breast, lung, colon, oesophageal,
prostate, and hepatocellular carcinomas.10-12
Classical NSAIDs (aspirin, ibuprofen, meclofenamic acid and indomethacin) block the activity of both
COX isoforms non-selectively to exhibit their anti-inflammatory effects, which leads to unwanted side
effects by the inhibition of COX-1.13,14 Inhibition of consecutively expressed COX-1 isoform and/or
downfall in the production of physiological PGs by classical NSAIDs is considered as the basis of life-
threatening side effects such as gastrointestinal irritation, ulcer, hepatic and renal toxicity.15-17 In this
context, selective inhibition of COX-2 was proposed to be a safer therapeutical approach to reduce
deleterious side effects of classical NSAIDs. As a result, a variety of selective COX-2 inhibitors
(COXIBs) such as celecoxib (1), rofecoxib (2), valdecoxib (3), etoricoxib (4) and lumiracoxib (5) have
been developed (Figure 1).18-21 Selective COX-2 inhibitors have widely been used for the treatment of
inflammation and a variety of diseases such as rheumatoid arthritis, osteoarthritis, Alzheimer’s disease
(AD) and Parkinson’s disease.22-24 Besides these therapeutic applications, NSAIDs have also been
found to play an important role in the prevention of several types of human cancer such as colon, lung,
breast and prostate cancers.12, 25
Over the last two decades, numerous studies have been carried out to improve the COX-2 selectivity
and safety profile.14, 26-29 However, various selective COX-2 inhibitors came under scrutiny due to an
increased risk of adverse cardiovascular side effects. This development led to the withdrawal of
rofecoxib and valdecoxib from the market and stimulated the development of novel classes of selective
3

and safe COX-2 inhibitors with reduced cardiovascular side effects .30-33 In this line, several nitric
oxide releasing NSAIDs and dual COX/LOX inhibitors have been developed recently. 34-36
Among the different classes of COXIBs, several vicinal diaryl heterocycles bearing a p-
methylsulfonyl- or p-aminosulfonyl-aryl substituent rings represent the most important class of
selective COX-2 inhibitors. Structure–activity relationship (SAR) data indicate that the nature and
position of substituents on two vicinal aryl rings is an important determinant.37, 38 It has been observed
that compounds containing RSO2 (R = NH2, CH3,) groups effectively interact with amino acid residues
of the COX-2 secondary pocket resulting in a generally high COX-2 selectivity and potency profile.
Recently, our group has reported the synthesis of various 1,4 and 1,5-diaryl substituted 1,2,3-triazoles
(6-11, Figure 1) as COX-2 inhibitors.39 From this study it was concluded that compounds containing a
vicinal diaryl substitution pattern display higher COX-2 inhibition potency compared to their
corresponding 1,4-diaryl-substituted counterparts. Both series of compounds showed moderate COX-2
selectivity profiles. As an extension to this work, we now describe the synthesis of a novel class of 1,4
diaryl-substituted triazoles as potential selective COX-2 inhibitors. Novel compounds were designed
based on Cu(I)-mediated click chemistry between azides containing the SO2NH2 COX-2
pharmacophore attached to an aryl ring and various aryl acetylenes containing different substitutents
(H, F, Cl, CH3 or OCH3) attached to the para position of the aryl ring. Furthermore, the size of the
molecule was increased through the introduction of an alkyl linker to enhance flexibility of the
compound to facilitate COX-2 binding. The COX-1/COX-2 inhibitory activities of these compounds
were determined in a COX binding assay, and plausible binding interactions within the COX-1/COX-2
active sites were explored using molecular docking studies.
4

Figure 1. Chemical structures of some COX-2 inhibitors and target compounds.
2. Chemistry
The methodologies used for the synthesis of target compounds 14–18, 21–25 and 28–32 are illustrated
in Scheme 1. Based on our intention to investigate the effect of chain length, size and flexibility of the
molecule on COX-1/COX-2 inhibitory potency and selectivity profile, we prepared three categories of
compounds exhibiting different chain lengths (n = 0, 1, 2). The syntheses of precursor compounds 4-
azido-benzenesulfonamide (13), 4-(azidomethyl)-benzenesulfonamide (20) and 4-(2-azidoethyl)-
benzenesulfonamide (27) were carried out according to reported procedures.40, 41 Employing popular
click chemistry approach, Cu(I)-mediated [3+2] cycloaddition reaction of three aromatic azides
(compounds 13, 20 and 27) with various para-substituted aryl acetylenes (4-H, 4-F, 4-Cl, 4-CH3, 4-
OCH3) provided 1,4 diaryl substituted triazoles 14–18, 21-25 and 28–32 (Scheme 1). For this purpose,
equimolar amounts of aryl acetylenes and azide 13/20/27 were used for click chemistry reaction in the
presence of EtOH:H2O (1:1), CuI and triethylamine at 60 °C for 14-16 hrs to afford desired triazoles
(14–18, 21-25 and 28–32) in moderate to good chemical yields (54-89%) after purification.
5

