Synthesis, biological evaluation, and molecular docking studies of novel 1,2,3-triazole derivatives as potent anti-inflammatory agents

Article abstract of DOI:10.1134/S1070363216050297

In the present study, a novel series of 1,2,3-triazole derivatives have been synthesized using click chemistry approach. The structures were confirmed by spectroscopic methods. The products were screened for their in vivo anti-inflammatory activity. The tested compounds 6a, 6f, 6g, 6i, 6j, 6n, and 6p, demonstrated potent anti-inflammatory activity compared to the reference drug ibuprofen. Molecular docking studies of these 1,2,3-triazole derivatives into the active site of human cyclooxygenase-2 (COX-2) (PDB code 4PH9) demonstrated good affinity for the enzyme and suggested binding properties similar to ibuprofen.

Full text of DOI:10.1134/S1070363216050297

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 5, pp. 1154–1162. © Pleiades Publishing, Ltd., 2016.
Synthesis, Biological Evaluation, and Molecular
Docking Studies of Novel 1,2,3-Triazole Derivatives
1
as Potent Anti-Inflammatory Agents
a
a
a
a
A. Kishore Kumar , V. Sunitha , B. Shankar , M. Ramesh ,
b
a*
T. Murali Krishna , and P. Jalapathi
a
Department of Chemistry, University College of Science, Osmania University,
Saifabad, Telangana, Hyderabad, 500004 India
*
e-mail: pochampalli.ou.chemi@gmail.com
b
Department of Biotechnology, Chaitanya Postgraduate College (Autonomous),
Kishanpura, Hanamkonda, Telangana, Warangal, 506001 India
Received December 15, 2015
Abstract—In the present study, a novel series of 1,2,3-triazole derivatives have been synthesized using click
chemistry approach. The structures were confirmed by spectroscopic methods. The products were screened for
their in vivo anti-inflammatory activity. The tested compounds 6a, 6f, 6g, 6i, 6j, 6n, and 6p, demonstrated
potent anti-inflammatory activity compared to the reference drug ibuprofen. Molecular docking studies of these
1
,2,3-triazole derivatives into the active site of human cyclooxygenase-2 (COX-2) (PDB code 4PH9)
demonstrated good affinity for the enzyme and suggested binding properties similar to ibuprofen.
Keywords: 1,2,3-triazoles, click chemistry, anti-inflammatory, docking
DOI: 10.1134/S1070363216050297
INTRODUCTION
tial in synthetic accessibility by click chemistry [7],
chemotherapy [8] and as anti-inflammatory agents [9].
,4-Disubstituted 1,2,3-triazoles obtained from copper(I)-
catalyzed azide–alkyne cycloaddition (CuAAC) reac-
tions possess wide applications in synthetic organic
Pharmacological effects of nonsteroidal anti-
inflammatory drugs (NSAIDs) relate to the suppres-
sion of prostaglandin synthesis from arachidonic acid
by inhibiting the membrane enzyme cyclooxygenases
1
[10], biological [11] and medicinal [12] chemistry. We
(
COXs) [1] with a different degree of selectivity [2].
hereby report synthetic approach to some novel 1,4-
disubstituted 1,2,3-triazole derivatives by click che-
mistry. The synthesized compounds were screened for
their in vivo anti-inflammatory activity. Docking
studies were directed towards the active site of human
COX-2 to predict the binding affinity and orientation
of these novel triazole analogues 6a–6p.
COX enzymes exist in two isoforms: COX-1 which is
a housekeeping enzyme found in most of the cells and
plays an important role in the protection of gastric
mucosa, platelet aggregation and renal blood flow.
COX-2 is an inducible isozyme significantly expressed
during inflammation. Long term use of NSAIDs can
lead to several adverse effects including gastro-
intestinal (GI) ulcerations [3], cardiovascular toxicity
RESULTS AND DISCUSSION
[
4], renal failure [5], and asthma [6]. These serious
General approach to synthesis of the target
regioselective 1,4-disubstituted 1,2,3-triazoles was
achieved by a 3-steps protocol (Scheme 1). Resorcinol
side effects are limiting the use of NSAIDs in common
inflammation cases. Therefore, development of novel
compounds with anti inflammatory activity and
improved safety profile is of considerable importance.
2
upon condensation with phenylacetic acid 1 in the
presence of freshly fused ZnCl produced 1-(2,4-di-
2
Among numerous applications in biology and
medicine 1,2,3-triazoles demonstrate significan poten-
hydroxyphenyl)-2-phenylethanone (3). Selective O-alkyla-
tion of compound 3 was achieved by its refluxing with
propargyl bromide and potassium carbonate to afford
para alkylated compound 4 with 90% yield. Formation
1
The text was submitted by the authors in English.
1
154

SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES
1155
Scheme 1. Synthesis of 1,4-disubstituted 1,2,3-triazoles.
O
Br
O
OH
ZnCl2,
20−140°C
OH
K CO
3
1
2
+
OH
3
0 min, 75%
acetone
reflux, 8 h
9
0%
OH
OH
1
2
3
O
.
