Novel 1,2,3-triazole compounds: Synthesis, In vitro xanthine oxidase inhibitory activity, and molecular docking studies

Article abstract of DOI:10.1016/j.molstruc.2020.128060

In this study, novel 1,2,3-triazole compounds containing carbasugar frameworks (5 and 6) were synthesized by the copper-catalyzed azide-alkyne cycloaddition reactions and their in vitro inhibition effects on the enzyme xanthine oxidase were investigated. All of the synthesized compounds were characterized by spectroscopic methods. According to the enzyme inhibition results, compounds 5 (IC₅₀ = 0.586 ± 0.017 μM) and 6 (IC₅₀ = 0.751 ± 0.021 μM) showed stronger inhibition effects than allopurinol (IC₅₀ = 1.143 ± 0.019 μM), which is a standard drug used for inhibition of xanthine oxidase. The binding modes of the 1,2,3-triazole compounds (5 and 6) with the active site of xanthine oxidase were explained based on molecular docking studies. The molecular docking studies showed that the aromatic structure, π-π interactions and hydrophobic interactions play a major role in xanthine oxidase inhibition for compounds 5 and 6.

Full text of DOI:10.1016/j.molstruc.2020.128060

Journal of Molecular Structure 1211 (2020) 128060
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Novel 1,2,3-triazole compounds: Synthesis, In vitro xanthine oxidase
inhibitory activity, and molecular docking studies
Ayse Tan
Vocational School of Technical Sciences, Mus Alparslan University, Mus, 49250, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 January 2020
Received in revised form
In this study, novel 1,2,3-triazole compounds containing carbasugar frameworks (5 and 6) were syn-
thesized by the copper-catalyzed azide-alkyne cycloaddition reactions and their in vitro inhibition effects
on the enzyme xanthine oxidase were investigated. All of the synthesized compounds were character-
10 March 2020
ized by spectroscopic methods. According to the enzyme inhibition results, compounds
IC50 ¼ 0.586 ± 0.017 M) and 6 (IC50 ¼ 0.751 ± 0.021 M) showed stronger inhibition effects than
M), which is a standard drug used for inhibition of xanthine oxidase.
5
Accepted 11 March 2020
Available online 16 March 2020
(
m
m
allopurinol (IC50 ¼ 1.143 ± 0.019
m
The binding modes of the 1,2,3-triazole compounds (5 and 6) with the active site of xanthine oxidase
Keywords:
were explained based on molecular docking studies. The molecular docking studies showed that the
1,2,3-Triazole
aromatic structure,
p-p interactions and hydrophobic interactions play a major role in xanthine oxidase
Carbasugar
Xanthine oxidase
inhibition for compounds 5 and 6.
1,3-Dipolar cycloaddition
© 2020 Elsevier B.V. All rights reserved.
Molecular docking
1
. Introduction
containing different bioactive frameworks have been designed and
it was reported that these compounds exhibited strong biological
activity [18,19]. Thus, in the present study, novel bioactive hybrid
molecules that contain 1,2,3-triazole structures and carbasugar
frameworks were designed and synthesized. As 1,2,3-triazoles,
carbasugars are very important compounds attracting the interest
of synthetic organic chemists [20] and these compounds, named
pseudosugars, are carbohydrate derivatives [21] and have various
biological activities, such as antiviral, antitumor, and antifungal,
particularly as antibiotics and glycosidase inhibitors [21,22].
Gout is an inflammatory_rheumatic disease formed by crystal-
lization of uric acid in the joints. Uric acid occurs in the last step of
purine metabolism [1]. This process is catalyzed by the enzyme
xanthine oxidase (XO) [2]. Therefore, XO causes gout [3]. In the
treatment of this disease, many drugs are used, such as probenecid
[
4], benzbromarone [4,5], colchicine [6], loxoprofen sodium [7], and
allopurinol [5] (Fig. 1). Allopurinol and other gout drugs are XO
inhibitors [5]. Allopurinol, which contains purine in its structure,
prevents the conversion of purine metabolites to uric acid by
inhibiting XO [8].
