Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles as novel selective cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2011.01.057

A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All compounds were evaluated by cyclooxygenase (COX) ass

Full text of DOI:10.1016/j.bmcl.2011.01.057

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1823–1826
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of 1,5-diaryl-substituted tetrazoles
as novel selective cyclooxygenase-2 (COX-2) inhibitors
Baker Jawabrah Al-Hourani a, Sai Kiran Sharma a,b, Jonathan Y. Mane a, Jack Tuszynski a,
Vickie Baracos a, Torsten Kniess c, Mavanur Suresh b, Jens Pietzsch c, Frank Wuest a,b,
⇑
a Department of Oncology, University of Alberta, Edmonton, Canada
b Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada
c Institute of Radiopharmacy, Research Center Dresden-Rossendorf, Dresden, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 1,5-diaryl-substituted tetrazole derivatives was synthesized via conversion of readily available
diaryl amides into corresponding imidoylchlorides followed by reaction with sodium azide. All com-
pounds were evaluated by cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibi-
tory potency and selectivity. Tetrazoles 3a–e showed IC50 values ranging from 0.42 to 8.1 mM for COX-1
Received 9 November 2010
Revised 11 January 2011
Accepted 13 January 2011
Available online 21 January 2011
and 2.0 to 200
lM for COX-2. Most potent compound 3c (IC50 (COX-2) = 2.0 lM) was further used in
molecular modeling docking studies.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Cyclooxygenase
COX-2 inhibitors
1,5-Diaryl-tetrazoles
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most
widely used therapeutics worldwide for the treatment of inflam-
mation, pain, fever, and for the prevention of thrombosis.
The mechanisms of their pharmacological effects are based on
inhibition of the catalytic domain of cyclooxygenase enzymes by
sterically hindering the entrance of arachidonic acid as their phys-
iological binder. This results in a reduced production of prostaglan-
dins and thromboxanes, which contribute as important autocrine
and paracrine mediators in many physiologic and pathophysiologic
responses.1–4
Cyclooxygenases (COXs) are membrane-bound heme proteins
which exist in two distinct isoforms, a constitutive form (COX-1)
and an inducible form (COX-2). COX-1 and COX-2 share the same
substrates, produce the same products and catalyze the same reac-
tion using identical catalytic mechanisms. The X-ray crystal struc-
ture of both enzymes suggests that the proteins are very similar in
their tertiary conformation.5,6 The amino acids which serve as sub-
strate binding pocket and catalytic site are nearly identical in both
enzymes. The COX-1 enzyme is expressed in resting cells of most
tissues, functions as a housekeeping enzyme, and is responsible
for maintaining homeostasis (gastric and renal integrity) and nor-
mal production of eicosanoids. COX-2 is predominantly found in
brain and kidney while being virtually absent in most other tissues.
However, COX-2 expression is significantly upregulated as part of
various acute and chronic inflammatory conditions. It is also well
documented that COX-2 is overexpressed in numerous human can-
cers such as colorectal, gastric, and breast cancer.7
Recognition of the importance of COX-2 in inflammation and
carcinogenesis has prompted the synthesis of various COX-2 selec-
tive inhibitors over the last two decades.
The close structural similarities of both COX isoforms represent
a formidable challenge for the development of selective COX-2
inhibitors. In COX-1, the space of the selectivity pocket is reduced
due to the presence of Ile523, while in COX-2 the presence of
Val523. The presence of valine in COX-2 induces a conformational
change, thereby forming an additional hydrophobic secondary
internal pocket protruding off the primary binding site which is ab-
sent in COX-1.8
Over the last two decades a large number of compounds have
been synthesized and investigated for selective COX-2 inhibition.
Many selective COX-2 inhibitors belong to the class of diaryl-
heterocyclic compounds. A common structural feature is the
presence of two vicinal aryl rings attached to a central five- or
six-membered carbocyclic or heterocyclic motif. Prominent exam-
ples including Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib, and
SC57666 are depicted in Figure 1.9
Selective COX-2 inhibitors as shown in Figure 1 demonstrate
that a broad variety of 1,2-diaryl-substituted carbocycles and het-
erocycles containing a sulfonamide or methylsulfonyl pharmaco-
phore are acceptable for binding to the cyclooxygenase active
site in the COX-2 enzyme. Recent reviews on the current status
of COX-2 inhibitors have further confirmed the flexibility of
⇑
Corresponding author.
