Docking studies and the crystal structure of two tetrazole derivatives: 5-(4-chlorophenyl)-1-{4-(methylsulfonyl)phenyl}-1H-tetrazole and 4-{5-(4-methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide

Article abstract of DOI:10.1016/j.molstruc.2015.08.025

The structures of 5-(4-chlorophenyl)-1-{4-(methylsulfonyl)phenyl}-1H-tetrazole (3) and 4-{5-(4-methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide (5) have been determined by X-ray crystallography. Tetrazoles 3 and 5 crystallize in the monoclinic space gro

Full text of DOI:10.1016/j.molstruc.2015.08.025

Journal of Molecular Structure 1101 (2015) 21e27
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Docking studies and the crystal structure of two tetrazole derivatives:
5-(4-chlorophenyl)-1-{4-(methylsulfonyl)phenyl}-1H-tetrazole and
4-{5-(4-methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide
,
Baker Jawabrah Al-Hourani a *, Musa I. El-Barghouthi b, Robert Mcdonald c,
Wajdy Al-Awaida a, Frank Wuest d
a Faculty of Science, American University of Madaba, Amman 11821, Jordan
b Department of Chemistry, The Hashemite University, Zarqa 13115, Jordan
c Department of Chemistry, University of Alberta, Edmonton, AB T6G 2G2, Canada
d Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The structures of 5-(4-chlorophenyl)-1-{4-(methylsulfonyl)phenyl}-1H-tetrazole (3) and 4-{5-(4-
methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide (5) have been determined by X-ray crystallog-
raphy. Tetrazoles 3 and 5 crystallize in the monoclinic space groups Ia and P21/c, respectively. The cell
Received 5 May 2015
Received in revised form
8 August 2015
Accepted 10 August 2015
Available online 12 August 2015
dimensions of azole 3 are a ¼ 11.0413 (5) Å, b ¼ 11.8428 (5) Å, c ¼ 12.2483 (5) Å3,
b
¼ 111.7129 (4)ꢀ,
V ¼ 1487.95 (11) Å3, and Z ¼ 4. Its structure was refined to R1 ¼ 0.0254 (for 3429 observed reflections
[I ꢁ 2 (I)]) and wR2 ¼ 0.0651 (for all 3300 unique reflections). The cell dimensions of azole 5 are
s
a ¼ 17.112 (3) Å, b ¼ 6.5904 (10) Å, c ¼ 12.935 (2) Å3,
b
¼ 93.1981 (19)ꢀ, V ¼ 1456.5 (4) Å3, and Z ¼ 4. Its
Keywords:
structure was refined to R1 ¼ 0.0336 (for 3010 observed reflections [I ꢁ 2 (I)]) and wR2 ¼ 0.0875 (for all
s
1,5-diaryl tetrazoles
COX-2 inhibitors
(methylsulfonyl)phenyl
Molecular docking
(aminosulfonyl)phenyl
Crystal structure
2463 unique reflections). The tetrazole rings are essentially planar, while the aryl rings at the 1- and 5-
positions of each compound show no conjugation to the tetrazole groups. Compound 5 exhibits a
network of intermolecular hydrogen bonds generated by interactions between adjacent sulfonamide
groups. The molecular docking studies were carried out to understand the orientation and the inter-
action of each molecule inside the active site of the cyclooxygenase-2 enzyme, followed by comparison
with the bioassay studies as COX-2 inhibitors.
© 2015 Elsevier B.V. All rights reserved.
1. Introduction
kidneys, and the gastrointestinal tract and is believed to be
responsible for the maintenance of physiological functions such as
Cyclooxygenases (COXs) are involved in the complex conversion
of arachidonic acid to various prostanoids like prostaglandins,
prostacyclin and thromboxanes [1e3]. COX is a membrane-bound
heme, protein that exists in two distinct isoforms, a constitutive
form (COX-1) and an inducible form (COX-2) [4,5]. Recently, a novel
COX-1 splice variant termed as COX-3 has been reported [6]. The X-
ray structures of both enzymes COX-1 and COX-2, which catalyze
the same reactions using identical catalytic mechanisms, suggest
that the proteins are very similar in their tertiary conformation
[7,8]. The house keeping enzyme (COX-1) is found in platelets,
gastro protection and vascular homeostasis [9]. However, the COX-
2 expression is significantly upregulated as part of various acute
and chronic inflammatory conditions and is also found in
neoplastic tissues [10,11].