Synthesis of compounds 14, 15, 17 and 18 as potential inhibitors of carbonic anhydrases VA and VB
was reported recently.42
Scheme 1. Synthesis of 1,4 diaryl-substituted triazoles (14-18, 21-25 and 28-32).
6

3. Results and Discussion
The COX-1/2 inhibitory potency and selectivity profile of compounds 14-18, 21-25, and 28-32 was
determined in triplicate using a fluorescent COX-1/COX-2 inhibitor screening assay kit. The results of
all synthesized compounds (category I: 14-18; n = 0, R = H, F, Cl, CH3, OCH3), (category II: 21-25;
(n = 1, R = H, F, Cl, CH3, OCH3), (category III: 28-32; (n = 2, R = H, F, Cl, CH3, OCH3), are
summarized in Table 1.
In vitro COX-1/COX-2 inhibition studies (Table 1) revealed that compounds (14–18, 21-25 and 28–
32) are more potent inhibitors of COX-2 (IC50 = 0.17–28.0 µM range) than inhibitors of COX-1
(IC50 = 21.0–>100 µM range). Among the first series of compounds (14-18) possessing a p-
benzenesulfonamide (Ph-SO2NH2) substituent attached directly to N-1 of the triazole ring, compound
14 (n = 0, R = H) was identified as the most potent and selective COX-2 inhibitor (COX-1 IC50 = >100
µM, COX-2 IC50 = 1.3 µM, SI >77). Although compound 16 (n = 0, R = Cl), exhibited satisfactory
COX-2 inhibitory potency (COX-2 IC50 = 1.3 µM) its COX-2 selectivity was smaller (SI = 16.1).
In the second series of compounds (21-25) containing benzenesulfonamide (Ph-SO2NH2) substituent
attached to N-1 of the triazole ring through aCH2 linker (n =1), compound 24 (R = CH3) was the most
potent and selective inhibitor of COX-2 (COX-1 IC50 >100 µM, COX-2 IC50 = 1.2 µM, SI >83.
Compound 22 (R = F) also displayed comparable COX-2 inhibitory potency (COX-2 IC50 = 1.5 µM)
but COX-2 selectivity index of compound 22 was smaller than that of compound 24 (SI = 13.3 vs. SI
>83). Among the third series of compounds (28-32) which contained a CH2CH2 linker (n = 2),
compound 30 (R = Cl) was identified as the most potent COX-2 inhibitor (COX-1 IC50 >100 µM,
COX-2 IC50 = 0.17 µM) with an appreciable high COX-2 selectivity index (SI >588). Within this
group of compounds (28-32), compounds 28 (R = H, COX-1 IC50 >100 µM, COX-2 IC50 = 1.1 µM, SI
>91) and 29 (R = F, COX-1 IC50 >100 µM, COX-2 IC50 = 1.0 µM, SI >100) also displayed low
micromolar inhibitory potency towards COX-2 while showing favorable COX-2 selectivity profile
(SI >90).
Direct comparison of inhibitory potency and selectivity profiles of all three categories of compounds
14-18 (n = 0), 21-25 (n = 1) and 28-32 (n = 2) revealed that compounds of categories I (14-18) and II
(21-25) possess comparably low COX-2 inhibitory potency and selectivity, except for compound 24.
However, significant improvement of COX-2 inhibitory potency and selectivity was achieved with
compounds of category III (28-32) containing a more flexible molecular geometry through the
introcuction of a ethyl linker chain with the exception of compound 32.
7

Since the discovery of selective COX-2 inhibitors, the presence of two vicinal (adjacent) aryl
substituents at a central heterocyclic/carbocyclic ring structure has been discussed as an important
structural feature to provide favorable COX-2 inhibitory potency and selectivity. This rigid molecular
geometry seems to fit into the COX-2 active site. Substituents present at adjacent positions have easy
access to secondary subpocket residues and the compound can interact with amino acid residues
effectively. Interestingly, the results of this study suggest that an increase in the flexibility of the
molecule also results in an appreciable COX-2 inhibitory potency and selectivity profile.
8