E-mail address: wuest@ualberta.ca (F. Wuest).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.057

1824
B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1823–1826
F
SO2NH2
MeO2S
MeO2S
H3C
MeO2S
H2NO2S
Cl
N
N
N
N
O
N
O
O
H3C
CF3
Celecoxib
Rofecoxib
Valdecoxib
Etoricoxib
SC57666
Figure 1. Chemical structures of selective COX-2 inhibitors.
various carbocycles or heterocycles as central core motifs for selec-
tive and potent COX-2 binding.10
of CO2, which is the driving force of the reaction. Subsequent reac-
tion of reactive imidazolide intermediate with various para-substi-
tuted anilines (R = H, Me, OMe, F, Cl) afforded desired amides 2a–e
in high chemical yields of 90–97%. Amides 2a–e were treated with
thionylchloride under reflux to prepare corresponding imidoyl-
chloride intermediates. After removal of the excess of SOCl2 and
washing the crude reaction mixture with hexane, the residue
was re-dissolved in dry DMF. Treatment of imidoylchlorides with
a two-fold excess of NaN3 gave desired 1,5-diaryl-substituted tet-
razoles 3a–e in good to very good 70–87% yield after purification
using column chromatography. Tetrazoles 3a–e were obtained as
readily crystalline compounds, which were fully characterized
using 1H NMR, 13C NMR and high resolution mass spectrometry.20
Tetrazoles 3a–e were evaluated in a fluorescence-based COX as-
say21 to determine the different steric and electronic effects upon
COX-1 and COX-2 inhibitory potency and selectivity. Compounds
3a–e possess a tricyclic scaffold containing a central heterocyclic
ring system with two vicinal aryl substituents as typically found
in numerous selective and potent COX-2 inhibitors. One of the aryl
rings bears a methylsulfonyl (SO2Me) group, which was shown to
be an important pharmacophore to confer COX-2 selectivity and
potency. Thus, 1,5-diaryl-substituted tetrazoles 3a–e are structur-
ally related to several selective COX-2 inhibitors depicted in Figure
1, and to our previously prepared series of 1,5-diaryl-substituted
1,2,3-triazoles.11 Potent and selective COX-2 inhibitor Celecoxib
was used as reference compound in the COX assay. The determined
enzyme inhibitory data, the respective COX-2 selectivity index
(COX-2 SI), and calculated lipophilicity values (Log Po/w) are sum-
marized in Table 1.
Recently, our group has reported on the synthesis and charac-
terization of various 1,5-diaryl 1,2,3-triazoles as a novel class of po-
tent and selective COX-2 inhibitors.11 As an extension to this work
and our continuing interest in the design and synthesis of COX-2
inhibitors as molecular probes for molecular imaging of COX-2
expression in vivo, we want to explore the effect of various 1,2-dia-
ryl-substituted tetrazoles upon COX-2 binding. To the best of our
knowledge, 1,2-diaryl-substituted tetrazoles have not yet been
studied as COX-2 inhibitors. Herein we describe the synthesis,
in vitro COX-1 and COX-2 inhibitory activity, and molecular mod-
eling docking experiments of a series of 1,5-diaryl-substituted tet-
razoles as novel class of selective COX-2 inhibitors.
1,5-Disubstituted tetrazoles have found many applications in
medicinal chemistry and drug development as important cis-amide
isosteres. Important examples include glucokinase activators,12
NAD(P)H oxidase inhibitors,13 anti-migraine agents,14 and hepati-
tis C virus serine protease NS3 inhibitors.15
Many different preparative methods for 1,5-disubstituted tetra-
zoles have been developed. Popular and frequently used methods
consist of (1) reactions of imidoylchlorides with various azide
sources,16,17 (2) reactions of oximes, nitriles and nitrilium triflates
with azides,18 and (3) reactions of amidrazones with dinitrogen
tetroxide or nitrous acid. Other methods involve various alkylation
reactions of 5-substituted tetrazoles.19
1,5-Diaryl-substituted tetrazoles 3a–e as novel COX-2 inhibi-
tors were prepared based on the reaction of imidoylchlorides with
sodium azide as the key step within the reaction sequence. The
synthesis route is outlined in Figure 2.