O
CuSO4 5H O
Sodium ascorbate
2
t-BuOH + H O (1 : 1),
room temperature
2
OH
OH
R
N
N
N
N3
R
O
O
5
a−5p
6a−6p
4
of para alkylated product may be explained by meso-
meric effect and steric factors: in compound 3 ortho
hydroxy group is of lower nucleophilicity than para
to Huisgen’s [2+3]-cycloaddition reaction [15] of 1-[2-
hydroxy-4-(prop-2-yn-1-yloxy)phenyl]-2-phenyletha-
none (4) with various aromatic and aliphatic azides
1
1
hydroxy group. H NMR spectra demonstrated
5a–5p. In H NMR spectra of the prducts the singlet
characteristic singlet at 12.91 ppm attributed to
chelated phenolic hydrogen of ortho hydroxy group
recorded in the range of 7.53–8.21 ppm indicated the
formation of 1,2,3-triazoles (Fig. 2).
and two singlets at 4.73 (O–CH –, 2H) and 2.59 ppm
2
Pharmacology. In vivo anti-inflammatory activity.
The products 6a–6p were screened for in vivo anti-
inflammatory activity by using carrageenan-induced
hind paw oedema model [16] of the oral dose of
(
≡CH, 1H) that indicated O-propargylation with forma-
tion of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl]-2-
phenylethanone (4) as the major product. Various
aliphatic and aromatic azides 5a–5p (Fig. 1) were syn-
thesized by utilizing literature protocols [13, 14].
1
0 mg/kg body weight and compared with the standard
drug ibuprofen of the same oral dose. Anti-in-
flammatory activity was calculated at hourly intervals
up to 6 h (Table 1). The differences of paw volumes
The targeted regioselective 1,4-disubstituted 1,2,3-
triazole derivatives 6a–6p were synthesized according
Cl
Me
Cl
Me
Me
Me
6
4
N3
N3
N3
5c, 90%
N3
5d, 80%
N3
5e, 94%
N3
N3
N
3
5
a, 83%
5b, 88%
5f, 77%
5g, 85% 5h, 95%
O N
2
Me
NO2
Br
Me
Me
Me
Me
O
1
0
4
N3
N3
5j, 90%
N3
N3
N3
N3
N3
N3
5
i, 95%
5k, 70% 5l, 72%
5m, 80% 5n, 88% 5o, 47% 5p, 80%
Fig. 1. Synthesized azides 5a–5p.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 5 2016

1
156
KISHORE KUMAR et al.
Me
Me
Me
Cl
Me
6
4
N
N
N
N
N
N
N
N
N
N
N
N
R1
N
N
R1
N
R1
R1
N
N
N
R1
6e, 81%
R1
6
a, 83%
6b, 87%
6c, 90%
6d, 76%
6f, 77%
O N
2
Cl
Me
Me
Me
Me
1
0
N
N
N
N
N
N
N
N
N
N
N
N
N
N
R1
N
R1
R1
N
R1
R1
N
R1
N
6
g, 83%
6h, 86%
6i, 92%
6j, 89%
6k, 75%
6l, 80%
Me
NO2
Br
O
4
N
N
N
N
N
N
N
N
N
N
N
R1
R1
R1
N
R1
6
m, 76%
6n, 83%
6o, 67%
6p, 84%
O
R =
1
.
OH
O
Fig. 2. Derivatives of target compound 6a–6p.
were compared with the control group and the treated
animals. Percentage inhibition was calculated as:
matory activity. The compound 6j which had p-nitro-
benzyl group at the first position of triazole ring
exhibited the most potent activity. Replacement of the
benzyl group for an aryl group on triazole resulted in
0 t 0
Inhibition = [(V – V )/V ] × 100%,
where V is a volume of the paw control at time t, V is
the decrease of activity. para-Substituted phenyl [NO
2
0
t
a volume of the paw of drug treated at time t.
(6p) or Cl (6g) or Me (6n)] group at the first position
of triazole influenced the activity making it more
pronounced. Compounds 6b, 6c, 6e, and 6h showed
considerable inhibition of oedema (Table 1).
Most of the test compounds demonstrated maxi-
mum activity at 4 h and then it decreased gradually
over the following 2 h. All triazole derivatives 6a–6p
exhibited mild to strong anti-inflammatory activity
compared to ibuprofen (Table 1). Compounds 6a, 6f,
Molecular docking. Genetic optimization for
ligand docking (GOLD) version 2.0 [17] was used for
all synthesized compounds 6a–6p. Those were docked
6
g, 6i, 6j, 6n, and 6p exhibited excellent anti-inflam-
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SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES
1157
Table 1. In vivo anti-inflammatory activity of 1,2,3-triazoles 6a–6p
a
b
Volume of edema (mL) and % AI
Compound no.