However, it has been reported that allopurinol and other drugs
have a wide variety of serious side effects [9]. Therefore, the dis-
covery of alternative drugs that are strong XO inhibitors is essential.
2. Results and discussion
2.1. Synthesis
1
,2,3-Triazole compounds and their substituted derivatives are
1
,2,3-Triazole compounds (5 and 6) containing carbasugar
of great importance in organic chemistry, medical chemistry, and
drug discovery due to their wide variety of biological activities [10]
Fig. 2), such as antiallergic [11], antimicrobial [12], antibacterial
10], anticancer [8], antitubercular [10], -glucosidase inhibitory
13,14], SGLT2 inhibitory [15], IDO inhibitory [16], and acidic
frameworks were synthesized starting from maleic anhydride and
butadiene sulfone [23] (Scheme 1). Compounds 1, 2, and 3 were
synthesized and purified as described previously [23]. Epoxidation
of compound 2 with m-CPBA at room temperature gave an isomeric
mixture of epoxides (anti-3a and syn-3b) in a ratio of 3:1 [23]. The
isomeric mixture was separated by column chromatography. To
synthesize compound 4, the epoxide ring of anti-3a was opened
(
[
[
a
corrosion inhibitory [17].
In recent years, many hybrid 1,2,3-triazole derivatives
3
with NaN in MeOH. The opening mechanism of the epoxide ring is
given in Scheme 2. The attack of the azide group on the epoxide
ring was proposed based on X-ray diffraction analysis of compound
E-mail address: a.tan@alparslan.edu.tr.
https://doi.org/10.1016/j.molstruc.2020.128060
0
022-2860/© 2020 Elsevier B.V. All rights reserved.

2
A. Tan / Journal of Molecular Structure 1211 (2020) 128060
Fig. 1. Some of drugs used in the treatment of gout.
Fig. 2. Some bioactive molecules containing 1,2,3-triazolyl scaffold.
5
, which is shown in Fig. 3 The azido-alcohol formed by opening of
1
crystallizes in the monoclinic space group P2 /c with four mole-
the ring was easily determined by the IR spectrum of compound 4.
According to this spectrum (Fig. S7 in supporting inf), a (OH)
(NeN)
stretching vibration was seen at 2096.42 cm . The aliphatic (CH)
stretching vibrations of compound 4 were observed between
cules in the unit cell and each one has the same stereochemistry.
Cyclohexane unit has the chair conformation, CeC (cyclohexane)
distances are in the range of 1.526(4)-1.540(4) Å, all have the single
bond character. N2¼N3 double bond in triazole unit is 1.318(4) Å,
the triazole heterocycle with phenyl ring is almost planar. Structure
contains four asymmetric carbon atoms, stereogenic centers are as
follows; C9(S), C10(S), C12(S), C13(R). Intermolecular OeH/N [D …
A ¼ 2.916 Å] interaction, which leads to the formation of dimeric
structure.
n
ꢀ1
stretching vibration was seen at 3460.71 cm
and a n
ꢀ1
n
ꢀ
1
ꢀ1
3
007.14 and 2882.14 cm . The strong band at 1725.35 cm was
attributed to the stretching vibration of ester carbonyl groups
n
(C¼O) of 4. 1,2,3-Triazole compounds have been the focus of in-
terest for organic and pharmaceutical chemists for many years, and
several methods [24] have been proposed for the synthesis of these
compounds [25]. A method applied by Worel et al. [26] was used to
synthesize 1,2,3-triazole derivatives (5 and 6). Therefore, com-
pound 4 was reacted with terminal alkynes (phenyl acetylene and
2.2. In vitro xanthine oxidase (XO) inhibitory activity
The in vitro XO inhibitory activity results of 1,2,3-triazole com-
pounds 5 and 6 are summarized in Table 1 as IC50 values. The
experimental results indicated that compounds 5 and 6 showed
higher activity than allopurinol against XO. The IC50 values for XO
inhibition vary as follows: 5 ˃ 6 ˃ allopurinol.