Table 1. In vitro COX-1 and COX-2 enzyme inhibition data
N
N
n
N
O
S
NH2
O
R
IC50 (µM)a
COX-2
SIb
Compound
n
R
COX-1
COX-2
0
0
H
F
>100
1.3
>77
14
15
>100
21
13.5
1.3
14
>7.4
0
0
0
1
1
1
1
1
Cl
CH3
OCH3
H
16.1
4.6
16
17
18
21
22
23
24
65
>100
39
11
>9.1
6
6.5
1.5
28
F
20
13.3
Cl
>100
>100
>3.6
>83
CH3
1.2
OCH3
>100
>100
>100
13
1.1
1.0
>7.7
25
28
29
2
2
H
F
>91
>100
2
2
2
Cl
>100
>100
0.17
3.4
30
31
>588
>29
CH3
OCH3
>100
>1
27
32
3.7
0.02
>50
Celecoxib
a
The in vitro test compound concentration required to produce 50% inhibition of ovine COX-1 or
human recombinant COX-2. The result (IC50, µM) is the mean of three determinations acquired using
the COX Fluorescent Inhibitor Screening Assay Kit (Item No. 700100, Cayman Chemical Company,
Ann Arbor, MI, USA) and the deviation from the mean is <10% of the mean value.
b In vitro COX-2 selectivity index (IC50 COX-1/IC50 COX-2).
9

4. Molecular modeling (docking) studies
Molecular modeling (docking) studies were carried out for compounds (16, 23, 30) to gain more
insights into the probable nature of their respective binding interactions within the active site of COX-
1 and COX-2 isozymes. Docking experiments were performed using X-ray crystal structure data for
COX-1 and COX-2 obtained from the protein data bank.43, 44
Compound 16, when docked into the COX-2 binding site (Figure 2a), comfortably enters into the
COX-2 active site and places its para-Cl-phenyl substituent near S530, L531residues, while one of the
nitrogen atom of the triazole ring indicates hydrogen bonding interactions with V523 residue of COX-
2 active site (N---O = 1.55 Å). The SO2NH2 group as prominent and effective COX-2 pharmacophore)
is pointed near the COX-2 isozyme secondary pocket amino acid residues (A516, F518, R513 Q192
and H90).
(a)
(b)
Figure 2. a) Molecular modeling (docking) of compound 16 (carbon atoms in pink) in the binding site
of COX-2 (PDB ID: 6COX; Eintermolecular = -10.21 kcal mol-1) and b) COX-1 (PDB ID: 1EQG;
Eintermolecular = -8.12 kcal mol-1). Hydrogen atoms of amino acid residues have been removed for clarity.
In a comparable manner, compound 23 displays a favorable orientation in the COX-2 active site and
the SO2NH2 group is oriented at the entrance of the secondary pocket. This places the SO2NH2 group
near the R513, L352 residues (Figure 3a). The 4-chlorophenyl substituent was moved near to the L359
amino acid of the COX-2 binding site.
10

(a)
(b)
Figure 3. a) Molecular modeling (docking) of compound 23 (carbon atoms in pink) in the binding site
of COX-2 (PDB ID: 6COX; Eintermolecular = -8.55 kcal mol-1) and b) COX-1 (PDB ID: 1EQG;
Eintermolecular = -6.12 kcal mol-1). Hydrogen atoms of amino acid residues have been removed for clarity.
A similar molecular docking simulation for compound 30 within the COX-2 active site (Figure 4a),
showed noticeable interactions between compound 30 and active binding site residues (Eintermolecular = -
12.48 Kcal mol-1). The SO2NH2 group in compound 30 deeply enters into the secondary pocket region
of the COX-2 active site, where it is oriented towards Q192, R513, H90, and S353 residues. The
nitrogen atom of the SO2NH2 group indicates hydrogen bonding interactions with the oxygen of
carbonyl group of Q192 (N----O=C = 2.85 Å), and one of the oxygen atom of SO2NH2 group is
hydrogen bonded to the nitrogen atom of H90 residue (S=O----N = 2.38 Å) (Figure 4a).
However, in contrast to binding interactions of compound 16 (Figure 2a) and 23 (Figure 3a), the
docking results of compound 30 (Figure 4a) indicate that upon increasing the size of the linker chain (n
= 2), there is an increase in the flexibility of the molecule which facilitates the deeper insertion of the
SO2NH2 group into the secondary binding pocket and more significant intermolecular binding
interactions. This favorable orientation and electrostatic binding interactions of compound 30 with
COX-2 active site residues are consistent with experimentally observed high COX-2 inhibitory
potency (COX-2 IC50 = 0.17 µM). A comparison of the binding mode of compounds 16, 23 and 30 in
the COX-2 active site using a molecular docking structure containing all three compounds (16, 23 and
30) docked in the same COX-2 active site is given in the supplementary section (Figure S1).
11

