Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.01.093

A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity. Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only low inhibitory potency towards COX-2. Most potent compounds showed IC₅₀ values of 6 and 7 μM for COX-2. All compounds showed IC₅₀ values greater 100 μM for COX-1 inhibition.

Full text of DOI:10.1016/j.bmcl.2012.01.093

Bioorganic & Medicinal Chemistry Letters 22 (2012) 2235–2238
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors
Baker Jawabrah Al-Hourani a,c, Sai Kiran Sharma a,b, Mavanur Suresh b, 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 Department of Chemistry, Faculty of Science, American University of Madaba, Madaba, Jordan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 5-substituted 1H-tetrazoles as cyclooxygenase-2 (COX-2) inhibitors was prepared via
treatment of various diaryl amides with tetrachlorosilane/sodium azide. All compounds were tested in
cyclooxygenase (COX) assays in vitro to determine COX-1 and COX-2 inhibitory potency and selectivity.
Tetrazoles contained a methylsulfonyl or sulfonamide group as COX-2 pharmacophore displayed only
Received 14 December 2011
Revised 22 January 2012
Accepted 24 January 2012
Available online 2 February 2012
low inhibitory potency towards COX-2. Most potent compounds showed IC50 values of 6 and 7
COX-2. All compounds showed IC50 values greater 100 M for COX-1 inhibition.
Ó 2012 Elsevier Ltd. All rights reserved.
lM for
l
Keywords:
Cyclooxygenase
COX-2 inhibitors
5-Substituted 1H-tetrazoles
Cyclooxygenases (COXs) are involved in the complex conver-
sion of arachidonic acid to various prostanoids like prostaglandins,
prostacyclin and thromboxanes.1–3 As signaling molecules, prosta-
noids trigger as autocrine and paracrine chemical messengers
many physiological and pathophysiological events. COX is a mem-
brane-bound heme protein which exists in two distinct isoforms,
a constitutive form (COX-1) and an inducible form (COX-2). More
recently, a novel COX-1 splice variant termed as COX-3 has been
reported.4
The X-ray crystal structures of both enzymes suggest that the
proteins are very similar in their tertiary conformation.5,6 The ami-
no acids which constitute the substrate binding pocket and cata-
lytic site are nearly identical in both enzymes. The COX-1
enzyme is expressed in resting cells of most tissues, functions as
the flexibility of the carbocyclic/heterocyclic core motif upon
COX-2 binding.7
Recently, we have described various 1,5-diaryl substituted tetra-
zoles containing a 4-(methylsulfonyl)phenyl substituent attached
to position 1 of the tetrazole ring as novel class of COX-2 inhibitors.
All compounds studied displayed only weak COX-2 inhibitory
potency in the micromolar range.8 This finding is consistent with
recently reported 1,5-diaryl substituted tetrazoles containing a
3,4-difluorophenyl motif displaying IC50 values of >30
lM for
COX-2 inhibitory potency.9
However, a docking study involving our most potent tetrazole
containing a 4-(methylsulfonyl)phenyl substitutent attached to
position 1 suggests the flexibility of the COX-2 binding pocket to
accommodate 1,5-diaryl-substituted tetrazoles with reversed sub-
stitution pattern of the vicinal aryl rings.8 Therefore, in this work
we describe the synthesis and in vitro COX-1 and COX-2 inhibitory
activity evaluation of a series of 1,5-diaryl-substituted tetrazoles
containing a benzene sulfonamide or 4-(methylsulfonyl)phenyl
moiety attached to position 5 of the tetrazole ring. Vicinal aryl
groups contain a broad variety of different functional groups to
study their steric and electronic effects upon COX-1 and COX-2
binding.
Whereas 5-substituted 1H tetrazoles have found numerous
applications in medicinal chemistry as carboxylic acid isostere, con-
siderably less use of 1,5-disubstituted tetrazoles has been reported
in the literature. Several reports describe the use of 1,5-disubsti-
tuted tetrazoles as isosters of the cis-amide bond in peptides. It
was shown that the tetrazole-containing compounds adopt almost
the same conformation as the original peptide, and prominent
a
housekeeping enzyme, and is responsible for maintaining
homeostasis (gastric and renal integrity) and normal production
of prostaglandins. COX-2 is predominantly found in brain, kidney
and endothelial cells while being virtually absent in most other
tissues. However, COX-2 is induced by mitogenic and inflamma-
tory stimuli resulting in an enhanced prostaglandin synthesis in
neoplastic and inflamed tissue.