In general, tetrazole compounds have been widely used in many
applications such as medicine, pharmacology and explosives
[12e14]. 5-Substituted 1H tetrazoles have found numerous appli-
cations in medicinal chemistry as carboxylic acid isostere. Consid-
erably less use of 1,5-disubstituted tetrazoles has been reported in
the literature. Several reports describe the use of 1,5-disubstituted
tetrazoles as isosteres of the cis-amide bond in peptides. It was
shown that the tetrazole-containing compounds adopt almost the
same conformation as the original peptide. Prominent examples
* Corresponding author. Faculty of Science, American University of Madaba, P.O.
Box 2882, Amman 11821, Jordan.
involve
a-methylene tetrazole-based peptidomimetics as HIV-
protease inhibitors [15]. Other 1,5-disubstituted tetrazoles have
E-mail address: b.jawabrah@aum.edu.jo (B. Jawabrah Al-Hourani).
http://dx.doi.org/10.1016/j.molstruc.2015.08.025
0022-2860/© 2015 Elsevier B.V. All rights reserved.

22
B. Jawabrah Al-Hourani et al. / Journal of Molecular Structure 1101 (2015) 21e27
been described in recent patent literature such as glucokinase ac-
tivators [16], NAD(P)H oxidase inhibitors [17], anti-migraine agents
[18], and hepatitis C virus serine protease NS3 inhibitors [19].
Recently, we have described various 1,5-diaryl substituted tet-
razoles containing the 4-(methylsulfonyl)phenyl or 4-(amino-
sulfonyl)phenyl substituent attached to position 1 (N ꢂ 1) or
position 5 (C ꢂ 5) of the tetrazole ring as a novel class of COX-2
inhibitors [20e22]. In this work, we are reporting the docking
studies and the single crystal X-ray structures of the two previously
prepared [21] 1,5-diaryl substituted tetrazoles: 5-(4-chlorophenyl)-
1-{4-(methylsulfonyl)phenyl}-1H-tetrazole (3) and 4-{5-(4-
methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide (5), as
shown in Scheme 1.
reaction vessel with N2, dry CH3CN (4 mL) was added under N2
atmosphere. Perchlorosilane (4.0 equiv.). The reaction vessel closed
and immersed in a pre-heated oil bath at 90 ꢀC. After stirring tet-
razole 3 for 24 h and tetrazole 5 for 72 h the reaction was worked
out as stated below.
The reaction vessel was opened and immersed in the oil bath
under a stream of nitrogen to reduce the amount of the CH3CN to be
just under 1 mL. After the reaction was cooled to r. t., a cold satu-
rated solution of K2CO3 (40 mL) was carefully added and stirred for
30 min. The precipitate was filtered off and washed with water
(3 ꢃ 20 mL) and diethyl ether (2 ꢃ 5 mL) to give quantitatively the
pure tetrazoles 5-(4-chlorophenyl)-1-(4-(methylthio)phenyl)-1H-
tetrazole (2) and 4-{5-(4-methoxyphenyl)-1H-tetrazol-1-yl}ben-
zenesulfonamide (5). Tetrazole 2 was used directly for the next
step.
2. Experimental
Tetrazole 2 was dissolved in acetone, CH2Cl2, or MeOH (20 mL),
followed by the addition of a solution of potassium perox-
ymonosulfate (20 mL, 2.5 equiv.). After 3 h water (60 mL) was
added, and the precipitate was filtered off and washed with water
(3 ꢃ 20 mL) and ether (3 ꢃ 5 mL) to give a quantitative and pure
yield of 5-(4-Chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tet-
razole (3).