(a)
(b)
Figure 4. Molecular modeling (docking) of compound 30 (carbon atoms in pink) in the binding site of
COX-2 (PDB ID: 6COX; Eintermolecular = -12.48 kcal mol-1) and b) COX-1 (PDB ID: 1EQG; Eintermolecular
= -5.90 kcal mol-1). Hydrogen atoms of amino acid residues have been removed for clarity.
Alternatively, docking results for compound 16, 23 and 30 in COX-1 active site show that compound
16 comfortably enters into the COX-1 active site (Figure 2b) and its p-Cl-phenyl substituent has
moved into the hydrophobic subpocket of COX-1isozyme constituted by W387, Y385 and F381
residues. However, during docking studies of compound 23 (Figure 3b) and 30 (Figure 4b) into COX-
1, compounds were not able to enter into the COX-1 active site completely (Figure 3b and 4b). This
inability is likely due to the increase in their size or/and due to the steric conflict with side chains of
amino acid residues of the active site. This body of data evidently supports the experimentally
observed weak COX-1inhibitory activity of compound 23 and 30.
12

5. Conclusions
In conclusion, a new class of 1,4-diaryl-substituted triazoles was synthesized using high yielding
Cu(I)-mediated click chemistry. In vitro COX-1/COX-2 inhibition studies showed that some
compounds of this novel class of 1,4-diaryl-substituted triazoles are able to inhibit COX-2 with high
otency and selectivity. Especially compounds (28-30) were identified as highly potent (IC50 range
0.17–1.1 µM) and selective novel COX-2 inhibitors (SI >91–>588). Among all investigated
compounds, a "lead compound" 4-{2-[4-(4-Chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfon-
amide was identified that exhibited appreciable COX-2 inhibitory potency and selectivity (COX-1 IC50
>100 µM, COX-2 IC50 = 0.17 µM; SI > 588). Molecular docking analyses for compounds 16, 23 and
30 on the COX-1/COX-2 isozymes complement the experimental results. From both the experimental
structure–activity data and the molecular docking results it can be concluded that an increase of the
length of the linker chain is accompanied with an enhancement in molecular interactions between
functional groups of the compounds and amino acid residues of the secondary pocket of the COX-2
active site.
13

6. Experimental
6.1. General
Melting points were measured in capillaries using a Thomas-Hoover capillary apparatus and are
uncorrected.1H and13C NMR spectra were recorded on a Bruker Avance III 600 MHz NMR
spectrometer using DMSO-d6 as solvent. Chemical shifts are given in parts per million (ppm) with
tetramethylsilane (TMS) as an internal reference. Mass spectra (MS) were recorded on a Water’s
Micromass ZQ 4000 mass spectrometer using the ESI ionization mode. The purity of the compounds
was established using elemental analyses which were performed for C, H, N by the Microanalytical
Service Laboratory, Department of Chemistry, University of Alberta. Compounds showed a single spot
on Macherey-Nagel Polygram Sil G/UV254 silica gel plates (0.2 mm) using a low, medium, and
highly polar solvent system, and no residue remained after combustion, indicating a purity >98%. All
other commercial reagents and solvents were used without further purification. Compound 13, 20, and
27 were prepared according to already reported procedure .40, 41
6.2. Chemical Synthesis
6.2.1. 4-(Azidomethyl)-benzenesulfonamide (20)41
1H NMR (600 MHz, DMSO-d6): δ 4.57 (s, 2H, CH2), 7.40 (s, 2H, NH2), 7.57 (d, J = 8.4 Hz, 2H, Ar-
H), 7.86 (d, J = 8.4 Hz, 2H, Ar-H).
6.2.2. 4-(2-Azidoethyl)-benzenesulfonamide (27) 41
1
1H NMR (600 MHz, DMSO-d6): H NMR (600 MHz, DMSO-d6): δ 2.94 (t, J = 6.9 Hz, 2H,
N3CH2CH2), 3.63 (t, J = 6.9 Hz, 2H, N3CH2CH2), 7.31 (s, 2H, NH2, 7.48 (d, J = 8.4 Hz, 2H, Ar-H),
7.77 (d, J = 8.4 Hz, 2H, Ar-H).
6.2.3. General procedure for the Cu (I)-catalyzed synthesis of triazoles (14–18, 21-25 and 28–32)39
A mixture of respective aryl acetylene (0.575 mmol), CuI (0.0575 mmol) and triethylamine (0.0575
mmol) in 15 ml of EtOH/H2O (1:1) was stirred at room temperature for 15 min. Then, 4-Azido-
benzenesulfonamide/ 4-(Azidomethyl)-benzenesulfonamide/ 4-(2-Azidoethyl)-benzenesulfonamide
(0.575 mmol) in 5 ml of EtOH/H2O (1:1) was added and the resulting mixture was stirred at 60°C for
14-16 h. The precipitate obtained were filtered and washed with water and then with diethyl ether.
These precipitates were further recrystallized from ethanol.
14

