Synthesis, molecular docking, and pharmacological evaluation of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives as selective COX-2 inhibitors and anti-inflammatory agents

Article abstract of DOI:10.1002/ardp.201800008

A series of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives (3am) was synthesized and evaluated for their in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC₅₀ < 1 μM) were evaluated in vivo for their anti-inflammatory potential by the carrageenan-induced rat paw edema method. Out of 13 newly synthesized compounds, 3a, 3b, 3d, 3g, 3j, and 3k were found to be the most potent COX-2 inhibitors in the in vitro enzymatic assay, with IC₅₀ values in the range of 0.06–0.71 μM. The in vivo anti-inflammatory activity of these six compounds (3a, 3b, 3d, 3g, 3j, and 3k) was assessed by the carrageenan-induced rat paw edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated significant anti-inflammatory activity compared to the standard drug ibuprofen (65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A docking study was done using the crystal structure of human COX-2, to understand the binding mechanism of these inhibitors to the active site of COX-2.

Full text of DOI:10.1002/ardp.201800008

Received: 10 January 2018
Revised: 12 April 2018
Accepted: 17 April 2018
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DOI: 10.1002/ardp.201800008
FULL PAPER
Synthesis, molecular docking, and pharmacological evaluation
of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide
derivatives as selective COX-2 inhibitors and
anti-inflammatory agents
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|
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Avneet Kaur
Dharam P. Pathak
Vidushi Sharma
Sharad Wakode
Department of Pharmaceutical Chemistry,
Delhi Institute of Pharmaceutical Sciences and
Research (DIPSAR), New Delhi, India
Abstract
A series of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives (3a–m)
was synthesized and evaluated for their in vitro inhibitory activity against COX-1 and
COX-2. The compounds with considerable in vitro activity (IC50 < 1 μM) were evaluated
in vivo for their anti-inflammatory potential by the carrageenan-induced rat paw edema
method. Out of 13 newly synthesized compounds, 3a, 3b, 3d, 3g, 3j, and 3k were found
tobethe mostpotent COX-2 inhibitorsintheinvitroenzymatic assay, withIC50 values in
the range of 0.06–0.71 μM. The in vivo anti-inflammatory activity of these six
compounds (3a, 3b, 3d, 3g, 3j, and 3k) wasassessed by the carrageenan-induced rat paw
edema method. Compounds 3d (84.09%), 3g (79.54%), and 3a (70.45%) demonstrated
significant anti-inflammatory activity compared to the standard drug ibuprofen
Correspondence
Avneet Kaur, Department of Pharmaceutical
Chemistry, Delhi Institute of Pharmaceutical
Sciences and Research (DIPSAR), Mehrauli-
Badarpur Road, PushpVihar, Sector-3, New
Delhi-110017, India.
Email: avneetkaur.dipsar@gmail.com
Funding information
Department of Science and Technology,
Ministry of Science and Technology,
Grant number: INSPIRE CODE: 130575 No.
DST/INSPIRE Fellowship/2013/495
(
65.90%) and were also found to be safer than ibuprofen, by ulcerogenic studies. A
docking study was done using the crystal structure of human COX-2, to understand the
binding mechanism of these inhibitors to the active site of COX-2.
K E Y W O R D S
anti-inflammatory activity, COX-1, COX-2, N-(3,5-dimethoxphenyl)-benzoxazole, ulcerogenic
activity
1
|
INTRODUCTION
protection. On the contrary, COX-2 is an inducible isozyme responsi-
[3]
ble for prostaglandin synthesis that triggers inflammatory responses.
Inflammation is a local defense reaction to any noxious stimulus that
threatens the host to cellular infection and injury. It is characterized by
NSAID's available in the market such as flurbiprofen (A), ibuprofen (B),
and indomethacin (C) (Figure 1) show their anti-inflammatory effect
through nonselective inhibition of COX. The adverse effects
associated with the chronic use of these drugs results in gastrointesti-
[1]
swelling, heat, redness, and pain. Non-steroidal anti-inflammatory
NSAID's) drugs are found to be an important and frequently
(
[
4–7]
prescribed group of the therapeutic agents used for the treatment
of inflammation and to relieve pain by suppressing cyclooxygenase
nal complications such as stomach erosions,
silent intestinal
[8,9]
[10,11]
ulcerations,
and kidney problems.
Many selective COX-2
(
COX) enzyme. COX is
a
protein necessary for prostaglandin
inhibitors (coxibs) such as celecoxib (D), valdecoxib (E), and rofecoxib
(F) (Figure 1) are developed for the treatment of inflammation and have
shown to produce lower GI side effects. However, prolonged use of
[2]
synthesis and occurs in two isoforms: COX-1 and COX-2. COX-1,
a constitutive isozyme, performs vital functions of gastro and vascular
|
Arch Pharm Chem Life Sci. 2018;00008.
wileyonlinelibrary.com/journal/ardp
© 2018 Deutsche Pharmazeutische Gesellschaft
1 of 14
https://doi.org/10.1002/ardp.201800008