In our enzyme inhibitory assay, Celecoxib showed high COX-2
The synthesis of tetrazoles 3a–e commenced with the conver-
sion of commercially available 4-(methylsulfonyl)benzoic acid 1
into amides 2a–e through treatment of 1 with 1,10-carbonyldiimid-
azole (CDI) to form the corresponding imidazolide derivative in
situ. Imidazolide formation can easily be monitored by evolution
inhibitory potency and selectivity with IC50 values of 0.03
lM for
COX-2 and 9.4 M for COX-1, which is in the same range as previ-
l
ously reported in the literature. All prepared tetrazoles 3a–e are
selective COX-2 inhibitors as reflected by the COX-2 SI values rang-
ing from 4.5 (3e) to 237 (3d).
Compounds 3c and 3d showed high COX-2 SI values of 210 and
237, respectively, which is in the same order of magnitude as
determined for reference compound Celecoxib (COX-2 SI = 313).
However, inhibitory potency of all compounds 3a–e is much lower
R
O
CO2H
a, b
N
H
MeO2S
MeO2S
Table 1
1
COX-1 and COX-2 enzyme inhibitory data
2a R = H
2b R = Me
2c R = OMe
2d R = F
2e R = Cl
a
c
R
IC50
COX-1
(l
M)
COX-2
COX-2 SIb
Log Po/w
N
Celecoxib
9.4
0.03
200
45
2.0
2.7
313
18.5
180
210
237
4.5
3.0
2.3
2.8
2.2
2.4
2.9
N
N
N
3a
3b
3c
3d
3e
H
3700
8100
420
640
500
c, d
3a R = H
Me
OMe
F
3bR = Me
3c R = OMe
3d R = F
Cl
110
R
MeO2S
3e R = Cl
a
b
c
Values are means of two determinations.
In vitro COX-2 selectivity index (IC50 COX-1/IC50 COX-2).
Log Po/w values have been calculated based on ACDLabs predictions.
Figure 2. Reagent and conditions: (a) CDI, THF; (b) 4-substituted anilines; (c) SOCl2,
reflux, 2 h; (d) NaN3, DMF, room temperature, 24 h (70–87%).

B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1823–1826
1825
compared to Celecoxib, ranging from 2.0
l
M for compound 3c
with selected amino acid residues of the binding pocket. The dock-
(R = OMe) to 200 M for compound 3a (R = H). The determined
l
ing of compound 3c into the COX-2 binding pocket resulted in a
IC50 values of all tetrazoles are also significantly lower in direct
comparison to our previously prepared set of 1,4-substituted
1,2,3-triazoles as novel selective and potent COX-2 inhibitors,
which displayed IC50 values in the submicromolar range (0.03–
calculated binding free energy
D
G = ꢀ10.01 kcal/mol.
The presence of Val523 in the COX-2 isoenzyme results in the
formation of a secondary hydrophobic binding pocket which
accommodates the 4-MeO-phenyl substituent of compound 3c.
The oxygen of the methoxy-group is involved in a H-bond with
the hydroxyl-group of Ser530. The measured distance of 2.49 Å is
in the range typically found for H-bonding interactions. Compound
3c is further stabilized in the binding pocket through two addi-
tional H-bonds between the oxygen atoms of the methylsulfonyl
group of the other phenyl ring with the 4-OH-group of Tyr385
and the OH-group of Ser353. The measured distances of 2.81 Å
and 2.58 Å agree with H-bonding interactions. Trp387, Leu384,
Met522, and Val523 form a hydrophobic environment within the
COX-2 binding pocket which surrounds both phenyl rings attached
to the central tetrazole moiety of compound 3c. The found H-bond-
ing interaction of the OMe-group in 3c with Ser530, and to a lesser
extent with the guanidine group of Arg120 (distance = 5.58 Å),
would also explain the observed high potency of compound 3d
0.36
inhibitor possessing the lowest IC50 value (2.0
l
M).11 Compound 3c (R = OMe) is the most potent COX-2
lM) within the ser-
ies of tetrazoles. This is about 10 times higher compared with the
corresponding OMe-substituted analog within the 1,2,3-triazole
series (IC50 = 0.17 l
M).11 However, tetrazole compound 3c shows
much higher selectivity towards COX-2 (COX-2 SI = 210) compared
to the corresponding 1,2,3-triazole compound (COX-2 SI = 4.9).11
Thus, changing the 1,2,3-triazole central heterocycle to a tetrazole
heterocycle seems to have a detrimental effect upon COX-2 inhib-
itory potency but enhances COX-2 selectivity.