1
6.2.3.1. 4-(4-Phenyl-[1,2,3]triazol-1-yl)-benzenesulfonamide (14). Yield: 70%; mp 210-212°C; H
NMR (600 MHz, DMSO-d6): δ 7.40 (m, 1H, Ar-H), 7.51 (m, 2H, Ar-H), 7.55 (s, 2H, NH2), 7.95 (m,
13
2H, Ar-H), 8.06 (d, J = 8.4 Hz, 2H, Ar-H), 8.18 (d, J = 8.4, 2H, Ar-H), 9.43 (s, 1H, CH); C NMR
(150 MHz, DMSO-d6): δ 119.73, 120.08, 125.27, 127.45, 128.33, 128.96, 129.85, 138.50, 143.72,
147.48; ESI-MS: 301 [M+H]+; Anal Calcd for C14H12N4O2S: C, 55.99; H, 4.03; N, 18.65; S, 10.68;
Found: C, 55.25; H, 3.92; N, 17.83; S, 10.36.
6.2.3.2. 4-[4-(4-Fluoro-phenyl)-[1,2,3]triazol-1-yl]-benzenesulfonamide (15). Yield: 81%; mp 118-
119°C; 1H NMR (600 MHz, DMSO-d6): δ 7.37 (m, 2H, Ar-H), 7.55 (s, 2H, NH2), 7.99 (m, 2H, Ar-H),
8.06 (d, J = 8.3 Hz, 2H, Ar-H), 8.17 (d, J = 8.3 Hz, 2H, Ar-H), 9.42 (s, 1H, CH); 13C NMR (150 MHz,
DMSO-d6): δ 116.54 (d, JC-F = 21.0 Hz), 120.26, 120.68, 127.02 (d, JC-F = 3.0 Hz), 127.94 (d, JC-F
=
9.0 Hz), 128.06, 139.05, 144.36, 147.20, 162.57 (d, JC-F = 243.0 Hz); ESI-MS: 319 [M+H]+; Anal
Calcd for C14H11FN4O2S: C, 52.82; H, 3.48; N, 17.60; S, 10.07; Found: C, 52.15; H, 3.11; N, 17.22; S,
9.78.
6.2.3.3. 4-[4-(4-Chloro-phenyl)-[1,2,3]triazol-1-yl]-benzenesulfonamide (16). Yield: 82%; mp 215-
217°C; 1H NMR (600 MHz, DMSO-d6): δ 7.55 (s, 2H, NH2), 7.59 (d, J = 8.4 Hz, 2H, Ar-H), 7.97 (d, J
= 8.4 Hz, 2H, Ar-H), 8.06 (d, J = 8.4 Hz, 2H, Ar-H), 8.16 (d, J = 8.4, 2H, Ar-H), 9.47 (s, 1H, CH); 13C
NMR (150 MHz, DMSO-d6): δ 120.14, 126.95, 127.47, 128.77, 129.06, 132.78, 138.42, 143.40,
143.81, 146.38; ESI-MS: 335 [M+H]+; Anal Calcd for C14H11ClN4O2S: C, 50.23; H, 3.31; N, 16.74; S,
9.58; Found: C, 49.89; H, 3.13; N, 16.03; S, 9.26.
1
6.2.3.4. 4-(4-p-Tolyl-[1,2,3]triazol-1-yl)-benzenesulfonamide (17). Yield: 89%; mp 211-212°C; H
NMR (600 MHz, DMSO-d6): δ 2.36 (s, 3H, CH3), 7.32 (d, J = 8.0 Hz, 2H, Ar-H), 7.54 (s, 2H, NH2),
7.84 (d, J = 8.0 Hz, 2H, Ar-H), 8.05 (d, J = 8.4 Hz, 2H, Ar-H), 8.17 (d, J = 8.4, 2H, Ar-H), 9.37 (s, 1H,
CH); 13C NMR (150 MHz, DMSO-d6): δ 20.80, 119.28, 120.04, 125.22, 127.07, 127.45, 129.52,
137.75, 138.53, 143.67, 147.57; ESI-MS: 315 [M+H]+; Anal Calcd for C15H14N4O2S: C, 57.31; H,
4.49; N, 17.82; S, 10.20; Found: C, 56.97; H, 4.21; N, 17.55; S, 9.79.
6.2.3.5. 4-[4-(4-Methoxy-phenyl)-[1,2,3]triazol-1-yl]-benzenesulfonamide (18). Yield: 83%; mp
1
199-201°C; H NMR (600 MHz, DMSO-d6): δ 3.81 (s, 3H, OCH3), 7.08 (d, J = 8.8 Hz, 2H, Ar-H),
7.54 (s, 2H, NH2), 7.88 (d, J = 8.8 Hz, 2H, Ar-H), 8.05 (d, J = 8.4 Hz, 2H, Ar-H), 8.16 (d, J = 8.4, 2H,
13
Ar-H), 9.31 (s, 1H, CH); C NMR (150 MHz, DMSO-d6): δ 55.13, 114.39, 118.67, 119.97, 122.37,
15