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KAUR ET AL.
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FIGURE 1 Chemical structures of non-selective NSAIDs (A–C), COX-2 selective drugs (D–F), and the reported benzoxazole derivatives
G–I) with COX-2 activity
(
some coxibs found to possess high incidence of thromboembolic risk in
hydrophobic secondary internal pocket protruding off the primary
[17]
[12]
cardiovascular disease patient,
due to which valdecoxib (E) and
binding site which is absent in COX-1.
[13]
rofecoxib (F) are withdrawn from the market.
Therefore, it is
Benzamides and benzoxazole derivatives are known to possess a
[
18–23]
imperative to come out with the scaffolds which have the anti-
inflammatory effect but reduced side effects and improved gastric
wide array of biological activities such as anti-inflammatory,
anti-
and analgesic
The literature data showed that benzamides and
benzoxazole moiety (G–I) (Figure 1) can be a potent template for COX-
[24–26]
[26,27]
[28]
bacterial,
antifungal,
anti-convulsant,
[14,15]
[23,29,30]
safety profile.
activity.
Development of selective COX-2 inhibitors is a challenge to drug
discovery because of the close structural similarity between both the
[
21,23,31,32]
2 inhibitory activity, with GI safety margins.
Whereas,
[16]
COX isoforms.
They both have a hydrophobic tunnel through which
3,5-dimethoxyphenyl moiety is also found to play an important role in
[
33]
the substrate enters the active site of enzyme. The presence of Ile523
in COX-1 makes its binding shorter in comparison to the COX-2 which
has Val523 at the same place. This Val523 in COX-2 produces a
conformational change in COX-2, thereby forming an additional
anti-inflammatory activity.
Based on the aforementioned findings, in our current study,
we combined 3,5-dimethoxyphenyl moiety with benzoxazole and
benzamides and reported the synthesis of thirteen novel

KAUR ET AL.
| 3 of 14
N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide derivatives
and their biological evaluation by in vitro COX-1/COX-2 enzyme
inhibition assay, in vivo anti-inflammatory, and ulcerogenic activity. To
confirm their COX-2 binding, we performed molecular docking of
newly synthesized molecules in the crystal structure of human COX-2.
Computer-aided drug design assists in designing selective and potent
inhibitors as well as vaccines. Among others, molecular docking
approach is one of the most rational and authentic approaches in the
drug design and discovery for studying the molecular interaction of
The compound 2-(3,5-dimethoxyphenyl)-benzoxazol-5-amine (1) was
prepared by the reaction of 2,4-diaminophenol dihydrochloride with
3,5-dimethoxybenzoic acid followed by cyclization in presence of
polyphosphoric acid (PPA). Different substituted acid were further
reacted with dicyclohexylcarodiimide (DCC) to form their respective
anhydrides (2a–m). Finally, the title compound was prepared by
the nucleophilic attack of benzoxazole amine with their respective
anhydride in presence of glacial acetic acid and Zn dust in variable yield
(35–82%) (3a–m).
[34–36]
small molecules.
Besides, ADME analyses were performed to
The progress of the reaction was checked by TLC. Structures of
evaluate their suitability as active drug molecules.
prepared analogs were confirmed by elemental analysis, FTIR,
1
13
H
nuclear magnetic resonance (NMR),
C NMR, and mass
spectrometry. The spectral data obtained were in full agreement
with the proposed structures. The IR spectroscopic data of benzox-
azole derivatives showed absorption bands between 1600 and
2
2
|
RESULTS AND DISCUSSION
Chemistry
.1
|
−
1
−1
1
690 cm
(─NH─CO─) and 3280–3355 cm
(─NH) indicating
1
N-(2-(3,5-Dimethoxyphenyl)-benzoxazole-5-yl)benzamides derivatives
3a–m) were synthesized as outlined in synthetic Scheme 1.
the synthesis of the compounds. H NMR spectra of the desired
compounds revealed the signals of methyl/ethyl, methoxy/dimethoxy,
(
SCHEME 1 Synthetic scheme of the title compounds (3a–m). Reagents and conditions: (a) PPA, 5–6 h, 80–95°C; (b) dichloromethane; (c)
Zn dust, glacial acetic acid, dichloromethane, 4–5 h. R1: 3a = phenyl; 3b = 4-chlorophenyl; 3c = 3-chlorophenyl; 3d = 2-chlorophenyl; 3e =
4
-methylphenyl; 3f = 3-methylphenyl; 3g = 2-methylphenyl; 3h = 4-ethylphenyl; 3i = 3,4-dimethoxyphenyl; 3j = 4-nitrophenyl; 3k = 2-chloro-4-
nitrophenyl; 3l = 3-nitrophenyl; 3m = 4-methoxyphenyl