2.1. Instrumentation and materials
1H and 13C NMR spectra were recorded on a Varian Inova
600 MHz NMR spectrometer, with the solvent as internal reference
in the case of 1H, 13C. The mass spectra were performed at the Mass
Spectrometry Laboratory at the Department of Chemistry, Univer-
sity of Alberta. High resolution ESI mass spectra were recorded on a
Kratos-Analytical MS-50 spectrometer at the University of Alberta.
Melting points measured using BÜCHI B-545 ranged between
(25e400 ꢀC). All samples were measured with a starting temper-
ature at 25 ꢀCe280 ꢀC with gradient of 3 ꢀC/min. Flash chroma-
tography was performed on silica gel 0.04e0.063 mm columns.
Thin layer chromatography (TLC) was carried out on POLYGRAM SIL
G/UV254 ready foils from MACHEREY-NAGEL company. Commer-
cially available starting materials and solvents were purchased
from TCI America, Fisher, and Caledon Laboratory Chemicals.
5-(4-Chlorophenyl)-1-(4-(methylsulfonyl)phenyl)-1H-tetrazole
(3) White solid; crystallization from methanol gave a white solid;
2.2. Syntheses
The synthesis of 5-(4-chlorophenyl)-1-{4-(methylsulfonyl)
phenyl}-1H-tetrazole (3) and 4-{5-(4-methoxyphenyl)-1H-tetra-
zol-1-yl}benzenesulfonamide (5) was obtained by the treatment of
the aryl-benzamides with tetrachlorosilane/sodium azide in
acetonitrile at 90 ꢀC, followed by the oxidation for tetrazole 2 of the
methyl sulfide functionality as depicted in Scheme 1 [21].
2.3. General procedure for the synthesis of 5-(4-chlorophenyl)-1-
(4-(methylsulfonyl)phenyl)-1H-tetrazole (3) and 4-{5-(4-
methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfonamide (5)
Amide (1.0 equiv.) (1, 4) and powdered sodium azide (4.0 equiv.)
were added to a 48 mL HW pressure vessel. After flashing the
N
N
N
N
N
N
SCH3
O
N
N
b
a
N
H
Cl
SCH3
SO2CH3
Cl
Cl
1
2
3
N
N
N
SO2NH2
O
N
a
N
H
O
CH3
SO2NH2
O
CH3
4
5
Fig. 1. Molecular structures of tetrazole 3 (a) and tetrazole 5 (b). Atomic displacement
ellipsoids are drawn at the 50% probability level, except for hydrogens, which are
shown with arbitrarily-small isotropic displacement parameters.
Scheme 1. Reagents: (a) SiCl4/NaN3, CH3CN, 90 ꢀC, 1e3 days; (b) oxone®/acetone/
MeOH/H2O, 3 h, r. t.

B. Jawabrah Al-Hourani et al. / Journal of Molecular Structure 1101 (2015) 21e27
23
Table 1
Crystal data and experimental details of X-ray diffraction for compounds 3 and 5.
3
5
formula
formula weight
C14H11ClN4O2S
334.78
C14H13N5O3S
331.35
crystal dimensions (mm)
crystal system, space group
a (Å)
b (Å)
c (Å)
0.31 ꢃ 0.30 ꢃ 0.20
0.72 ꢃ 0.17 ꢃ 0.07
monoclinic, P21/c (No. 14)
17.112 (3)
6.5904 (10)
12.935 (2)
93.1981 (19)
1456.5 (4)
4
monoclinic, Ia (an alternate setting of Cc [No. 9])
11.0413 (5)
11.8428 (5)
12.2483 (5)
111.7129 (4)
1487.95 (11)
4
b
(deg)
V (Å3)
Z
D, calculated density (g cmꢂ3
)
1.494
0.409
1.511
0.246
m
(mmꢂ1
)
diffractometer
radiation ( [Å])
Bruker D8/APEX II CCD
graphite-monochromated Mo K
l
a (0.71073)
temperature (K)
scan type
data collection 2
173(1)
u
scans (0.3ꢀ) (15 s exposures)
u
scans (0.3ꢀ) (20 s exposures)
53.00
q
limit (deg)
55.04
total data collected
independent reflections (Rint
6575 (ꢂ14 ꢄ h ꢄ 14, ꢂ15 ꢄ k ꢄ 15, ꢂ15 ꢄ l ꢄ 15)
11,239 (ꢂ21 ꢄ h ꢄ 21, ꢂ8 ꢄ k ꢄ 8, ꢂ16 ꢄ l ꢄ 16)
)
(I))
3429 (Rint ¼ 0.0151)
3010 (Rint ¼ 0.0330)
observed reflections (I ꢁ 2
structure solution method
refinement method
absorption correction method
range of transmission factors
data/restraints/parameters
extinction coefficient (x)
s
3300
2463
direct methods (SHELXD)
full-matrix least-squares on F2 (SHELXL-97)
Gaussian integration (face-indexed)
0.9241e0.8827
3429/0/200
0.0017(4)
0.9839e0.8424
3010/0/216
Flack absolute structure param.