126.68, 127.45, 138.56, 143.61, 147.45, 159.31; ESI-MS: 331 [M+H]+; Anal Calcd for C15H14N4O3S:
C, 54.53; H, 4.27; N, 16.96; S, 9.71; Found: C, 54.07; H, 4.11; N, 16.47; S, 9.35.
6.2.3.6. 4-(4-Phenyl-[1,2,3]triazol-1-ylmethyl)-benzenesulfonamide (21).Yield: 72%; mp 210-
1
213°C; H NMR (600 MHz, DMSO-d6): δ 5.76 (s, 2H, CH2), 7.30-7.36 (m, 1H, Ar-H), 7.38 (s, 2H,
NH2), 7.44-7.47 (m, 2H, Ar-H), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.83-7.87 (m, 4H, Ar-H), 8.68 (s, 1H,
CH); 13C NMR (150 MHz, DMSO-d6): δ 52.83, 122.28, 125.66, 126.63, 128.43, 128.79, 129.39,
131.05, 140.23, 144.31, 147.21; ESI-MS: 315 [M+H]+; Anal Calcd for C15H14N4O2S: C, 57.31; H,
4.49; N, 17.82; S, 10.20; Found: C, 57.25; H, 4.52; N, 17.63; S, 10.16.
6.2.3.7. 4-[4-(4-Fluoro-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzenesulfonamide (22). Yield: 80%;
mp 197-200°C; 1H NMR (600 MHz, DMSO-d6): δ 5.76 (s, 2H, CH2), 7.28-7.31 (m, 2H, Ar-H), 7.38 (s,
2H, NH2), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.84 (d, J = 8.4 Hz, 2H, Ar-H), 7.89-7.91 (m, 2H, Ar-H),
8.67 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δ 52.89, 116.17 (d, JC-F = 22.5 Hz), 122.19, 126.64,
127.62 (d, JC-F = 3.0 Hz), 127.70 (d, JC-F = 7.5 Hz), 128.81, 140.17, 144.33, 146.36, 162.28 (d, JC-F
=
243.0 Hz); ESI-MS: 333 [M+H]+; Anal Calcd for C15H13FN4O2S: C, 54.21; H, 3.94; N, 16.86; S, 9.65;
Found: C, 54.17; H, 3.92; N, 16.79; S, 9.52.
6.2.3.8. 4-[4-(4-Chloro-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzenesulfonamide (23). Yield: 54.2%;
1
mp 212-215°C; H NMR (600 MHz, DMSO-d6): δ 5.76 (s, 2H, CH2), 7.39 (s, 2H, NH2), 7.50-7.53 (m,
4H, Ar-H), 7.84 (d, J = 8.4 Hz, 2H, Ar-H), 7.88 (d, J = 8.4 Hz, 2H, Ar-H), 8.73 (s, 1H, CH); 13C NMR
(150 MHz, DMSO-d6): δ 52.93, 122.63, 126.68, 127.73, 128.84, 129.45, 129.96, 132.84, 140.10,
144.35, 146.13; ESI-MS: 349 [M+H]+; Anal Calcd for C15H13ClN4O2S: C, 51.65; H, 3.76; N, 16.06; S,
9.19; Found: C, 51.58; H, 3.66; N, 16.11; S, 9.12.
6.2.3.9. 4-(4-p-Tolyl-[1,2,3]triazol-1-ylmethyl)-benzenesulfonamide (24). Yield: 75.3%; mp 215-
1
217°C; H NMR (600 MHz, DMSO-d6): δ 2.33 (s, 3H, CH3), 5.74 (s, 2H, CH2), 7.26 (d, J = 7.8 Hz,
2H, Ar-H), 7.38 (s, 2H, NH2), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.74 (d, J = 7.8 Hz, 2H, Ar-H), 7.84 (d, J
13
= 8.4 Hz, 2H, Ar-H), 8.62 (s, 1H, CH); C NMR (150 MHz, DMSO-d6): δ 21.31, 52.84, 121.83,
125.60, 126.62, 128.29, 128.80, 129.92, 137.73, 140.25, 144.30, 147.27; ESI-MS: 329 [M+H]+; Anal
Calcd for C16H16N4O2S: C, 58.52; H, 4.91; N, 17.06; S, 9.76; Found: C, 58.48; H, 4.95; N, 17.11; S,
9.69.
16