Since the discovery of the COX-2 enzyme in the early 1990s,
many efforts have been made in the development of COX-2 selec-
tive inhibitors. A common structural feature of many selective
COX-2 inhibitors is the presence of two vicinal aryl rings contain-
ing a sulfonamide or methylsulfonyl pharmacophore attached to a
central 5-membered heterocyclic or carbocyclic motif. Recent
reviews on the current status of COX-2 inhibitors further confirm
examples involve
a-methylene tetrazole-based peptidomimics as
⇑
Corresponding author.
E-mail address: wuest@ualberta.ca (F. Wuest).
HIV-protease inhibitors.10 Other 1,5-disub-stituted tetrazoles have
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2012.01.093

2236
B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2235–2238
been described in recent patent literature such as glucokinase acti-
vators,11 NAD(P)H oxidase inhibitors,12 anti-migraine agents,13 and
hepatitis C virus serine protease NS3 inhibitors.14
Likewise, many different preparative methods for 1,5-disubsti-
tuted tetrazoles have been developed. Popular and frequently used
methods consist of (1) reactions of imidoyl chlorides with various
azide sources,15,16 (2) reactions of oximes, nitriles and nitrilium tri-
flates with azides,17 and (3) reactions of amidrazones with dinitro-
gen tetroxide or nitrous acid. Other methods involve various
alkylation reactions of 5-substituted tetrazoles.18
Synthesis of 1,5-diaryl-substituted tetrazoles usually involves
conversion of various aryl-benzamides into corresponding imidoyl
chlorides using SOCl2 or PCl5 followed by treatment with azide. For
the synthesis of our new set of 1,5-disubstituted tetrazoles we
envisaged a novel approach based upon the tetrachlorosilane/so-
dium azide system. Tetrachlorosilane reacts with sodium azide in
acetonitrile to form an equilibrated mixture of chloroazidosilanes
according to the molar ratio of added sodium azide.19 Treatment
of various aryl benzamides with tetrachlorosilane/sodium azide
furnished the desired 1,5-diaryl-substituted tetrazoles in high
yield. The synthesis of 1,5-diaryl-substituted tetrazoles is depicted
in Figure 1.
tetrazoles 6a–h also in quantitative yield. All tetrazoles were ob-
tained as readily crystalline compounds, which were fully charac-
terized using 1H NMR, 13C NMR and high resolution mass
spectrometry.20
Tetrazoles 4a–h and 6a–h were evaluated in a fluorescence-
based COX assay to determine the different steric and electronic ef-
fects upon COX-1 and COX-2 inhibitory potency and selectivity.21
The determined COX-1 and COX-2 inhibitory data, and calculated
lipophilicity values (LogPo/w) are summarized in Table 1.
All tetrazoles possess a tricyclic scaffold containing a central
heterocyclic ring system with two vicinal aryl substituents as typ-
ically found in many selective and potent COX-2 inhibitors. One
series (4a–h) contains a sulfonamide (SO2NH2) group, the other
series of tetrazoles (6a–h) contains a methylsulfonyl (SO2Me)
group. Both groups were shown in numerous examples to be
important pharmacophores to confer COX-2 selectivity and po-
tency. Potent and selective COX-2 inhibitor celecoxib was used as
reference compound in the COX assay.