0.02(4)
1.045
0.0254, 0.0637
0.0269, 0.0651
goodness-of-fit (S)a (all data)
1.032
R1, wR2 (I ꢁ 2
s
(I))b
0.0336, 0.0445
0.0817, 0.0875
0.287, ꢂ0.405
R1, wR2 (all data)b
largest difference peak and hole (e Åꢂ3
)
0.316, ꢂ0.263
a
S ¼ [Sw(F2o ꢂ F2c)2/(n ꢂ p)]1/2 (n ¼ number of data; p ¼ number of parameters varied; w ¼ [
s
2(F2o) þ (a0P)2 þ a1P]ꢂ1 where P ¼ [Max(Fo2, 0) þ 2Fc2]/3; for 3, a0 ¼ 0.0367,
a1 ¼ 0.4652; for 5, a0 ¼ 0.0398, a1 ¼ 0.6839.
b
R1 ¼ SjjFoj ꢂ jFcjj/SjFoj; wR2 ¼ [Sw(F2o ꢂ Fc2)2/Sw(Fo4)]1/2
.
Table 2
130.8, 129.1, 128.7, 126.7, 122.0, 43.1; HRMS (m/z) [M þ Na]þ calcd
for C14H11ClN4NaO2S, 357.0183; found 357.0184.
4-{5-(4-methoxyphenyl)-1H-tetrazol-1-yl}benzenesulfona-
mide (5) White solid; crystallization from methanol gave a white
Bond lengths (Å) for compounds 3 and 5.
3
5
CleC24
SeO1
SeO2
SeN5
SeC14
1.7355(17)
1.4396(14)
1.4382(13)
solid; mp: 235 ꢀC. 1H NMR (DMSO-d6)
d
8.01 (d, J ¼ 8.4 Hz, 2H), 7.77
1.4350(12)
1.4341(12)
1.6054(15)
1.7629(16)
(d, J ¼ 8.4 Hz, 2H), 7.61 (s, 2H, SO2NH2) 7.48 (d, J ¼ 8.4 Hz, 2H), 7.05
(d, J ¼ 8.4 Hz, 2H), 3.79 (s, 3H, OMe); 13C NMR (DMSO-d6)
d 161.4
1.7735(16)
1.7584(18)
SeC17
(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 þ H]þ calcd for C14H14N5O3S, 332.0812; found 332.0813.
O3eC24
O3eC27
N1eN2
N1eC1
N1eC11
N2eN3
N3eN4
N4eC1
C1eC21
C11eC12
C11eC16
C12eC13
C13eC14
C14eC15
C15eC16
C21eC22
C21eC26
C22eC23
C23eC24
C24eC25
C25eC26
1.3675(19)
1.427(2)
1.3634(18)
1.354(2)
1.433(2)
1.288(2)
1.364(2)
1.318(2)
1.474(2)
1.386(2)
1.389(2)
1.380(2)
1.387(2)
1.393(2)
1.376(2)
1.386(2)
1.394(2)
1.389(2)
1.388(2)
1.390(2)
1.381(2)
1.3667(18)
1.350(2)
1.426(2)
1.286(2)
1.360(2)
1.316(2)
1.468(2)
1.382(2)
1.392(2)
1.389(2)
1.387(2)
1.392(2)
1.377(2)
1.389(2)
1.398(2)
1.386(2)
1.382(2)
1.386(2)
1.381(2)
2.4. Single crystal X-ray structure determination
Colorless single crystals of both compounds 3 and 5 were ob-
tained by slow evaporation of chloroform solutions of the com-
pounds at room temperature. Suitable single crystals were selected,
coated with Paratone-N oil, and attached to glass fibers. Diffraction
data for both compounds were collected on a Bruker D8 diffrac-
tometer equipped with an APEX II CCD detector. Diffraction mea-
surements were made with the crystals cooled to 173(1) K and
using graphite-monochromated Mo K
a
radiation (
l
¼ 0.71073 Å).