6.2.3.10. 4-[4-(4-Methoxy-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzenesulfonamide (25). Yield: 78.7
%; mp 218-220°C; 1H NMR (600 MHz, DMSO-d6): δ 3.76 (s, 3H, OCH3), 5.73 (s, 2H, CH2), 7.01 (d,
J = 8.4 Hz, 2H, Ar-H), 7.38 (s, 2H, NH2), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.78 (d, J = 8.4 Hz, 2H, Ar-
H), 7.84 (d, J = 8.4 Hz, 2H, Ar-H), 8.56 (s, 1H, CH); 13C NMR (150 MHz, DMSO-d6): δ 52.81, 55.71,
114.77, 121.29, 123.63, 126.63, 127.01, 128.77, 140.29, 144.32, 147.46, 159.52; ESI-MS: 345
[M+H]+; Anal Calcd for C16H16N4O3S: C, 55.80; H, 4.68; N, 16.27; S, 9.31; Found: C, 55.89; H, 4.60;
N, 16.19; S, 9.31.
6.2.3.11. 4-[2-(4-Phenyl-[1,2,3]triazol-1-yl)-ethyl]-benzenesulfonamide (28). Yield: 80.4%; mp 220-
222°C; 1H NMR (600 MHz, DMSO-d6): δ 3.32 (t, J = 6.9 Hz, 2H, NCH2CH2), 4.71 (t, J = 6.9 Hz, 2H,
NCH2CH2), 7.30 (s, 2H, NH2), 7.32-7.35 (m, 1H, Ar-H), 7.42-7.49 (m, 4H, Ar-H), 7.73 (d, J = 8.4 Hz,
13
2H, Ar-H), 7.81 (d, J = 8.4 Hz, 2H, Ar-H), 8.58 (s, 1H, CH); C NMR (150 MHz, DMSO-d6): δ
35.61, 50.62 121.79, 125.55, 126.22, 129.17, 129.39, 129.55, 131.23, 142.28, 142.96, 146.68; ESI-MS:
329 [M+H]+; Anal Calcd for C16H16N4O2S: C, 58.52; H, 4.91; N, 17.06; S, 9.76; Found: C, 58.58; H,
4.97; N, 17.12; S, 9.71.
6.2.3.12. 4-{2-[4-(4-Fluoro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (29). Yield:
78.2%; mp 175-179°C; 1H NMR (600 MHz, DMSO-d6): δ 3.32 (t, J = 7.2 Hz, 2H, NCH2CH2), 4.71 (t,
J = 7.2 Hz, 2H, NCH2CH2),7.27-7.29 (m, 2H, Ar-H), 7.30 (s, 2H, NH2), 7.42 (d, J = 8.4 Hz, 2H, Ar-
13
H), 7.73 (d, J = 8.4 Hz, 2H, Ar-H), 7.83-7.87 (m, 2H, Ar-H), 8.57 (s, 1H, CH); C NMR (150 MHz,
DMSO-d6): δ 35.60, 50.65, 116.32 (d, JC-F = 22.5 Hz), 121.70, 126.23, 127.56 (d, JC-F = 7.5 Hz),
127.80 (d, JC-F = 3.0 Hz), 129.58, 142.25, 142.97, 145.83, 162.21 (d, JC-F = 243.0 Hz); ESI-MS: 347
[M+H]+; Anal Calcd for C16H15FN4O2S: C, 55.48; H, 4.36; N, 16.17; S, 9.26; Found: C, 55.45; H,
4.36; N, 16.11; S, 9.34.
6.2.3.13. 4-{2-[4-(4-Chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (30). Yield:
76.2%; mp 200-205°C; 1H NMR (600 MHz, DMSO-d6): δ 3.32 (t, J = 7.2 Hz, 2H, NCH2CH2), 4.72 (t,
J = 7.2 Hz, 2H, NCH2CH2), 7.30 (s, 2H, NH2), 7.42 (d, J = 8.4 Hz, 2H, Ar-H), 7.52 (d, J = 9.0 Hz, 2H,
13
Ar-H), 7.73 (d, J = 8.4 Hz, 2H, Ar-H), 7.83 (d, J = 9.0 Hz, 2H, Ar-H), 8.63 (s, 1H, CH); C NMR
(150 MHz, DMSO-d6): δ 35.58, 50.68, 122.15, 126.20, 127.25, 129.46, 129.68, 130.13, 132.72,
142.22, 142.98, 145.61; ESI-MS: 363 [M+H]+; Anal Calcd for C16H15ClN4O2S: C, 52.96; H, 4.17; N,
15.44; S, 8.84; Found: C, 52.89; H, 4.23; N, 15.46; S, 8.88.
17