1
-pentyne) in the presence of sodiumL-ascorbate and CuSO
4 2
.5H O
in a MeOHeH O solvent system. The target products (5 and 6) were
2
obtained in very good yields (Scheme 1). According to this method,
sodium-L-ascorbate has been used as the reducing agent to
generate the active Cu(I) catalyst from Cu(II) salt. 1,2,3-triazoles
have been obtained by the active Cu(I)-catalyzed azide-alkyne
cycloaddition reactions (Scheme 3) [26]. The structures of com-
2.3. Molecular docking studies
1
13
pounds 5 and 6 were assigned based on H NMR, C NMR, IR, and
HR-MS analyses (see experimental part).
Molecular docking studies were carried out to understand the
binding pose of compounds (5, 6, and allopurinol) that interact
with the active site of XO. Allopurinol was used as a reference in-
hibitor compound for XO. Compounds 5, 6, and allopurinol were
similarly docked into the active site of the receptor. The docking
The exact structure of the dimethyl (1S,2R,4R,5R)-4-hydroxy-5-
(
4-phenyl-1H-1,2,3-triazol-1-yl) cyclohexane-1,2-dicarboxylate (5)
was confirmed by X-ray diffraction analysis (Fig. 3). Compound 5

A. Tan / Journal of Molecular Structure 1211 (2020) 128060
3
Scheme 1. Synthesis of compounds 5 and 6 from maleic anhydride and butadiene sulfone. Reagents and conditions: a) Xylene, reflux; b) cat. H
2
SO
4
, MeOH, reflux; c) m-CPBA, DCM,
3 4 4 2
room temperature; d) NaN , NH Cl, MeOH, reflux; e) Terminal alkyne, CuSO .5H O, Sodium-L-ascorbate, MeOH, room temperature.
Scheme 2. Proposed mechanism for the formation of compound 4.
studies exhibited that 5, 6, and allopurinol could easily fit into the
active site of XO. The binding energies of all compounds were
consistent with the experimental results. Binding energy values
and the interactions of compounds 5, 6, and allopurinol with the
active site of XO were given in Table 2. Interaction residues were
given by sequence alignment (Fig. 7). When the molecular in-
teractions of these three compounds (5, 6, and allopurinol) were
examined (see Figs. 4-6), it was observed that the aromatic group,
Sigma-Aldrich without further purification. The 1H NMR and 13
C
NMR spectra were recorded on a Bruker 400 MHz spectrometer.
Chemical shifts were given in parts per million (ppm). Abbrevia-
tions used to define multiplicities are as follows: s ¼ singlet;
d ¼ doublet; t ¼ triplet; q ¼ quartet; m ¼ multiplet. The IR spectrum
was recorded with a PerkinElmer spectrophotometer using an ATR
ꢀ
1
head in the range of 4000e600 cm . Melting point (M.p.) was
measured with a Thermo Scientific melting point device. The mass
spectra were recorded on an Agilent Technologies 6530 Accurate-
Mass Q-TOF LC/MS.
p-p interactions and hydrophobic interactions had more effect on
the interaction with the active site of XO for compounds 5 and 6.
However, for allopurinol, the conventional hydrogen bond and
hydrophobic interactions had a greater effect on the interaction.