The structures were solved by iterative dual-space direct methods
using SHELXD [23] and were refined by full-matrix least-squares
procedures on F2, using SHELXL-97 [24]. The positions of the
hydrogen atoms were generated based on the sp2 or sp3 hybrid-
izations of their parent carbon atoms, and assigned isotropic
displacement parameters 120% of the Ueq's for their parent atoms.
The molecular structure and the atomic numbering scheme of 3
and 5 are shown in Fig. 1.
m.p. 183.6 ꢀC. 1H NMR (DMSO-d6)
d
8.15 (d, J ¼ 8.4 Hz, 2H), 7.85 (d,
J ¼ 9.0 Hz, 2H), 7.60 (d, J ¼ 8.4 Hz, 2H), 7.65 (d, J ¼ 9.0 Hz, 2H), 3.33
(s, 3H, SO2Me). 13C NMR (DMSO-d6)
d
152.9, 142.3, 137.6, 136.3,

24
B. Jawabrah Al-Hourani et al. / Journal of Molecular Structure 1101 (2015) 21e27
Table 3
3. Results and discussion
Bond angles (deg) for compounds 3 and 5.
3.1. Crystal structure analysis
3
5
O1eSeO2
O1eSeN5
O1eSeC14
O1eSeC17
O2eSeN5
O2eSeC14
O2eSeC17
N5eSeC14
C14eSeC17
C24eO3eC27
N2eN1eC1
N2eN1eC11
C1eN1eC11
N1eN2eN3
N2eN3eN4
N3eN4eC1
118.15(8)
118.63(8)
107.55(8)
107.13(7)
Table 1 lists crystallographic and experimental details for the
diffraction experiments, while the molecular structure and the
atomic numbering scheme of 3 and 5 are shown in Fig. 1.
108.49(8)
109.38(9)
106.57(8)
108.08(8)
Bond lengths and angles for these compounds are listed in
Tables 2 and 3, respectively. A side-by-side comparison of these
lengths and angles shows the effects of the 4-chloro (3) vs. 4-
methoxy (5) and 4-methylsulfonyl (3) vs. 4-sulfonamide (5) sub-
stitutions upon the geometries of the phenyl and tetrazole groups
to be essentially negligible. For both compounds, the intra-
molecular dihedral angles between the ring planes (Table 4) indi-
cate no conjugation between attached rings of the molecules.