Within the series of all studied tetrazoles, compounds 3c and 3d
containing an electron-donating 4-OMe and a strongly electron-
withdrawing 4-F group showed the highest COX-2 potency and
selectivity. No systematic effect of the chemical nature of various
para-substituents (R = H, Me, OMe, F, Cl) within tetrazoles 3a–e
upon COX-2 selectivity and inhibitory potency profile could be
observed.
Replacement of the central 1,2,3-triazole ring with a tetrazole
heterocyle resulted in a slight increase of lipophilicity as expressed
by the calculated Log P values of 2.2–2.9 for tetrazole-containing
compounds 3a–e. Previously reported 1,2,3-triazoles containing a
comparable substitution pattern showed Log P values of 1.7–2.4.11
The binding of the most potent tetrazole compound 3c within
the active site of the COX-2 enzyme was further studied through
docking experiments using the known crystal structure of active
site of murine COX-2.22 The result is depicted in Figure 3.
Compound 3c binds to binding pocket of COX-2 through the for-
mation of various distinct H-bonds and hydrophobic interaction
(R = F) towards COX-2 (IC50 = 2.7 lM) within the series of com-
pounds studied (Table 1). Fluorine is a very strong H-bond acceptor
capable of forming comparable H-bonding interactions with
Ser530 and Arg120 as shown for compound 3c.
The found H-bonding and hydrophobic interactions of the dock-
ing experiment are in good agreement with the determined COX-2
inhibitory activity of compound 3c and they may also provide a
reasonable explanation for the comparable inhibitory activity of
compound 3d.
In summary, we have prepared and evaluated a series of 1,5-
diaryl-substituted tetrazoles as novel selective cyclooxygenase-2
(COX-2) inhibitors. However, the determined COX-2 inhibitory po-
tency of compounds 3a–e is almost an order of magnitude lower in
comparison with our previously prepared 1,4-diaryl substituted
1,2,3-triazoles.11
Acknowledgments
The authors thank Dr. Hicham Fenniri (Department of Chemis-
try and National Institute for Nanotechnology) for his support to
record NMR spectra, and Dr. Carlos Velazquez (Faculty of Pharmacy
and Pharmaceutical Sciences) for his help and support to perform
the COX binding assays. F.W. thanks the Dianne and Irving Kipnes
Foundation and the Canadian Institute for Health Research (CIHR)
for supporting this work.
References and notes
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Figure 3. Docked position of tetrazole 3c with the active site of murine COX-2.
Hydrogen atoms have been removed to improve clarity except for amino acids
involved in hydrogen bonding.

1826
B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1823–1826
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16. Artamonova, T. V.; Zhivich, A. B.; Dubinskii, M. Y.; Koldobskii, G. I. Synthesis
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13C NMR (DMSO-d6) d 160.6, 152.7, 142.9, 129.8, 128.4, 127.6, 127.4, 126.4,
115.0, 55.6, 43.0; HR-MS (m/z) [M+Na]+ calcd for C15H14N4NaO3S, 353.0679;
found 353.0680.
1-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-1H-tetrazole 3d: mp 205.0 °C
1H NMR (DMSO-d6) d 8.04 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 (dd,
JH,H = 8.7 Hz, 4JF,H = 4.5 Hz, 2H), 7.48 (dd, JH,H = 8.7 Hz, 3JF,H = 8.7 Hz, 2H), 3.28 (s,
3H); 13C NMR (DMSO-d6) d 162.9 (d, JF,C = 249 Hz), 152.8, 142.9, 130.1 (d,
3
4JF,C = 3.6 Hz), 129.9, 128.6 (d, JF,C = 9.3 Hz), 128.2, 127.5, 117.01 (d,
2JF,C = 23 Hz), 43.1; HR-MS (m/z) [M+Na]+ calcd for C14H11FN4NaO2S,
341.0479; found 341.0481.