3.1.1. Synthesis
3
. Experimental
Compounds 1, 2 and anti-3a were synthesized and purified as
described in previous studies [23]. Epoxides anti-3a and syn-3b
were obtained from compound 2. The isomeric mixture was
separated by column chromatography (EtOAc/n-hexane, 1:3), and
anti-3a was obtained as a light yellow viscous liquid (yield: 55%)
3
.1. Chemistry
All reagents and anhydrous solvents were purchased from

4
A. Tan / Journal of Molecular Structure 1211 (2020) 128060
added 50 mL of EtOAc and then extraction was performed with H
3 ꢁ 10 mL). The organic layer was dried over Na SO . The crude
product was purified by column chromatography [(CC; SiO (30 g),
EtOAc/n-hexane, 50:50)] and gave compound 5 (Yield: 89% (0.56 g,
.56 mmol), Compound 5 was crystallized from EtOH and obtained
2
O
(
2
4
2
1
ꢂ
1
as bright white crystals. M.p. 198e199 C. H NMR (
00 MHz, DMSO‑d
): 8.59 (d, J ¼ 1.6, 1H), 7.88 (d, J ¼ 7.6, 2H), 7.44 (t,
J ¼ 7.2, 2H), 7.32 (m, 1H), 5.23 (d, J ¼ 5.2, 1H), 4.42 (m, 1H), 3.81 (m,
H), 3.68 (s, 3H), 3.61 (s, 3H), 3.04 (m, 1H), 2.51 (d, J ¼ 1.6, 1H), 2.35
d, ppm,
4
6
1
13
(
m, 2H), 1.80 (td, J ¼ 12.4, 5.2, 1H). C NMR (
DMSO‑d ): 172.78, 172.23, 145.74, 130.93, 128.80, 127.67, 125.06,
20.88, 67.93, 64.36, 51.88, 51.67, 40.99, 40.83, 34.96, 29.87. IR
d, ppm, 100 MHz,
6
1
ꢀ
1
(cm ): 3328.57, 3142.85, 3010.71, 2953.57, 2896.42, 1712.86,
1
[
486.36, 1448.91, 1434.64. HR-ESI-MS (C18
21
H N
3
O
5
): m/z 360.15394
M þ H]þ (calcd. 360.14667 [M þ H] )
þ
3
1
.1.1.3. Synthesis of dimethyl (1S,2R,4R,5R)-4-hydroxy-5-(4-propyl-
H-1,2,3-triazol-1-yl)cyclohexane-1,2-dicarboxylate (6). To a stirred
solution of 4 (0.45 g, 1.76 mmol) in 10 mL of methanol were added
solutions of sodium-L-ascorbate (0.35 g, 1.76 mmol) and
CuSO .5H O (0.03 g, 0.16 mmol) in 6 mL of H O, consecutively. 1-
4 2 2
pentyne (0.17 mL, 1.76 mmol) was added to the reaction medium
at room temperature. The mixture was stirred at room temperature
for 24 h and checked by TLC [28]. To reaction mixture was added
5
(
0 mL of EtOAc and then extraction was performed with H
3 ꢁ 10 mL). The organic layer was dried over Na SO . The crude
product was purified by column chromatography [(CC; SiO (30 g);
EtOAc/n-hexane, 50:50)] and gave compound 6 (Yield: 75% (0.42 g,
2
O
2
4
2
1
.32 mmol), Compound 6 was crystallized from EtOH and obtained
ꢂ
as white crystals. M.p. 133e134 C.
1
3
H NMR (d, ppm, 400 MHz, CDCl ): 7.34 (s, 1H), 4.19 (s, 1H), 4.01
(m,1H), 3.66 (s, 3H), 3.64 (s, 3H), 3.37 (s, 1H), 2.66 (m, 1H), 2.55 (m,
2
H), 2.44 (m, 2H), 1.75 (td, J ¼ 13.6, 5.2, 1H), 1.58 (m, 2H), 0.88 (t,
Fig. 3. The dimeric structure of 5, with displacement ellipsoids drawn at the 40%
probability level. Dashed lines indicate H-bonding geometry (up). Unit cell with the
stacking of the dimeric molecules viewed down along the c-axis (down).
13
J ¼ 7.2, 3H). C NMR (
3
d, ppm, 100 MHz, CDCl ):172.90, 172.22,
147.51, 120.77, 68.77, 65.18, 52.16, 52.13, 42.22, 41.03, 34.63, 29.50,
ꢀ1
2
2
7.54, 22.47, 13.79. IR (cm ): 3207.14, 3142.85, 3017.85, 2957.14,
932.14, 2867.85, 1739.61, 1723.56, 1552.35, 1452.48, 1431.08. HR-
3
.1.1.1. Synthesis of dimethyl (1R,2S,4R,5R)-4-azido-5-
hydroxycyclohexane-1,2-dicarboxylate (4). To a stirred solution of
anti-3a (0.5 g, 2.33 mmol) in 10 mL of MeOH were added NaN
0.46 g, 7 mmol) and NH Cl (0.37 g, 7 mmol) at room temperature.