107.67(8)
108.10(9)
108.58(8)
104.14(9)
117.33(14)
107.85(13)
119.00(13)
132.96(14)
106.48(13)
111.15(13)
106.15(14)
127.53(15)
124.09(15)
120.39(14)
118.08(14)
121.44(15)
119.00(15)
119.95(15)
119.92(12)
119.33(13)
120.67(15)
119.57(15)
119.35(15)
127.53(15)
121.06(15)
119.45(15)
119.42(15)
120.66(16)
119.34(16)
120.41(15)
119.79(16)
120.36(16)
107.82(13)
119.80(12)
132.38(13)
106.26(12)
111.25(13)
106.25(13)
108.43(13)
127.78(14)
123.70(14)
120.18(14)
118.02(14)
121.80(15)
119.27(15)
118.96(15)
120.25(13)
118.20(12)
121.54(15)
119.45(15)
118.97(15)
121.93(15)
117.66(14)
120.17(15)
120.01(15)
119.09(16)
121.71(16)
119.13(15)
119.90(15)
119.70(13)
118.59(13)
Compound 3 exhibits an intermolecular
p-stacking arrange-
ment of the tetrazole group and the 4-chlorophenyl group of the
adjacent molecule related by the (ꢂ1/2 þ x, 1 ꢂ y, z) symmetry
operation. The dihedral angle between these ring planes is
6.43(10)ꢀ. The distances of the symmetry-related 4-chlorophenyl
group atoms out of the tetrazole ring plane are as follows: Cl:
3.623(2) Å; C21: 3.192(4) Å; C22: 3.319(4) Å; C23: 3.462(3) Å; C24,
3.471(3) Å; C25: 3.349(3) Å; C26: 3.208(4) Å. The closest hetero-
atomehydrogen interaction between neighboring molecules in-
cludes O2/ H25(at x, y,1 þ z) ¼ 2.45 Å, N4/H17C(at ꢂ1/2 þ x,1 ꢂ y,
z ꢂ 1) ¼ 2.45 Å, and Cl/H17B(at 1/2 þ x, ꢂ1/2 þ y, ꢂ1/2 þ z) ¼ 2.69 Å.
For compound 5 the most notable intermolecular interactions
are those between the sulfonamide groups of adjacent symmetry-
related molecules. The SO2NH2 groups related by the inversion
center (1/2, ꢂ1/2, 0) form a cyclic interaction, specifically through
hydrogen bonds between O2 and the inversion-related H5NB, and
vice versa as shown in Fig. 2. The O1 atom is hydrogen-bonded to
H5NA at (ꢂx, ꢂ1/2 þ y, 1/2 ꢂ z), while H5NA interacts with O1 at (ꢂx,
1/2 þ y, 1/2 ꢂ z). Thus an additional chain propagating in a direction
N1eC1eN4
N1eC1eC21
N4eC1eC21
N1eC11eC12
N1eC11eC16
C12eC11eC16
C11eC12eC13
C12eC13eC14
SeC14eC13
SeC14eC15
C13eC14eC15
C14eC15eC16
C11eC16eC15
C1eC21eC22
C1eC21eC26
C22eC21eC26
C21eC22eC23
C22eC23eC24
C23eC24eC25
C24eC25eC26
C21eC26eC25
CleC24eC23
CleC24eC25
O3eC24eC23
O3eC24eC25
parallel to the crystal b-axis is formed. An intermolecular p-stack-
ing interaction is observed between the tetrazole ring and the
methoxyphenyl group related by (x, 1/2 ꢂ y, ꢂ1/2 þ z), where the
dihedral angle between the tetrazole and phenyl ring planes is
2.02(12)ꢀ. The symmetry-related atoms closest to the tetrazole
rings, and their distances to the tetrazole ring plane, are as follows:
O3: 3.5106(18) Å; C23, 3.466(2) Å; C24: ꢂ3.4999(19) Å; C25:
124.37(15)
115.22(15)
Table 4
Dihedral angles (deg) between ring planes for compounds 3 and 5.
3.532(2) Å. The closest heteroatomehydrogen interaction between
1
neighboring molecules includes H25/N4(at x, 3/2
ꢂ
y,
/
3
5
2 þ z) ¼ 2.55 Å, H16/O1(at x, ꢂ1/2 ꢂ y, e1/2 þ z) ¼ 2.61 Å,
H22/O3(at x, 1/2 ꢂ y, e1/2 þ z) ¼ 2.65 Å, and H25/N3(at x, 3/2 ꢂ y,
1/2 þ z) ¼ 2.66 Å.
Angle between planes A and B
Angle between planes A and C
Angle between planes B and C
46.48(6)
38.63(4)
58.73(5)
24.23(8)
62.26(5)
69.51(4)
Plane A: N1, N2, N3, N4, C1 (tetrazole).
Plane B: C11, C12, C13, C14, C15, C16 (4-(methylsulfonyl)phenyl (3) or 4-(amino-
sulfonyl)phenyl (5)).
3.2. Molecular docking studies
Plane C: C21, C22, C23, C24, C25, C26 (4-chlorophenyl (3) or 4-methoxyphenyl (5)).