Both series of 1,5-disubstituted tetrazoles displayed compara-
ble inhibitory potencies in the micromolar range as observed with
our previously reported tetrazoles possessing a reversed attach-
ment of the aryl rings to the tetrazole ring. In our enzyme inhibi-
tory assay, celecoxib showed high COX-2 inhibitory potency and
The synthesis of 5-aryl-1H-tetrazol-1-yl-benzenesulfonamides
4a–h and 1-(4-(methylsulfonyl)-phenyl)-5-aryl-1H-tetrazoles 5a–
h commenced with the conversion of commercially available
para-substituted benzoic acids 1a–h (R = H, Me, OMe, F, Cl, CF3,
NO2, and NMe2) into amides 2a–h and 3a–h through treatment of
1a–h with 1,10-carbonyldiimidazole (CDI) to form the correspond-
ing imidazolide derivatives in situ. Imidazolide formation can easily
be monitored by the evolution of CO2, which is the driving force of
the reaction. Subsequent reaction of imidazolide intermediates
with 4-(aminosulfonyl)aniline and 4-(methylthio)benzenamine
afforded desired amides 2a–h and 3a–h in moderate chemical
yields of 35–50% in the case of compounds 2a–h and high chemical
yields of 90–97% for compounds 3a–h. Amides 2a–h and 3a–h were
dissolved in dry THF and treated with tetrachlorosilane/sodium
azide in a sealed vial at 90 °C to afford tetrazoles 4a–h and 5a–h
in quantitative yields. To the best of our knowledge this is the first
example of a synthesis of 1,5-diaryl-substituted tetrazoles starting
from aryl-benzamides and treatment with tetrachlorosilane/so-
dium azide. The described reaction is very simple and high yielding
compared to previously reported methods involving treatment of
aryl-benzamides with SOCl2 and PCl5 to form corresponding imi-
doyl chlorides as intermediates followed by reaction with an azide
source. Subsequent oxidation of tetrazoles 5a–h with oxoneÒ gave
selectivity with IC50 values of 0.06 lM for COX-2 and 10.0 lM for
COX-1, which is in agreement with previously reported data in
the literature. All prepared tetrazoles did not inhibit binding to
COX-1 in the concentration range (10ꢀ9 to 10ꢀ4 M) studied.
Compounds containing a SO2Me group displayed slightly higher
COX-2 inhibitory potency compared to their respective counter-
parts possessing a sulfonamide group. This is somewhat in contrast
to previous reports where COX-2 inhibitors containing a SO2NH2
pharmocophore showed more COX-2 inhibitory potency as their
SO2Me pharmacophore-containing counterparts.
However, inhibitory potency of all tested compounds is much
lower compared to reference compound celecoxib, displaying IC50
values ranging from 6.0 lM to greater 100 lM. Compounds contain-
ing a OMe and a CF3 group did not show inhibitory potency within
the used concentration range (10ꢀ9 to 10ꢀ4 M) of the COX inhibition
assay. The determined IC50 values for COX-2 inhibition were greater
than 100 lM for compounds 4c, 4f, 6c, and 6f. Methyl and nitro
group-containing compounds 4b and 4g from the sulfonamide ser-
ies also displayed no inhibitory potency for COX-2 as indicated by
the determined IC50 value of greater 100
itory potency was found for compounds 4h and 6h possessing a
NMe2 group in both series. The determined IC50 values were 7
lM. Highest COX-2 inhib-
l
M
N
N
N
N
N
N
N
N
SMe
O
a, c
e
d
N
H
R
SMe
SO2Me
R
R
3a-h
5a-h
6a-h
CO2H
a: R = H
R
N
1a-h
b: R = Me
c: R = OMe
d: R = F
N
N
N
SO2NH2
O
d
a, b
e: R = Cl
N
H
f: R = CF3
g: R = NO2
R
SO2NH2
R
h: R = NMe2
2a-h
4a-h
Figure 1. Reagents: (a) CDI, THF; (b) 4-(aminosulfonyl)aniline; (c) 4-(methylthio)benzenamine; (d) SiCl4/NaN3, CH3CN, 90 °C, 1 d; (e) oxoneÒ/acetone/MeOH/H2O, 3 h, r.t.

B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2235–2238
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Table 1
6. Jiménez, P.; García, A.; Santander, S.; Piazuelo, E. Curr. Pharm. Des. 2007, 13,
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7. (a) Ramalho, T. C.; Rocha, M. V.; da Cunha, E. F.; Freitas, M. P. Expert Opin. Ther.
Patents 2009, 19, 1193; (b) Jawabrah Al-Hourani, B.; Sharma, S. K.; Suresh, M.;
Wuest, F. Expert Opin. Ther. Pat. 2011, 21, 1339.
COX enzyme inhibitory data of tetrazoles 4a–h and 6a–h
a
b
Compound
R
IC50
COX-1
(
lM)
LogPo/w
COX-2
8. Jawabrah Al-Hourani, B.; Sharma, S. K.; Mane, J. Y.; Tuszynski, J.; Baracos, V.;
Kniess, T.; Suresh, M.; Pietzsch, J.; Wuest, F. Bioorg. Med. Chem. Lett. 1823, 2011,
21.