4 h
5 h
6 h
swelling
inhibition, %
93.43
77.37
73.72
48.17
72.99
91.97
87.59
71.53
80.29
96.35
66.42
53.28
43.79
83.21
51.82
88.32
–
swelling
inhibition, %
93.12
75.62
71.87
45.00
74.37
90.51
87.50
70.62
79.37
95.62
68.75
51.25
48.12
81.25
51.25
87.50
–
swelling
inhibition, %
c
c
c
6
a
b
c
d
e
f
0.09±0.041
0.31±0.079
0.36±0.031
0.71±0.056
0.37±0.023
0.11±0.091
0.17±0.039
0.39±0.032
0.27±0.033
0.05±0.032
0.46±0.056
0.64±0.072
0.77±0.039
0.23±0.067
0.66±0.072
0.16±0.042
1.37±0.012
0.06±0.027
0.11±0.054
0.39±0.017
0.45±0.028
0.88±0.063
0.41±0.028
0.13±0.029
0.20±0.064
0.47±0.051
0.33±0.036
0.07±0.045
0.50±0.071
0.78±0.045
0.83±0.05
0.15±0.046
0.47±0.096
0.55±0.029
0.86±0.032
0.45±0.086
0.18±0.081
0.24±0.056
0.63±0.074
0.40±0.055
0.12±0.025
0.54±0.062
0.73±0.043
0.99±0.066
0.36±0.042
0.78±0.062
0.26±0.049
1.89±0.009
0.10±0.021
92.06
75.13
70.89
54.49
76.19
90.47
87.30
66.66
78.83
93.65
71.42
61.37
47.61
80.95
58.73
86.24
–
d
d
d
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
c
c
c
c
c
c
g
h
i
d
c
d
c
d
c
j
k
l
m
n
o
p
d
d
d
d
d
0.30±0.072
0.78±0.045
0.20±0.038
1.60±0.019
0.07±0.027
d
Control (–)
Ibuprofen
95.62
95.62
94.70
a
b
c
d
Values are expressed as mean ±SEM from six observations and Data is analyzed by one way ANOVA followed by Dunnett’s “t” test.
Values in parentheses. AI (%) is a percentage anti-inflammatory activity.
Indicates P < 0.001.
Indicates P < 0.01. Control (–) (0.1 mL of saline solution).
into the active site of COX-2 (PDB code 4PH9) (Table 2).
Binding energies were calculated using ArgusLab [18]
docking software (Table 2). Discovery studio
visualizer has been utilized to visualize the binding
conformations of these analogues 6a–6p in the active
site of 4PH9 protein.
bonds with TYR356, ARG121, VAL89, VAL117,
ILE92, LEU93, LEU360 amino acids. For 6j ibupro-
phen like interactions with hydrogen bond distances
viz. 3.00, 3.47 Å for ARG121 and 2.40, 2.63 Å for
TYR356 were found (Fig. 4). Compound 6j had high
Gold fitness (67.63) and Chem scores (34.74) (Table 2).
Molecular binding pattern of ibuprofen with COX-2
EXPERIMENTAL
(
Fig. 3) revealed that it had hydrogen bonds with
TYR356, ARG121, TRP388, TYR386, PHE519,
VAL350, ALA528, LEU360, VAL117, LEU537 amino
acids at the active site region. Among these amino
acids TYR356 with bond distances 2.42, 5.21 Å and
ARG121 with bond distances 3.01, 2.97 Å play an
important role in formation of hydrogen bonds with
COX-2 inhibitor. Compound 6j formed hydrogen
Commercially available reagents were used as
supplied and some of those were distilled before use.
All reactions were performed in oven dried glassware.
All solvents were removed by evaporation at below
45°C under reduced pressure. Melting points were
determined in open capillary tubes. IR spectra were
recorded in KBr discs on an Infracold 337 Perkin-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 5 2016

1
158
KISHORE KUMAR et al.
Table 2. Gold fitness, Chem scores, and ArgusLabs binding
energy values of 1,2,3-triazoles 6a–6p
were washed with 20% HCl (50 mL), saturated
NaHCO (25 mL) and brine (2 × 25 mL). The organic
3
layer was dried over anhydrous sodium sulphate,
filtered and concentrated under reduced pressure. The
crude product was purified by column chromatography
GOLD scores
ArgusLabs Energies
Comp.
no.
Argus B.E, GA Dock B.E,
gold chem
fitness score
kcal/mol
kcal/mol
(
10% ethyl acetate/pet ether eluent) to afford 1-(2,4-
(
elapsed time) (elapsed time)
dihydroxyphenyl)-2-phenylethanone as off-white
1
6
a
66.61 32.89
–14.02 (3)
–11.51 (14)
crystalline solid. Yield 76%, mp 112–117°C. H NMR
spectrum, δ, ppm: 12.70 s (1H), 7.77 d (J = 8.38 Hz,
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
b
c
d
e
f
61.00 30.64
63.05 30.20
57.87 29.65
59.06 31.97
60.41 33.37
58.66 33.59
57.03 30.76
62.69 37.99
67.63 34.74
57.05 27.54
49.83 30.53
51.86 29.93
55.88 33.01
49.61 30.81
58.02 32.54
–14.32 (5)
–12.84 (5)
–12.43 (4)
–13.94 (4)
–13.14 (3)
–13.02 (4)
–12.70 (3)
–12.39 (4)
–12.28 (3)
–12.23 (4)
–12.04 (4)
–12.27 (2)
–10.07 (2)
–11.58 (2)
–12.20 (2)
–10.52 (3)
–11.80 (17)
–11.74 (41)
–7.78 (14)
–12.62 (16)
–13.91 (37)
–11.06 (14)
–11.21 (14)
–8.37 (20)
–12.44 (15)
–10.25 (14)
–9.01 (14)
–12.17 (15)
–14.47 (14)
–9.19 (14)
–10.93 (15)
–10.11 (11)
1
H), 7.39–7.33 m (2H), 7.31–7.27 m (3H), 6.42–6.37
1
3
m (2H), 4.24 s (2H). C NMR spectrum, δ , ppm:
C
2
02.3, 165.9, 163.4, 134.9, 133.5, 130.0 (2C), 129.4
+
(
2C), 127.8, 114.2, 108.9, 104.5, 46.1. LRMS: (ES )
m/z = 229 [M + 1].