1-(4-Chlorophenyl)-5-(4-(methylsulfonyl)phenyl)-1H-tetrazole 3e: mp 207.7 °C;
1H NMR (DMSO-d6) d 8.05 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 9.0 Hz, 2H), 7.70 (d,
J = 9.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 3.28 (s, 3H); 13C NMR (DMSO-d6) d 152.7,
143.0, 135.5, 132.6, 130.0, 129.2, 128.2, 127.9, 127.5, 43.1; HR-MS (m/z)
[M+Na]+ calcd for C14H11ClN4NaO2S, 357.0183; found 357.0183.
21. In vitro cyclooxygenase (COX) inhibition assay: The ability of compounds 3a–e
and Celecoxib to inhibit ovine COX-1 and recombinant human COX-2 was
determined using a COX fluorescence inhibitor assay (catalog number 700100,
Cayman Chemical, Ann Arbor, MI, USA) according to the manufacturer’s assay
protocol. Compounds 3a–e were assayed in concentrations ranging from 10ꢀ9
M to 10ꢀ3 M. PRISM5 software was used for the calculation of IC50 values.
22. The crystal structure of COX-2 inhibitor diclofenac bound to murine COX-2
enzyme was obtained from the RCSB Protein Data Bank (PDB identifier 1PXX).
For the docking studies we used only chain A of 1PXX. Docking of compound 3c
was performed using AutoDock 4. The following protocol was used for the
docking studies: application of the Lamarckian genetic algorithm with 150
individuals in the population; a maximum of 25 ꢁ 106 energy evaluations; a
mutation rate of 0.02; a crossover rate of 0.80, and the elitism value of 1. For
17. Kennedy, L. J. Tetrahedron Lett. 2010, 51, 2010.
18. (a) Butler, R. N.; O’Donoghue, D. A. J. Chem. Res., Synop. 1983, 18; (b) Ueyama,
N.; Yanagisawa, T.; Kawai, T.; Sonegawa, M.; Baba, H.; Mochizuki, S.; Kosakai,
K.; Tomiyama, T. Chem. Pharm. Bull. 1994, 42, 1841; (c) Amer, M. I. K.; booth, B.
L. J. Chem. Res., Synop. 1993, 4.
19. Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
20. 5-(4-(Methylsulfonyl)phenyl)-1-phenyl-1H-tetrazole 3a: mp 174.5 °C; 1H NMR
(DMSO-d6) d 8.03 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H), 7.66–7.60 (m, 5H),
3.28 (s, 3H); 13C NMR (DMSO-d6) d 152.6, 142.9, 133.7, 130.8, 129.96, 129.94,
128.3, 127.4, 126.0, 43.0; HR-MS (m/z) [M+Na]+ calcd for C14H12N4NaO2S,
323.0573; found 323.0575.
5-(4-(Methylsulfonyl)phenyl)-1-(p-tolyl)-1H-tetrazole 3b: mp 179.3 °C; 1H NMR
(DMSO-d6) d 8.12 (d, J = 7.8 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 8.4 Hz,
2H), 7.50 (d, J = 7.8 Hz, 2H), 3.37 (s, 3H), 2.44 (s, 3H); 13C NMR (DMSO-d6) d
152.6, 142.9, 140.8, 131.3, 130.4, 129.9, 128.4, 127.4, 125.8, 43.0, 20.8; HR-MS
(m/z) [M+Na]+ calcd for C15H14N4NaO2S, 337.0730; found 337.0729.
the local search, pseudo-Solis and Wets algorism was applied using
a
maximum of 300 iterations per local search. The probability of performing
local search on individuals in the populations was set to 0.6. The maximum
number of consecutive successes or failures before doubling or halving the
local search step was set to 4. 100 independent docking runs were performed.
Results differing by 2.0 Å in positional root–mean–square deviation were
clustered.
1-(4-Methoxyphenyl)-5-(4-(methylsulfonyl)phenyl)-1H-tetrazole
3c:
mp
189.5 °C; 1H NMR (DMSO-d6) d 8.03 (d, J = 9.0 Hz, 2H), 7.79 (d, J = 9.0 Hz, 2H),
7.54 (d, J = 9.0 Hz, 2H), 7.13 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H), 3.27 (s, 3H);