9. Gauthier, J. Y.; Leblanc, Y.; Black, W. C.; Chan, C.-C.; Cromlish, W. A.; Gordon, R.;
Kennedey, B. P.; Lau, C. K.; Léger, S.; Wang, Z.; Ethier, D.; Guay, J.; Mancini, J.;
Riendeau, D.; Tagari, P.; Vickers, P.; Wong, E.; Xu, L.; Prasit, P. Bioorg. Med. Chem.
Lett. 1996, 6, 87.
10. May, B. C.; Abell, A. D. J. Chem. Soc., Perkin Trans. 1 2002, 172.
11. Nonoshita, K.; Ogino, Y.; Ishikawa, M.; Sakai, F.; Nakashima, H.; Nagae, Y.;
Tsukahara, D.; Arakawa, K.; Nishimura, T.; Eiki, J. PCT Int. Appl. WO 2004-
JP19843, 2005; Chem. Abstr. 2005, 143, 153371.
12. Seki, M.; Tarao, Y.; Yamada, K.; Nakao, A.; Usui, Y.; Komatsu, Y. PCT Int. Appl.
WO 2005-JP2974, 2005; Chem. Abstr. 2005, 143, 266938.
13. Luo, G.; Chen, L.; Degnan, A. P.; Dubowchik, G. M.; Macor, J. E.; Tora, G. O.;
Chaturvedula, P. V. PCT Int. Appl. WO 2004-US40721, 2005;Chem. Abstr. 2005,
143, 78091.
14. Miao, Z.; Sun, Y.; Nakajima, S.; Tang, D.; Wu, F.; Xu, G.; Or, Y. S.; Wang, Z. U.S.
Pat. Appl. Publ. US 2005153877, 2005; Chem. Abstr. 2005, 143, 153709.
15. Artamonova, T. V.; Zhivich, A. B.; Dubinskii, M. Y.; Koldobskii, G. I. Synthesis
1996, 1428.
Celecoxib
4a
4b
4c
4d
4e
4f
4g
10.0
0.06
15
>100
>100
56
3.0
H
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
1.70
2.16
1.86
1.92
2.46
2.67
1.66
2.12
1.87
2.33
2.04
2.09
2.64
2.84
1.83
2.29
Me
OMe
F
Cl
62
CF3
NO2
NMe2
H
Me
OMe
F
>100
>100
7
30
87
>100
15
32
>100
69
6
4h
6a19
6b
6c
6d
6e
6f
6g
6h
Cl
CF3
NO2
NMe2
a
Values are means of two determinations.
LogPo/w values have been calculated based on Molinspiration program predic-
b
16. Kennedy, L. J. Tetrahedron Lett. 2010, 2010, 51.
17. (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. 1841, 1994, 42; (c) Amer, M. I. K.; Booth, B.
L. Chem. Res. Synop. 1993, 4.
tions (http://www.molinspiration.com/cgi-bin/properties).
(4h) and 6 lM (6h), respectively. All compounds have lower lipo-
philicities (logP) values compared to reference compound
celecoxib.
18. Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
19. 1-(4-(Aminosulfonyl)phenyl)-5-phenyl-1H-tetrazole (4a). Mp: 233.6 °C. 1H NMR
(DMSO-d6) d 8.01 (d, J = 9.0 Hz, 2H), 7.77 (d, J = 9.0 Hz, 2H), 7.58–7.49 (m, 5H),
7.59 (s, 2H, SO2NH2); 13C NMR (DMSO-d6)
d 153.7 (C5-tetrazole), 145.7
The obtained results on COX-2 inhibitory potency and selectiv-
ity in this series of tetrazoles and our previously reported 1,5-dia-
ryl-substituted tetrazoles suggest that the central tetrazole motif is
not a suitable structural scaffold for the design of COX-2 inhibitors.
The introduction of a polar tetrazole moiety into the COX-2 binding
pocket seems to be detrimental as demonstrated by the very weak
inhibitory potency. Most highly potent selective COX-2 inhibitors
possess a lipophilic substituents at the central heterocyclic core
structure like a CF3, CH3 or Br group as demonstrated for celecoxib
(CF3 group), valdecoxib (CH3 group), and DuP-697 (Br group),
respectively.