6.2.3.14. 4-[2-(4-p-Tolyl-[1,2,3]triazol-1-yl)-ethyl]-benzenesulfonamide (31). Yield: 82.3%; mp
1
210-214°C; H NMR (600 MHz, DMSO-d6): δ 2.38 (s, 3H, CH3), δ 3.36 (t, J = 7.2 Hz, 2H,
NCH2CH2), 4.75 (t, J = 7.2 Hz, 2H, NCH2CH2), 7.30 (d, J = 7.8 Hz, 2H, Ar-H), 7.35 (s, 2H, NH2),
7.47 (d, J = 8.4 Hz, 2H, Ar-H), 7.75 (d, J = 8.4 Hz, 2H, Ar-H), 7.78 (d, J = 7.8 Hz, 2H, Ar-H), 8.56 (s,
13
1H, CH); C NMR (150 MHz, DMSO-d6): δ 21.30, 35.61, 50.58, 121.37, 125.50, 126.22, 128.46,
129.68, 129.77, 137.60, 142.30, 142.96, 146.74; ESI-MS: 343 [M+H]+; Anal Calcd for C17H18N4O2S:
C, 59.63; H, 5.30; N, 16.36; S, 9.36; Found: C, 58.74; H, 5.32; N, 16.30; S, 9.33.
6.2.3.15. 4-{2-[4-(4-Methoxy-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (32). Yield:
78.4%; mp 216-218°C; 1H NMR (600 MHz, DMSO-d6): δ 3.31 (t, J = 7.2 Hz, 2H, NCH2CH2), 3.78 (s,
3H, OCH3), 4.69 (t, J = 7.2 Hz, 2H, NCH2CH2), 7.01 (d, J = 8.4 Hz, 2H, Ar-H), 7.31 (s, 2H, NH2),
13
7.42 (d, J = 8.4 Hz, 2H, Ar-H), 7.73-7.75 (m, 4H, Ar-H), 8.46 (s, 1H, CH); C NMR (150 MHz,
DMSO-d6): δ 35.63, 50.55, 55.63, 114.79, 120.82, 123.83, 126.22, 126.90, 129.68, 142.32, 142.95,
146.62, 159.44; ESI-MS: 359 [M+H]+; Anal Calcd for C17H18N4O3S: C, 56.97; H, 5.06; N, 15.63; S,
8.95; Found: C, 56.90; H, 5.06; N, 15.69; S, 8.96.
6.3. In vitro cyclooxygenase inhibition assays
The ability of test compounds 14-18, 21-25 and 28-32 to inhibit COX-1 and COX-2 isozyme (IC50
values, µM) was determined using COX Fluorescent Inhibitor Screening Assay Kit (Item No. 700100,
Cayman Chemical Company, Ann Arbor, MI, USA).45, 46
6.4. Molecular modeling (docking) procedure
The molecular docking experiments were performed using crystal coordinates from the X-ray crystal
structure of COX-1 (ovine, 1EQG, ibuprofen bound in the active site) and COX-2 (murine, 6COX,
SC558 bound in the active site) were obtained from the protein data bank. Compounds were built using
the builder toolkit of the software package ArgusLab 4.0.1 (Mark, A. ArgusLab, Version 4.0.1;
Thompson Planaria Software LLC: Seattle, WA) and energy minimized using the semi-empirical
quantum mechanical method PM3. The monomeric structure of the enzyme was chosen and the active
site was defined around the ligand. The molecule to be docked in the active site of the enzyme was
inserted in the work space carrying the structure of the enzyme. The docking program implements an
efficient grid based docking algorithm which approximates an exhaustive search within the free
volume of the binding site cavity. The conformational space was surveyed by the geometry
optimization of the flexible ligand (rings are treated as rigid) in combination with the incremental
18

construction of the ligand torsions. Thus, docking occurred between the flexible ligand parts of the
compound and enzyme. The ligand orientation was determined by a shape scoring function based on
Ascore and the final positions were ranked by lowest interaction energy values. The Einteraction is the
sum of the energies involved in H-bond interactions, hydrophobic interactions and van der Waal’s
interactions. H-bond and hydrophobic interactions between the compound and enzyme were explored
by distance measurements.
Acknowledgements
The authors would like to thank the Dianne and Irving Kipnes Foundation and the Canadian Institute
for Health Research (CIHR) for supporting this work.
19

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