): m/z 326.17459 [M þ H]þ (calcd. 326.16729
ESI-MS (C15
H
23
N
3
O
5
þ
[M þ H] ).
3
(
4
3.2. In vitro assay of xanthine oxidase (XO) inhibitory activity
The mixture was refluxed for 24 h. The solution was evaporated
under reduced pressure [27]. To the mixture was added 15 mL of
The in vitro XO inhibitory assay method was reported by
EtOAc followed by extraction with H
organic phase was dried over Na SO
reduced pressure, and a crude product was obtained. The crude
product was purified by column chromatography [(CC; SiO (25 g);
EtOAc/n-hexane, 15:85)] and gave compound 4 as a light yellow
2
O (3 ꢁ 10 mL); then the
Sweeney A. P. et al. [29]. Enzyme activity was assayed by measuring
2
4
and evaporated under
ꢂ
the uric acid formation at 294 nm at 37 C. For calculation IC50 value
of XO inhibition different concentration of compounds 5, 6, and
Allopurinol were added to the reaction mixture. Briefly, the enzyme
assay protocol contains phosphate buffer (50 mM, pH ¼ 7.4), XO
2
1
viscous liquid (Yield: 85%, 0.51 g, 1.98 mmol), H NMR (
d
, ppm,
): 3.71 (s, 3H), 3.69 (s, 3H), 3.54 (m, 1H), 3.29 (m,
H), 2.63 (dt, J ¼ 12, 4, 1H), 2.42 (m, 2H), 2.02 (m, 1H), 1.65 (m, 1H).
(
(
0.2 U), and xanthine (1 mM). The enzyme was pre-incubated for
10 min) with tested compounds, then the reaction was started by
4
00 MHz, CDCl
3
2
adding xanthine to the reaction mixture. Tested compounds were
dissolved in DMSO, then diluted with phosphate buffer, last con-
centration of DMSO in the reaction mixture was less than (0.01% v/
v) and this ratio doesn’t interface with enzyme assay [30]. All the
experiments were performed in triplicates, and values were
expressed as means of three experiments. Allopurinol was used as a
positive control. The IC50 values were determined for all based
compounds were measured as percent inhibition of XO was studied
in terms of decrease in uric acid formation as compared to the
product formation in the absence of inhibitor. The percent inhibi-
tion IC50 of XO activity was calculated as the following:
1
3
3
C NMR (d, ppm, 100 MHz, CDCl ): 173.00, 172.53, 69.73, 65.15,
ꢀ
1
5
2.164, 52.13, 41.49, 40.49, 33.20, 27.85. IR (cm ): 3460.71, 3007.14,
950.00, 2882.14, 2096.42, 1725.35, 1434.64, 1354.39, 1324.07. HR-
2
ESI-MS (C10
H
15
N
3
O
5
): m/z 258.10791 [M þ H]þ (calcd. 258.10063
þ
[M þ H] ).
3
1
.1.1.2. Synthesis of dimethyl (1S,2R,4R,5R)-4-hydroxy-5-(4-phenyl-
H-1,2,3-triazol-1-yl)cyclohexane-1,2-dicarboxylate (5). To a stirred
solution of 4 (0.45 g, 1.76 mmol) in 10 mL of MeOH were added
solutions of sodium-L-ascorbate (0.35 g, 1.76 mmol) and
CuSO .5H O (0.03 g, 0.17 mmol) in 6 mL of H O, consecutively.