In summary, we have prepared and evaluated a series of 1,5-
diaryl-substituted tetrazoles with reversed substitution pattern
of the vicinal aryl rings as described in our previous work. All com-
pounds displayed much lower COX-2 inhibitory potency compared
to celecoxib and other previously reported COX-2 inhibitors dis-
playing a lipophilic substituent at the central heterocycle of the
molecular scaffold. We have described a novel and convenient syn-
thesis route for the preparation of 1,5-diaryl substituted tetrazoles
using the tetrachlorosilane/sodium azide system. This approach
afforded tetrazoles 4a–h and 6a–h very high yields starting from
the corresponding diarylamides.
(NH2SO2-Php), 136.3 (NH2SO2-Phi), 131.3, 128.96, 128.93, 127.2, 126.5, 123.1;
HRMS (m/z) [M+H]+ calcd for C13H12N5O2S, 302.0706; found 302.0704.
1-(4-(Aminosulfonyl)phenyl)-5-p-tolyl-1H-tetrazole (4b). Mp: 218 °C. 1H NMR
(DMSO-d6)
d 8.01 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.59 (s, 2H,
SO2NH2), 7.42 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 2.35 (s, 3H, Me); 13C
NMR (DMSO-d6) d 153.7 (C5-tetrazole), 145.6 (NH2SO2-Php), 141.4 (Me-Php),
136.4 (NH2SO2-Phi), 129.5, 128.8, 127.2, 126.4, 120.2, 20.9; HRMS (m/z) [M+H]+
calcd for C14H14N5O2S, 316.0863; found 316.0862.
1-(4-(Aminosulfonyl)phenyl)-5-(4-methoxyphenyl)-1H-tetrazole
(4c).
Mp:
235 °C. 1H NMR (DMSO-d6) d 8.01 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H),
7.61 (s, 2H, SO2NH2) 7.48 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H,
OMe); 13C NMR (DMSO-d6) d 161.4 (MeO-Php), 153.5 (C5-tetrazole), 145.6
(NH2SO2-Php), 136.6 (NH2SO2-Phi), 130.5, 127.2, 126.5, 114.9, 114.5, 55.4;
HRMS (m/z) [M+H]+ calcd for C14H14N5O3S, 332.0812; found 332.0813.
1-(4-(Aminosulfonyl)phenyl)-5-(4-fluorophenyl)-1H-tetrazole (4d). Mp: 239.9 °C.
1H NMR (DMSO-d6) d 8.01 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.62 (dd,
4
JH,H = 8.4 Hz, JF,H = 5.1 Hz, 2H), 7.60 (s, 2H, SO2NH2), 7.38 (dd, JH,H = 8.4 Hz,
1
3JF,H = 8.4 Hz, 2H); 13C NMR (DMSO-d6) d 163.6 (d, JF,C = 248.3 Hz), 153.0 (C5-
3
tetrazole), 145.5 (NH2SO2-Php), 136.2 (NH2SO2-Phi), 131.7 (d, JF,C = 9.3 Hz),
127.2, 126.4, 119.7 (d, 4JF,C = 3.6 Hz), 116.2 (d, 2JF,C = 21.8 Hz); 19F NMR (DMSO-
d6) [reference- trifluorotoluene in C6D6] d –109.05 (m, F); HRMS (m/z) [M+H]+
calcd for C13H11FN5O2S, 320.0612; found 320.0611.
1-(4-(Aminosulfonyl)phenyl)-5-(4-chlorophenyl)-1H-tetrazole (4e). Mp: 271.2 °C.
1H NMR (DMSO-d6) d 8.01 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.61 (d,
J = 8.4 Hz, 2H), 7.59 (s, 2H, SO2NH2), 7.56 (d, J = 8.4 Hz, 2H); 13C NMR (DMSO-
d6) d 152.9 (C5-tetrazole), 145.6 (NH2SO2-Php), 136.3 (NH2SO2-Phi), 136.1 (Cl-
Php), 130.8, 129.1, 127.2, 126.4, 122.1; HRMS (m/z) [M+H]+ calcd for
C13H11ClN5O2S, 336.0316; found 336.0316.