Synthesis of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)-
phenyl]-2-phenylethanone (4). To a well stirred
solution of compound 3 (3 g, 13.14 mmol) in dry
acetone and K CO (1.81 g, 13.14 mmol), propargyl
g
h
i
2
3
bromide 80% in toluene (1.87 g, 15.77 mmol) was
added drop wise and the reaction mixture was refluxed
for about 6–8 h. Progress of the reaction was
monitored by TLC. The reaction mixture was cooled
down to room temperature and the excess of acetone
was evaporated under reduced pressure. The residual
mixture was diluted with water (50 mL) and extracted
with ethyl acetate (3 × 50 mL). The combined organic
layers were washed with brine (2 × 25 mL) and dried
over anhydrous sodium sulphate, filtered and con-
centrated in vacuo. The crude product was purified by
column chromatography (eluent 5% ethyl acetate in
pet ether) to afford the product 4 as light yellow solid.
j
k
l
m
n
o
p
Ibuprofen 41.29 30.59
–
1
Yield 85%, mp 94–96°C. IR spectrum, ν, cm : 3402
1
1
Elmer spectrophotometer. H NMR spectra were recorded
on a Bruker AV 300 and 400 MHz spectrometer in
(C–OH), 3290 (≡C–H), 2136 (C≡C), 1674 (C=O). H
NMR spectrum, δ, ppm: 12.70 s (1H), 7.82–7.78 m
CDCl using TMS as the internal standard. TLC was
carried out on aluminium sheets coated with silica gel
(1H), 7.39–7.33 m (2H), 7.32–7.27 m (3H), 6.55–6.50
3
1
3
m (2H), 4.73 s (2H), 4.24 s (2H), 2.59 s (1H).
C
6
0 F254 (Merck, 1.05554) and visualized with UV light
NMR spectrum, δ , ppm: 202.2, 166.0, 164.3, 134.9,
C
at 254 nm or alternatively by staining with aqueous
basic potassium permanganate. Flash column chro-
matography was performed using silica gel (Merck,
132.8, 130.0 (2C), 129.4 (2C), 127.8, 114.5, 108.9,
103.1, 78.4, 77.4, 57.1, 46.2. LRMS: (ES ) m/z = 267
[M + 1], 289 [M + Na].
+
6
0A, 100–200 mesh).
General procedure for 1,4-disubstituted 1,2,3-tri-
azole analogues 6a–6p. Propargyl derivative (4) (100 mg,
0.375 mmol) was dissolved in 5 mL of aqueous t-BuOH
(50%). CuSO ·5H O (5 mol %), sodium ascorbate
(10 mol %) and azide (0.45 mmol) were added to the
solution. The reaction mixture was stirred for 1 h at
room temperature. Upon completion of the process the
reaction mixture was diluted with water (25 mL) and
extracted with ethyl acetate (3 × 25 mL). The com-
bined organic layers were washed with brine (2 × 25 mL).
Synthesis of 1-(2,4-dihydroxyphenyl)-2-phenyl-
ethanone (3). Phenylacetic acid (3 g, 22.03 mmol) was
added to freshly fused zinc chloride (3 g, 22.03 mmol)
and heated to 120°C for 30 min followed by addition
of resorcinol (2.42 g, 22.03 mmol). The reaction
mixture was heated to 140°C for 30 min (TLC
control), cooled down to room temperature, poured in
to ice cold water (100 mL), and extracted with ethyl
acetate (3 × 50 mL). The combined organic layers
4
2
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SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES
1159
H-Bonds
Donor
Acceptor
Fig. 3. Docking pose of ibuprofen into the COX-2 (4PH9) active site. Hydrogen bonds are shown in dotted lines.
H-Bonds
Donor
Acceptor
Fig. 4. Docking pose of compound 6j into the COX-2 (4PH9) active site. Hydrogen bonds are shown in dotted lines.
The organic layer was dried over anhydrous sodium
sulphate, filtered and concentrated in vacuo. The crude
product was purified by column chromatography (eluent
ethyl acetate in pet ether) to afford the corresponding
1-{2-Hydroxy-4-[(1-octyl-1H-1,2,3-triazol-4-yl)-
methoxy]phenyl}-2-phenylethanone (6b). Yield 87%,
–
1
white solid, mp 89–90°C. IR spectrum, ν, cm : 3436
1
(C–OH), 1665 (C=O). H NMR spectrum, δ, ppm:
1
,4-disubstituted 1,2,3-triazole analogues.