4 2 2
Phenyl acetylene (0.26 mL, 1.76 mmol) was added to the reaction
medium at room temperature. The mixture was stirred at room
temperature for 24 h and checked by TLC. To reaction mixture was
Inhibition ð%Þ ¼ ðA ꢀ BÞ=A ꢁ 100
Where A ¼ the absorbance at 294 nm without the test compound,

A. Tan / Journal of Molecular Structure 1211 (2020) 128060
5
Scheme 3. Proposed mechanism for the formation of compounds 5 and 6.
Table 1
B ¼ the absorbance at 294 nm with the test compound.
Xanthine oxidase inhibition activity.
Compound
IC50
(
m
M)
R2
3
.2.1. Molecular docking studies
Molecular docking analysis is the most appropriate approach to
5
6
0.586 ± 0.017
0.751 ± 0.021
1.143 ± 0.019
0.994
0.947
0.989
explore the interaction between the target protein and an inhibi-
tory molecule [31e34]. Docking studies were performed with the
Allopurinol
Table 2
Binding energy values and the interactions of compounds 5, 6, and allopurinol with the ligand binding site of XO.
Compounds
5
6
Allopurinol
Binding Energy Values ꢀ6.7
ꢀ6.2
ꢀ6.1
(
kcal/mol)
HIS875, SER876, PRO1076, GLU802, ALA1078, PHE649, ASN768, PRO1076, PHE1013, LYS771, GLU802, ARG310, SER306, LEU444, PRO506
Van der Waals
Interactions
PHE1013, LEU648, LSY771, THR1010, ARG880
ALA1078, ARG880, PHE649, THR1010
Carbon Hydrogen Bond GLU879
Interactions
LEU648
p
-
p
Stacked
Interactions
T-shaped
Interactions
PHE914
LEU1014
PHE344
p
-p
PHE1009
PHE439
LEU1014, VAL1011, LEU873, ALA1079
VAL1011, LEU873, LEU1014
LEU303, ALA508, ALA509,
p
-Alkyl Interactions
VAL1011, LEU1014, PHE1009, ALA1079, PHE914,
LEU873, GLU879
LEU648, LEU873, PHE914, ALA1079, PHE1009, VAL441, THR440, PHE439, ALA509,
Hydrophobic
Interactions
VAL1011, LEU1014
ALA508, PHE344, LEU303, GLU232
Conventional
Hydrogen Bond
Interactions
SER876
THR440, VAL441, GLU232
p
-Sigma Interactions
PHE914
Alkyl Interactions
ALA1079, PHE1009

6
A. Tan / Journal of Molecular Structure 1211 (2020) 128060
Fig. 4. The best binding pose of 5 (A), 6 (B), and allopurinol (C) with XO (PDB ID:3NVY).
Fig. 5. 3D ligand-receptor interactions: A) 5-XO, B) 6-XO, C) Allopurinol-XO and 2D ligand-receptor interactions: D) 5-XO, E) 6-XO, F) Allopurinol-XO.
program UCSF Chimera (1.13.1) [35]. The protein’s 3D crystallo-
graphic structure was downloaded from the Protein Data Bank
Chimera (1.13.1). Polar hydrogens and Gasteiger partial charges
were added and a grid box was created with Autodock Vina [38] in
UCSF Chimera. Grid box center values were arranged as X: 36 Å, Y:
22 Å, Z: 18 Å (grid size of 20 Å ). The results of docking were
visualized with Discovery Studio Visualizer (2016) [39].
(www.rcsb.org) [36] (PDB ID: 3NVY). 2D structures of the com-
3
pounds (5, 6, and allopurinol) were drawn on ChemDraw Ultra 12.0.
The 2D structures were optimized with Avogadro software [37].
Water and other residues for binding were deleted with UCSF

A. Tan / Journal of Molecular Structure 1211 (2020) 128060
7
Fig. 6. Hydrophobic interactions: A) 5-XO, B) 6-XO, C) Allopurinol-XO.
Fig. 7. Sequence alignment of interaction residues of 5 (A), 6 (B), and allopurinol (C) with active site of XO (interaction residues were colored with black).