Molecular docking study on the interaction of both molecules
with the binding site of COX-2 was conducted to have a clear pic-
ture of the types of interactions involved in the recognition process.
The docking of the 3 and 5 into the COX-2 binding site resulted in a
2.5. Molecular docking studies
calculated binding free energy
D
G ¼ ꢂ8.9 and ꢂ9.1 kcal/mol,
respectively. Similar amino acid residues, His90, Arg120, Gln192,
Tyr348, Val349, Leu352, Ser353, Tyr355, Tyr385, Trp387, Ala516,
Phe518, Val523, Gly526, Ala527, and Ser530, are interacting with
both ligands within a 4 Å distance. This indicates more or less a
similar location within the binding site of COX-2 (Fig. 3).
The cyclooxygenase-2 (COX-2) crystal structure was obtained
from the RCSB Protein Data Bank (PDB identifier 1PXX). Chain A of
1PXX was only used for the present study. The ligand flexible
docking study of compound 3 and 5 was achieved using AutoDock
Vina [25]. The used simulation box was adequately large to involve
the entire region of interaction between the ligand and the enzyme.
Default parameters were used except for the exhaustiveness
parameter in which it was set to 500. The most energetically
favorable conformation obtained was examined, and its binding
energy with COX-2 active site was evaluated.
Zooming in on the docked structure reveals that compound 3
forms four hydrogen bonds with the nearby amino acid residues
(Fig. 4 (left)). The presence of Tyr355 and Arg120 in the binding
moiety results in the formation of a hydrogen bonding interaction
between the hydroxyl group of Tyr355 and the guanidine group of
Arg120 with the N2 (distance ¼ 3.08 Å, moderate interaction) and

B. Jawabrah Al-Hourani et al. / Journal of Molecular Structure 1101 (2015) 21e27
25
Fig. 2. Illustration of hydrogen-bonded interactions (indicated by dotted lines) between the sulfonamide groups of adjacent molecules in the crystal lattice for the structure of 5.
Fig. 3. Docked structure of the tetrazole 3 (left) and tetrazole 5 (right) surrounded by selected amino acid residues involved in the recognition process in the COX-2 enzyme.
Fig. 4. Hydrogen bonding inside the catalytic site between compound 3 and the amino acid residues His90, Arg120, Tyr355, and Phe518 (left). Hydrogen bonding inside the catalytic
site between compound 5 and the amino acid residues His90, Arg120, Gln192, Ser353, Tyr355, and Phe518 (right).
N5 (distance ¼ 4.10 Å, weak interaction) of the central tetrazole
moiety, respectively. Furthermore, Phe518 and His90 form
hydrogen bonds with the two oxygen atoms of the methylsulfonyl
group (MeSO2) with distances of 2.60 (NH/O]S]O) and 3.02 Å
(O]S]O/NH), respectively. The two oxygen atoms of the sul-
fonamide pharmacophore unit (H2NSO2) of compound 5 form four

26
B. Jawabrah Al-Hourani et al. / Journal of Molecular Structure 1101 (2015) 21e27
Fig. 5. The hydrophobic environment of the amino acid residues in the catalytic site of COX-2 surrounding the compounds 3 (left) and 5 (right).
hydrogen bonds. Two of them result from the interaction with the
NH group of both Phe518 and His90 with distances of 2.69
(NH/O]S]O) and 2.19 Å (O]S]O/NH), respectively (Fig. 4
(right)). Obviously, there is a shorter hydrogen bond interaction
of the NH group (His90)/O]S(SO2) in compound 5 than in
compound 3. Two additional strong hydrogen bonds are observed
between the hydroxyl group of Ser353 and Gln192 with the hy-
drogens of NH2 group in the sulfonamide unit. Similar to adduct 3,
the N2 and N5 of the central tetrazole moiety establish hydrogen
bonds with the hydroxyl group of Tyr355 (2.86 Å) and with the
guanidine group of Arg120 (4.00 Å).
The phenyl groups of both compounds are surrounded by a
hydrophobic colony of Tyr385, Tyr348, Trp387, Ala527, Val349,
Gly526, Leu352, Phe518, Val523, Gly354, Tyr355, and Ala516
(Fig. 5).