-{4-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methoxy]-
-hydroxyphenyl}-2-phenylethanone (6a). Yield
12.67 s (1H), 7.79–7.76 m (1H), 7.60 s (1H), 7.37–
7
.26 m (5H), 6.54–6.50 m (2H), 5.22 s (2H), 4.35 t
1
(
J = 5.6 Hz, 2H), 4.22 s (2H), 1.94–1.86 m (2H), 1.33–
2
8
3
1
3
–1
1.25 m (10 H), 0.87 t (J = 5.3 Hz, 3H). C NMR
spectrum, δ , ppm: 202.2, 166.0, 165.1, 143.4, 134.9,
32.9, 130.0 (2C), 129.4 (2C), 127.7, 123.5, 114.3,
08.7, 103.0, 63.3, 51.7, 46.1, 32.5 (2C), 31.6, 27.5,
3%, white solid, mp 127–129°C. IR spectrum, ν, cm :
1
C
442 (C–OH), 1675 (C=O). H NMR spectrum, δ,
1
1
ppm: 12.66 s (1H), 7.77–7.75 m (1H), 7.53 s (1H),
7
5
2
.38–7.25 m (10H), 6.51–6.48 m (2H), 5.54 s (2H),
+
13
23.8 (2C), 15.4. LRMS: (ES ) m/z = 422 [M + 1], 444
M + Na].
.19 s (2H), 4.21 s (2H). C NMR spectrum, δ , ppm:
C
[
02.3, 166.2, 165.3, 144.2, 135.4, 135.3, 133.3, 130.5
(
1
(
2C), 130.3 (2C), 130.0, 129.8 (2C), 129.2 (2C), 128.2,
24.2, 114.8, 109.3, 103.5, 63.99, 56.2, 46.9. LRMS:
ES ) m/z = 422 [M + Na].
1-{4-[(1-Hexyl-1H-1,2,3-triazol-4-yl)methoxy]-2-
hydroxyphenyl}-2-phenylethanone (6c). Yield 90%,
+
–1
white solid, mp 86–88°C. IR spectrum, ν, cm : 3430
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KISHORE KUMAR et al.
1
(
1
7
C–OH), 1663 (C=O). H NMR spectrum, δ, ppm:
δ, ppm: 12.69 s (1H), 8.05 s (1H), 7.78–7.66 m (3H),
7.49 d (J = 6.7 Hz, 2H), 7.39–7.19 m (5H), 6.54 s
2.67 s (1H), 7.79–7.76 m (1H), 7.60 s (1H), 7.37–
.27 m (5H), 6.54–6.50 m (2H), 5.25 s (2H), 4.35 t
1
3
(2H), 5.28 s (2H), 4.21 s (2H). C NMR spectrum, δ ,
C
(
1
J = 7.1 Hz, 2H), 4.22 s (2H), 1.94–1.87 m (2H), 1.36–
.25 m (8H), 0.87 t (J = 6.9 Hz, 3H). C NMR
ppm: 202.1, 165.6, 164.4, 144.0, 135.3, 134.8, 134.2,
132.3, 130.0 (2C), 129.3 (2C), 128.7 (2C), 127.1,
121.7 (2C), 121.0, 113.7, 107.8, 102.2, 61.9, 44.9.
1
3
spectrum, δ , ppm: 202.1, 165.6, 164.7, 142.9, 134.3,
C
+
1
1
1
32.2, 129.3 (2C), 128.7 (2C), 127.1, 122.7, 113.5,
07.9, 102.2, 62.1, 50.5, 44.8, 31.1, 30.2, 26.1, 22.4,
LRMS: (ES ) m/z = 420 [M + 1].
1
-{4-[(1-Cyclopentyl-1H-1,2,3-triazol-4-yl)meth-
+
3.9. LRMS: (ES ) m/z = 394 [M + 1].
oxy]-2-hydroxyphenyl}-2-phenylethanone (6h). Yield
–
1
1
-{2-Hydroxy-4-[(1-isobutyl-1H-1,2,3-triazol-4-
86%, white solid, mp 115°C. IR spectrum, ν, cm :
1
yl)methoxy]phenyl}-2-phenylethanone (6d). Yield
7
3
3445 (C–OH), 1671 (C=O). H NMR spectrum, δ,
–
1
6%, white solid, mp 96–98°C. IR spectrum, ν, cm :
ppm: 12.68 s (1H), 7.80–7.76 m (1H), 7.62 s (1H),
7.38–7.32 m (2H), 7.31–7.26 m (3H), 6.55–6.52 m
(2H), 5.21 s (2H), 4.98–4.90 m (1H), 4.22 s (2H),
2.33–2.23 m (2H), 2.11–2.01 m (2H), 1.97–1.86 m
1
431 (C–OH), 1666 (C=O). H NMR spectrum, δ,
ppm: 12.68 s (1H), 7.80–7.78 m (1H), 7.60 s (1H),
.38–7.28 m (5H), 6.56–6.53 m (2H), 5.25 s (2H), 4.24
s (2H), 4.19 d (J = 7.23 Hz, 2H), 2.27–2.22 m (1H),
7
1
3
(2H), 1.83–1.71 m (2H). C NMR spectrum, δ , ppm:
C
1
3
0
2
1
5
.98 d (J = 6.70 Hz, 6H). C NMR spectrum, δ , ppm:
202.3, 166.3, 165.4, 143.5, 135.3, 133.3, 130.4, 129.8,
128.2, 122.8, 114.8, 109.2, 103.6, 64.1, 63.9, 46.9,
C
02.1, 165.6, 164.7, 142.8, 134.3, 132.2, 129.3 (2C),
28.7 (2C), 127.1, 123.2, 113.6, 107.9, 102.2, 62.2,
+
35.6 (2C), 26.4 (2C). LRMS: (ES ) m/z = 378 [M + 1].