3.3. X-ray diffraction analysis
performed using CrystalClear (Rigaku/MSC Inc.,2005) software
40]. The structures were solved by direct methods using SHELXS-
[
For the crystal structure determination, single-crystal of the
compound 5 was used for data collection on a four-circle Rigaku R-
AXIS RAPID-S diffractometer (equipped with a two-dimensional
97 [41], which allowed for the location of most of the heaviest
atoms, with the remaining non-hydrogen atoms being located from
different Fourier maps calculated from successive full-matrix least
squares refinement cycles on F2 using SHELXL-97 [41]. All non-
hydrogen atoms were refined using anisotropic displacement pa-
rameters. Hydrogens attached to carbons were located at their
geometric positions using appropriate HFIX instructions in SHELXL.
The final difference Fourier maps showed no peaks of chemical
area IP detector). Graphite-monochromated Mo-K
a
radiation
w ¼ 5 for
ꢂ
(l
¼ 0.71073 Å) and oscillation scans technique with
D
one image were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis of all
2
2
reflections with F > 2s(F ). Integration of the intensities, correction
for Lorentz and polarization effects and cell refinement were
21 3 5
significance. Crystal data for 5: C18H N O , crystal system, space

8
A. Tan / Journal of Molecular Structure 1211 (2020) 128060
group: monoclinic, P2
a ¼ 14.396(6), b ¼ 9.603(4), c ¼ 14.196(5) Å,
1
/c; (no:14); unit cell dimensions:
¼ 90, ¼ 114.540(8),
[7] S.L. Greig, K.P. Garnock-Jones, Loxoprofen: a review in pain and inflammation,
Clin. Drug Invest. 36 (2016) 771e781, https://doi.org/10.1007/s40261-016-
440-9.
a
b
0
ꢂ
3
g
¼ 90 ; volume: 1785.3(4) Å ; Z ¼ 4; calculated density: 1.337 g/
[
8] J. Baldwin, P. Kasinger, F. Novello, J. Sprague, D. Duggan, 4-
Trifluoromethylimidazoles and 5-(4-pyridyl)-1, 2, 4-triazoles, new classes of
xanthine oxidase inhibitors, J. Med. Chem. 18 (1975) 895e900, https://doi.org/
3
ꢀ1
cm ; absorption coefficient: 0.099 mm ; F(000) ¼ 760;
q-range for
ꢂ
data collection 2.8e28.3 ; refinement method: full matrix least-
10.1021/jm00243a007.
2
2
square on F ; data/parameters: 2790/239; goodness-of-fit on F :
.999; final R-indices [I > 2 (I)]: R ¼ 0.180; largest
¼ 0.066, wR
diff. peak and hole: 0.208 and ꢀ0.225e Å
[
9] B. Krishnamurthy, N. Rani, S. Bharti, M. Golechha, J. Bhatia, T.C. Nag, R. Ray,
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in rats, Chem. Biol. Interact. 237 (2015) 96e103, https://doi.org/10.1016/
j.cbi.2015.05.013.
0
s
1
2
ꢀ
3
.
Crystallographic data for all the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Center as supplementary publication No. CCDC-1973367 (5). Copies
of these data can be obtained free of charge by application to CCDC,
[
10] P.S. Phatak, R.D. Bakale, S.T. Dhumal, L.K. Dahiwade, P.B. Choudhari,
V.S. Krishna, D. Sriram, K.P. Haval, Synthesis, antitubercular evaluation and
molecular docking studies of phthalimide bearing 1,2,3-triazoles, Synth.
Commun.
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2017e2028,
https://doi.org/10.1080/
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IC50 ¼ 1.143 ± 0.019 M). The molecular docking studies showed
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Acknowledgements
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The author is grateful to Mr. Samir Abbas Ali Noma, Prof. Dr.
Burhan Ates, Prof. Dr. Ertan Sahin, and Prof. Dr. Yunus Kara for their
valuable contributions and to Atatürk University for some spec-
troscopic analysis.
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