Docking results exhibit better interactions of 5 with the COX-2
binding site; however, the reported IC50 values from the in vitro
bioassay studies indicate that 3 has higher inhibition potency than 5
[21]. The computed Log P values of 3 and 5 are 2.64 and 1.86,
respectively [21]. This significant difference of the lipophilicity
might explain the discrepancy between the docked results and the
bioassay screening values. A previous report indicates that the na-
ture of the substituent on the para position of the benzene rings
plays a significant role in the inhibition potency of the compound.
arrangement was found in compound 3 between the tetrazole
group and the 4-chlorophenyl group of the adjacent molecule
related by the (ꢂ1/2 þ x, 1 ꢂ y, z) symmetry operation. Hydrogen-
bonded interactions between sulfonamide groups dominate the
intermolecular framework within the solid-state structure of 5.
Compound
5 revealed a similar intermolecular p-stacking
arrangement of the tetrazole group and the 4-methoxyphenyl
ꢂ1
group of the adjacent molecule related by the (x, 1/2 ꢂ y,
/
2 þ z) symmetry operation. The intramolecular dihedral angles
between the ring planes show no conjugation between the
substituted phenyl rings and the tetrazole groups for either com-
pound. A number of weak nonbonded heteroatomehydrogen in-
teractions are observed in both compounds. Our molecular docking
studies explained the main interactions of compounds 3 and 5, as
weak COX-2 inhibitors, with the COX-2 enzyme. The docking
studies showed stronger hydrogen bonding between compound 5
and the active site of the COX-2 enzyme than compound 3. Sur-
prisingly, in vitro studies showed that no inhibition potency toward
the COX-2 enzyme was found by compound 5 and slightly better
inhibition potency could be observed by compound 3. The
discrepancy between the docked results and bioassay screening
values may be attributed to the significant difference of the
computed Log P values of 3 and 5, 2.64 and 1.86, respectively.
For example, replacing the MeO (Log P ¼ 1.86, IC50
(
m
M) > 100)
Acknowledgments
substituent with Cl on the phenyl (Log P ¼ 2.46, IC50
(m
M) ¼ 62) ring
of tetrazole 5 showed a better inhibition potency toward the COX-2
enzyme. A similar case was reported with 3 regarding replacement
The authors would like to thank the Scientific Support Research
Fund (BAS/1/1/2012), the Dianne and Irving Kipnes Foundation and
the Canadian Institute for Health Research (CIHR) for supporting
this work. We thank Mrs Erica Koby (eakoby@liberty.edu) for
editing the manuscript.
of the Cl group (Log P ¼ 2.64, IC50
(
m
M) ¼ 32) with the MeO sub-
stituent (Log P ¼ 2.04, IC50 M) > 100) [21]. Moreover, the present
(m
docking study was performed in a continuum solvation model.
Therefore the effect of explicit water molecules in the strength of the
interaction as well as the geometry of the molecular complex was
not addressed, which might have a decisive factor on such systems.
As a future study, molecular dynamics simulations using an explicit
solvation model should be carried out to investigate the role of
water in the binding process. Moreover, other substituents located
at the benzene ring ranging in their polarity should also be studied.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2015.08.025.
Supplementary data
4. Conclusions
Crystallography data for compounds 3 and 5 have been depos-
ited with the Cambridge Crystallographic Centre. CCDC No. 963302
and 1024261, respectively. The Data can be obtained free of charge
from CDCC, 12 Union Road, Cambridge CB2 1EZ, UK, Fax þ44 1223
336 033, email: deposit@cdcc.cam.ac.uk or http://www.ccdc.cam.
ac.uk/getstructures.
The molecular structures of 5-(4-chlorophenyl)-1-{4-(methyl-
sulfonyl)phenyl}-1H-tetrazole (3) and 4-{5-(4-methoxyphenyl)-
1H-tetrazol-1-yl}benzenesulfonamide (5) have been determined
by X-ray diffraction methods. An intermolecular
p-stacking

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27
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