+
7.7, 44.8, 29.7, 19.8 (2C). LRMS: (ES ) m/z = 366
1
-{4-[(1-Dodecyl-1H-1,2,3-triazol-4-yl)methoxy]-
[
M + 1].
2
-hydroxyphenyl}-2-phenylethanone (6i). Yield 92%,
–
1
1-{4-[(1-Cyclohexyl-1H-1,2,3-triazol-4-yl)methoxy]-
white solid, mp 80°C. IR spectrum, ν, cm : 3448
(C–OH), 1673 (C=O). H NMR spectrum, δ, ppm:
1
2
-hydroxyphenyl}-2-phenylethanone (6e). Yield 81%,
–
1
white solid, mp 106–108°C. IR spectrum, ν, cm :
3
ppm: 12.66 s (1H), 7.79–7.76 m (1H), 7.62 s (1H),
7
4
1
12.68 s (1H), 7.80–7.76 m (1H), 7.61 s (1H), 7.37–
7.32 m (2H), 7.28–7.26 m (3H), 6.53–6.51 m (2H),
5.22 s (2H), 4.36 t (J = 7.3 Hz, 2H), 4.22 s (2H), 1.96–
1.87 m (2H), 1.30–1.22 m (18H), 0.88 t (J = 6.81 Hz,
1
443 (C–OH), 1668 (C=O). H NMR spectrum, δ,
.37–7.26 m (5H), 6.56–6.52 m (2H), 5.21 s (2H),
.50–4.41 m (1H), 4.22 s (2H), 2.25–2.20 m (2H),
.96–1.91 m (2H), 1.79–1.72 m (3H), 1.53–1.40 m
1
3
3H). C NMR spectrum, δ , ppm: 202.2, 166.3, 165.3,
C
143.8, 135.3, 133.3, 130.4 (2C), 129.8 (2C), 128.2,
123.9, 114.8, 109.2, 103.6, 64.1, 52.5, 47.0, 34.2, 32.5,
32.0, 31.9 (2C), 31.8, 31.7, 31.3, 28.8, 25.1, 16.6.
1
3
(
2H), 1.34–1.26 m (1H). C NMR spectrum, δ , ppm:
C
2
1
6
02.2, 166.3, 165.4, 143.4, 135.3, 133.3, 130.4 (2C),
29.8 (2C), 128.2, 121.8, 114.9, 109.2, 103.6, 64.2,
+
LRMS: (ES ) m/z = 478 [M + 1].
+
2.2, 47.0, 35.8 (2C), 27.5 (2C), 27.4. LRMS: (ES )
1
-{2-Hydroxy-4-[(1-(4-nitrobenzyl)-1H-1,2,3-tri-
m/z = 392 [M + 1], 414 [M + Na].
azol-4-yl]methoxy)phenyl}-2-phenylethanone (6j).
1
-{4-[(1-(3-Chlorophenyl)-1H-1,2,3-triazol-4-yl)-
Yield 89%, light yellow solid, mp 160°C. IR spectrum,
–
1
1
methoxy]-2-hydroxyphenyl}-2-phenylethanone (6f).
ν, cm : 3431 (C–OH), 1660 (C=O). H NMR spec-
trum, δ, ppm: 12.68 s (1H), 8.29–8.23 m (2H), 7.82–
7.77 m (1H), 7.65 s (1H), 7.44 d (J = 8.65 Hz, 2H),
7.36 m (2H), 7.30 m (3H), 6.55–6.50 m (2H), 5.69 s
Yield 77%, white solid, mp 160°C. IR spectrum, ν,
–
1
1
cm : 3446 (C–OH), 1678 (C=O). H NMR spectrum,
δ, ppm: 12.69 s (1H), 8.06 s (1H), 7.78–7.64 m (3H),
.55–7.05 m (7H), 6.55 s (2H), 5.30 s (2H), 4.22 s
2H). C NMR spectrum, δ , ppm: 202.1, 165.6, 164.4,
44.1, 137.6, 135.7, 134.2, 132.3, 130.9, 129.3 (2C),
29.1, 128.7 (2C), 127.1, 121.0, 120.8, 118.6, 113.7,
1
3
7
(
1
1
1
(2H), 5.26 s (2H), 4.25 s (2H). C NMR spectrum, δ ,
C
13
ppm: 202.2, 166.0, 164.8, 148.7, 144.6, 141.8, 134.8,
132.9, 130.0 (2C), 129.4 (2C), 129.3 (2C), 127.8, 125.1
(2C), 123.7, 114.4, 108.6, 103.0, 63.2, 54.4, 46.2. LRMS:
C
+
+
07.8, 102.2, 62.0, 44.9. LRMS: (ES ) m/z = 419.9
(ES ) m/z = 445 [M + 1].
[
M + 1].