1-(4-(Aminosulfonyl)phenyl)-5-(4-trifluoromethylphenyl)-1H-tetrazole (4f). Mp:
210.5 °C. 1H NMR (DMSO-d6) d 8.01 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H),
7.79 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 7.59 (s, 2H, SO2NH2); 13C NMR
(DMSO-d6) d 152.8 (C5-tetrazole), 145.7 (NH2SO2-Php), 136.0 (NH2SO2-Phi),
Acknowledgments
2
131.2 (q, JF,C = 32.3 Hz) (CF3-Php), 130.1, 127.4, 127.3, 126.4, 125.9 (q,
F.W. thanks the Dianne and Irving Kipnes Foundation and the
Canadian Institute for Health Research (CIHR) for supporting this
work.
1
3JF,C = 3.8 Hz), 123.6 (q, JF,C = 271.2 Hz); 19F NMR (DMSO-d6) [reference-
trifluorotoluene in C6D6] d –62.33 (s, CF3); HRMS (m/z) [M+H]+ calcd for
C14H11F3N5O2S, 370.0580; found 370.0585.
1-(4-(Aminosulfonyl)phenyl)-5-(4-nitrophenyl)-1H-tetrazole (4g). Mp: 236.9 °C.
1H NMR (DMSO-d6) d 8.35 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 7.8 Hz, 2H), 7.83 (d,
J = 7.8 Hz, 2H), 7.79 (d, J = 7.8 Hz, 2H), 7.59 (s, 2H, SO2NH2); 13C NMR (DMSO-
Supplementary data
d6)
d 152.5 (C5-tetrazole), 148.9 (NO2-Php), 145.7 (NH2SO2-Php), 135.9
(NH2SO2-Phi), 130.7, 129.4, 127.2, 126.4, 123.9; HRMS (m/z) [M+H]+ calcd for
C13H11N6O4S, 347.0557; found 347.0558.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2012.01.093.
1-(4-(Aminosulfonyl)phenyl)-5-(4-dimethylaminophenyl)-1H-tetrazole (4h). Mp
253.0 °C. 1H NMR (DMSO-d6) d 8.02 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H),
7.61 (s, 2H, SO2NH2), 7.33 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 2.95 (s, 6H,
NMe2); 13C NMR (DMSO-d6) d 153.9 (C5-tetrazole), 151.7 (NMe2-Php), 145.5
(NH2SO2-Php), 137.0 (NH2SO2-Phi), 129.6, 127.2, 126.6, 111.5, 108.7, 39.4
(2xC,NMe2) ; HRMS (m/z) [M+H]+ calcd for C15H17N6O2S, 345.1128; found
345.1126.
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2238
B. J. Al-Hourani et al. / Bioorg. Med. Chem. Lett. 22 (2012) 2235–2238
3.33 (s, 3H, SO2Me). 13C NMR (DMSO-d6) d 153.7, 142.3, 137.8, 131.4, 128.99,
129.98, 128.6, 126.7, 123.1, 43.1; HRMS (m/z) [M+Na]+ calcd for
14H12N4NaO2S, 323.0573; found 323.0573.
(4-(Methylsulfonyl)phenyl)-5-p-tolyl-1H-tetrazole 6b. Mp 190.9 °C. 1H NMR
(DMSO-d6) 8.13 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.43
(d, J = 7.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 3.33 (s, 3H, SO2Me), 2.35 (s, 3H,
Me). 13C NMR (DMSO-d6) d 153.8, 142.3, 141.4, 137.9, 129.6, 128.8, 128.6,
126.7, 120.1, 43.1, 20.9; HRMS (m/z) [M+Na]+ calcd for C15H14N4NaO2S,
337.0730; found 337.0729.
5-(4-Methoxyphenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tetrazole 6c. Mp 177.1 °C.
1H NMR (DMSO-d6) d 8.14 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.48 (d,
J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H, OMe), 3.33 (s, 3H, SO2Me).
13C NMR (DMSO-d6) d 161.4, 153.5, 142.2, 138.0, 130.6, 128.7, 126.8, 114.9,
114.5, 55.3, 43.1; HRMS (m/z) [M+Na]+ calcd for C15H14N4NaO3S, 353.0679;
found 353.0683.