1
-{4-[(1-Butyl-1H-1,2,3-triazol-4-yl)methoxy]-2-
1
-{4-[(1-(4-Chlorophenyl)-1H-1,2,3-triazol-4-yl)-
hydroxyphenyl}-2-phenylethanone (6k). Yield 75%,
–
1
methoxy]-2-hydroxyphenyl}-2-phenylethanone (6g).
white solid, mp 84–86°C. IR spectrum, ν, cm : 3429
1
Yield 83%, white solid, mp 176°C. IR spectrum, ν,
(C–OH), 1658 (C=O). H NMR spectrum, δ, ppm:
–
1
1
cm : 3447 (C–OH), 1678 (C=O). H NMR spectrum,
12.69 s (1H), 7.83–7.77 m (1H), 7.63 s (1H), 7.40–
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 5 2016

SYNTHESIS, BIOLOGICAL EVALUATION, AND MOLECULAR DOCKING STUDIES
1161
7
5
1
3
1
1
1
.34 m (2H), 7.32–7.28 m (3H), 6.58–6.53 m (2H),
.26 s (2H), 4.40 t (J = 7.23 Hz, 2H), 4.25 s (2H),
.99–1.89 m (2H), 1.46–1.34 m (2H), 1.00 t (J = 7.33 Hz,
4.39 t (J = 7.15 Hz, 2H), 4.24 s (2H), 3.28 t (J =
6.77 Hz, 2H), 1.99–1.93 m (2H), 1.64–1.57 m (2H),
1
3
1.42 m (4H). C NMR spectrum, δ , ppm: 202.3,
C
1
3
H). C NMR spectrum, δ , ppm: 202.3, 166.2, 165.4,
166.1, 165.7, 143.5, 135.1, 133.2, 130.5 (2C), 129.9
(2C), 127.9, 124.1, 114.8, 108.9, 103.2, 63.5, 51.9,
C
43.7, 135.3, 133.3, 130.4 (2C), 129.8 (2C), 128.2,
24.0, 114.8, 109.2, 103.6, 64.0, 52.5, 46.9, 34.4, 22.1,
+
46.8, 37.5, 35.2, 31.1, 27.4, 26.3. LRMS: (ES ) m/z =
+
5.9. LRMS: (ES ) m/z = 388 [M + Na].
472 [M + 1].
1
-{4-[(1-(sec-Butyl)-1H-1,2,3-triazol-4-yl)methoxy]-
1
-{2-Hydroxy-4-[(1-(4-nitrophenyl)-1H-1,2,3-tri-
2
-hydroxyphenyl}-2-phenylethanone (6l). Yield 80%,
white solid, mp 72°C. IR spectrum, ν, cm : 3431
C–OH), 1660 (C=O). H NMR spectrum, δ, ppm:
2.69 s (1H), 7.82–7.74 m (1H), 7.61 s (1H), 7.40–
.25 m (5H), 6.58–6.49 m (2H), 5.19 s (2H), 4.66–4.53
m (1H), 4.22 s (2H), 1.96–1.82 m (2H), 1.57 d (J =
.63 Hz, 3H), 0.86 t (J = 7.16 H z, 3H). C NMR
spectrum, δ , ppm: 202.0, 165.6, 164.7, 142.7, 134.3,
32.2, 129.3 (2C), 128.7 (2C), 127.1, 120.8, 113.5,
azol-4-yl)methoxy]phenyl}-2-phenylethanone (6p).
Yield 84%, yellow solid, mp 158–160°C. IR spectrum,
ν, cm : 3449 (C–OH), 1677=O). H NMR spectrum,
δ, ppm: 12.70 s (1H), 8.46–8.42 m (2H), 8.18 s (1H),
.00 d (J = 8.50 Hz, 2H), 7.39–7.32 m (4H), 7.29–7.27
m (2H), 6.56–6.54 m (2H), 5.34 s (2H), 4.23 s (2H).
C NMR spectrum, δ , ppm: 202.2, 166.6, 165.7,
148.3, 144.1, 142.8, 134.4, 132.5, 130.3 (2C), 128.6
2C), 126.1, 124.5 (2C), 122.7, 121.1 (2C), 113.5,
07.9, 102.2. LRMS: (ES ) m/z = 431 [M + 1], 453
–
1
1
–
1
1
(
1
7
8
1
3
1
3
6
C
C
1
1
(
(
1
[
+
07.9, 102.1, 62.3, 59.1, 44.8, 30.3, 20.9, 10.4. LRMS:
+
ES ) m/z = 366 [M + 1].
M + Na].
1
-{2-Hydroxy-4-[(1-(2-methoxyphenyl)-1H-1,2,3-
Biological evaluation. Animals. Albino rats of
triazol-4-yl)methoxy]phenyl}-2-phenylethanone (6m).
Yield 76%, white solid, mp 136–138°C. IR spectrum,
ν, cm : 3435 (C–OH), 1667 (C=O). H NMR spec-
trum, δ, ppm: 12.71 s (1H), 8.21 s (1H), 7.78 d (J =
.14 Hz, 2H), 7.46–7.39 m (1H), 7.36–7.30 m (2H),
.29–7.23 m (3H), 7.13–7.04 m (2H), 6.59–6.52 m
2H), 5.29 s (2H), 4.21 s (2H), 3.87 s (3H). C NMR
spectrum, δ , ppm: 202.1, 165.6, 164.7, 151.0, 142.2,
34.3, 132.2, 130.3, 129.3 (2C), 128.7 (2C), 127.1,
26.0, 125.4, 125.3, 121.2, 113.6, 112.2, 108.0, 102.2,
2.1, 56.0, 44.9. LRMS: (ES ) m/z = 416 [M + 1].
Wistar strain male sex, weighing 150–250 g were pur-
chased from National Institute of Nutrition,
Hyderabad, India, and housed under standard environ-
mental conditions (temperature: 24 ± 1°C, light/dark
cycle: 10/14 h). The rats were fed with standard pellet
diet (Amrut laboratory animal feed, Maharashtra,
India) and water ad libitum. Animals were accli-
matized to laboratory conditions at least 1 week prior
to conducting the experiments according to the guide
lines of CPCSEA–New Delhi, (Registration no. 915/
ac/05/CPCSEA).
–
1
1
9
7
(
1
3
C
1
1
6
+
1
-{2-Hydroxy-4-[(1-(p-tolyl)-1H-1,2,3-triazol-4-
In vivo anti-inflammatory activity. The synthesized
compounds assessed for their anti-inflammatory
activity using carrageenan-induced rat paw edema
method. Male Wistar rats (150–250 g) were fasted
with access of water at least 24 h prior to the experi-
ments and divided randomly into groups (control,
standard and the test groups) of five rats each. The rat
paw edema was induced by subcutaneous injection of
yl)methoxy]phenyl}-2-phenylethanone (6n). Yield
3%, mp 148°C. IR spectrum, ν, cm : 3440 (C–OH),
671 (C=O). H NMR spectrum, δ, ppm: 12.69 s (1H),
.06–8.01 m (1H), 7.82–7.77 m (1H), 7.61 d (J = 7.91
Hz, 2H), 7.39–7.27 m (7H), 6.56 m (2H), 5.31 s (2H),
.23 s (2H), 2.43 s (3H). C NMR spectrum, δ , ppm:
02.3, 166.3, 165.2, 144.5, 140.1, 135.3, 133.3, 131.4
2C), 130.9, 130.4 (2C), 129.8 (2C), 128.2, 122.3,
21.7 (2C), 115.0, 109.2, 103.7, 64.0, 47.0, 23.5.
–
1
8
1
8
1
13
4
2
(
C
0
.1 mL of 1% freshly prepared saline solution of
1
carrageenan into the right hind paw of rats. The
standard drug ibuprofen (10 mg/kg body weight) was
given orally as a positive control. The control group
was administered orally with 0.9% of 0.1 mL of saline
solution only. The test groups were administered orally
with the synthesized compounds at the equimolar
dosage of the standard drug, 1 h before the admi-
nistration of carrageenan. The paw volumes were
measured using plethysmometer at interval of 1 h.
+
LRMS: (ES ) m/z = 400 [M + 1].
1
-{4-[(1-(6-Bromohexyl)-1H-1,2,3-triazol-4-yl)-
methoxy]-2-hydroxyphenyl}-2-phenylethanone (6o).
Yield 67%, white solid, mp 113–115°C. IR spectrum,
ν, cm : 3448 (C–OH), 1675 (C=O). H NMR spec-
trum, δ, ppm: 12.68 s (1H), 7.81–7.77 m (1H), 7.62 s
1H), 7.38–7.33 m (2H), 7.29 t (J = 3.33 Hz, 2H), 7.28
–
1
1
(
s (1H), 6.57–6.52 m (2H), 5.23 d (J = 8.36 Hz, 2H),
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 5 2016

1
162
KISHORE KUMAR et al.
Molecular modelling. Hyperchem 8.0, Swiss
REFERENCES
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and selectivity of compounds 6a–6p. Ligands energy
minimization was carried out by using Hyper chem.
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CONCLUSIONS
A group of novel 1-{4-[(1H-1,2,3-triazol-4-yl)meth-
oxy]-2-hydroxyphenyl}-2-phenylethanone derivatives
a–6p were synthesized using click chemistry and
6
characterized by spectroscopic methods. All synthe-
sized compounds demonstrated anti-inflammatory
activity. The products 6a, 6f, 6g, 6i, 6j, 6n, and 6p
exhibited excellent activity. Various substituents at the
first position of triazole ring demonstrated consi-
derable influence on anti-inflammatory activity. Most
of biological experimental data were correlated with
docking results and revealed that the molecules that
exhibited high Gold fitness scores demonstrated good
Chem scores. Molecular binding interactions of an in
silico data demonstrated that 6j had high specificity
towards the COX-2 binding site and could be a potent
anti-inflammatory compound.
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ACKNOWLEDGMENTS
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A. Kishore Kumar thanks to CSIR, New Delhi,
India, for financial support in the form of senior
research fellowship (SRF) and Central Facilities for
Research and Development, Osmania University,
Hyderabad, India, for providing analytical support. B.
Shankar thanks to UGC-BSR (RFSMS), New Delhi,
India, for financial support in the form of senior
research fellow.
1
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 5 2016