(6f). Mp: 140.0 °C. 1H NMR (DMSO-d6)
d 8.16 (d, J = 7.8 Hz, 2H), 7.91(d,
J = 7.8 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 3.33 (s, 3H,
C
SO2Me); 13C NMR (DMSO-d6) d 152.8 (C5-tetrazole), 142.4 (MeSO2-Php), 137.5
2
(MeSO2-Phi), 131.2 (q, JF,C = 32.2 Hz) (CF3-Php), 130.1, 128.7, 127.3, 126.6,
3
1
d
125.9 (q, JF,C = 3.4 Hz), 123.8 (q, JF,C = 271.4 Hz), 43.1; 19F NMR (DMSO-d6)
[reference-trifluorotoluene in C6D6] d –61.63 (s, CF3); HRMS (m/z) [M+Na]+
calcd for C15H11F3N4NaO2S, 391.0447; found 391.0450.
1-(4-(Methylsulfonyl)phenyl)-5-(4-nitrophenyl)-1H-tetrazole
(6g).
Mp:
189.8 °C. 1H NMR (DMSO-d6) d 8.35 (d, J = 8.4 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H),
7.87 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 3.33 (s, 3H, SO2Me); 13C NMR
(DMSO-d6) d 152.5 (C5-tetrazole), 148.9 (NO2-Php), 142.5 (MeSO2-Php), 137.4
(MeSO2-Phi), 130.7, 129.3, 128.8, 126.7, 124.0, 43.1; HRMS (m/z) [M+Na]+ calcd
for C14H11N5NaO4S, 368.0424; found 368.0426.
1-(4-(Methylsulfonyl)phenyl)-5-(4-dimethylaminophenyl)-1H-tetrazole (6h). Mp:
185.1 °C. 1H NMR (DMSO-d6) d 8.16 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 3.34 (s, 3H, SO2Me), 2.96 (s, 6H,
NMe2); 13C NMR (DMSO-d6) d 153.9 (C5-tetrazole), 151.7 (NMe2-Php), 142.1
(MeSO2-Php), 138.5 (MeSO2-Phi), 129.6, 128.7, 126.8, 111.5, 108.6, 43.1, 39.4
(2xC,NMe2); HRMS (m/z) [M+Na]+ calcd for C16H17N5NaO2S, 366.0995; found
366.0998.
5-(4-Fluorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tetrazole 6d. Mp: 173.1 °C.
1H NMR (DMSO-d6) d 8.14 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.62
4
3
(dd, JH,H = 8.4 Hz, JF,H = 5.4 Hz, 2H), 7.37 (dd, JH,H = 8.4 Hz, JF,H = 8.4 Hz, 2H),
3.33 (s, 3H, SO2Me). 13C NMR (DMSO-d6) d 163.6 (d, JF,C = 248.4 Hz), 153.1,
1
142.3, 137.7, 131.6 (d, 3JF,C = 9.2 Hz), 128.7, 126.7, 119.3 (d, 4JF,C = 2.4 Hz), 116.3
(d, JF,C = 22.2 Hz), 43.1. 19F NMR (DMSO-d6) [reference- trifluorotoluene in
20. 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 10ꢀ4 M. PRISM5 software was used for the calculation of IC50 values.
21. Khanna, I. K.; Weier, R. M.; Yu, Yi.; Xu, X. D.; Koszyk, F. J.; Collins, P. W.; Koboldt,
C. M.; Veenhuizen, A. W.; Perkins, W. E.; Casler, J. J.; Masferrer, J. L.; Zhang, Y. Y.;
Gregory, S. A.; Seibert, K.; Isakson, P. C. J. Med. Chem. 1997, 40, 1634.
2
C6D6] d ꢀ109.00 (m, F); HRMS (m/z) [M+Na]+ calcd for C14H11FN4NaO2S,
341.0479; found 341.0480.
5-(4-Chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tetrazole 6e. Mp 183.6 °C.
1H NMR (DMSO-d6) d 8.15 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.60
(d, J = 8.4 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H), 3.33 (s, 3H, SO2Me). 13C NMR
(DMSO-d6) d 152.9, 142.3, 137.6, 136.3, 130.8, 129.1, 128.7, 126.7, 122.0, 43.1;
HRMS (m/z) [M+Na]+ calcd for C14H11ClN4NaO2S, 357.0183; found 357.0184.
5-(4-(Trifluoromethyl)phenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tetrazole