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KAUR ET AL.
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and aromatic protons of benzoxazole ring. Coupling constants (J) are
TABLE 1 In vitro COX-1 and COX-2 inhibition and COX-2 selectivity
index (SI) data (3a–m)
given in Hz and spin multiples are given as s (singlet), d (doublet), dd
(
double doublet), t (triplet), m (multiplet), and br (broad). The singlet
around 3.77–3.99 δ ppm revealed the presence of dimethoxy group
and other aromatic protons appeared within the range 6.09–8.07 δ
2
ppm. The NH protons were observed as D O exchangeable protons.
13
While the peaks in C NMR spectra also confirmed the synthesis of
target compounds (3a–m). Mass spectra of compounds 3a–m showed
molecular ion peaks at an m/z corresponding to their molecular
formula. The elemental analysis data were within ±0.5% of the
theoretical values.
a
IC50 (μM)
b
Compound
R
1
COX-1
COX-2
SI
3
a
2.44
0.10
24.40
2
.2
|
Biological evaluation
In vitro cyclooxygenase (COX-1 and COX-2)
3b
5.73
0.28
2.48
20.46
4.27
2
.2.1
|
3
3
c
10.61
inhibition assay
d
2.32
0.06
38.66
The inhibitory activity of synthesized compounds 3a–m was evaluated
against ovine COX-1 and human recombinant COX-2 using enzyme
immunoassay (EIA) kit (Supplementary Figure S1) and the IC50 (μM)
values were determined (Table 1). The IC50 values of celecoxib for
COX-1 and COX-2 were observed as 6.20 and 0.15 μM, respectively.
The result of the in vitro COX-1 and COX-2 inhibitory studies revealed
that all the compounds selectively and potentially inhibit COX-2
3
3
e
f
5.15
1.40
3.25
3.67
4.49
14.61
3
g
4.68
0.30
15.6
(
IC50 = 0.06–22.24 μM range) over COX-1 (IC50 = 2.32–35.84 μM
range). Further, the selectivity index (SI) was found to be in the
3
3
h
i
23.13
35.84
14.53
22.24
1.59
1.61
range of 1.61–38.66. The results showed that the compounds
3
a
(COX-1/COX-2 = 2.44:0.10), 3b (COX-1/COX–2 = 5.73:0.28),
3
d (COX-1/COX-2 = 2.32:0.06), 3g (COX-1/COX-2 = 4.68:0.30), 3j
(
COX-1/COX–2 = 7.39:0.32), and 3k (COX-1/COX-2 = 9.42:0.71)
were found to be more potent inhibitors of COX-2 in comparison to
COX-1 among the synthesized compounds (Figure 2). Compound 3d
was found to be most potent inhibitor of the series with IC50 = 0.06 μM
3
3
j
7.39
9.42
0.32
0.71
23.09
13.26
k
(
2.50-fold higher) as compared to celecoxib (IC50 = 0.15 μM). These six
most active COX-2 inhibitors (3a, 3b, 3d, 3g, 3j, and 3k), IC50 < 1 μM,
were further evaluated for in vivo anti-inflammatory activity.
3
3
l
18.58
16.64
8.30
4.72
2.23
3.52
2
.2.2 In vivo anti-inflammatory activity
|
m
Anti-inflammatory activity of the selected compounds (3a, 3b, 3d,
g, 3j, and 3k) was assessed by the carrageenan-induced rat paw
Celecoxib
Ibuprofen
–
–
6.20
1.42
0.15
1.08
41.33
1.31
3
edema method (Table 2). Out of the six compounds, 3a, 3d, and 3g
demonstrated more anti-inflammatory activity than standard drug
ibuprofen (65.90%). Compound with 2-chlorophenyl (3d) emerged as
the most promising analog of the series with percentage inhibition of
a
IC50 value is the concentration of the compound required to produce 50%
of inhibition of COX-1 and COX-2, respectively, using enzyme immunoas-
say kit (catalogue no. 560131, Cayman Chemicals, Inc., Ann Arbor, MI,
USA).
8
4.09%. The compounds with 4-ethylphenyl (3g) and unsubstituted
b
In vitro COX-2 selectivity index (SI): (COX-1 IC50/COX-2 IC50).
phenyl (3a) also showed remarkable protection against inflammation
with percent inhibition of 79.54 and 70.45%, respectively. Whereas
compounds with 2-chloro-4-nitro (3k), 4-chlorophenyl (3b), and
2
.2.3 Acute ulcerogenic activity
|
4
-nitrophenyl (3j) exhibited percent inhibition of paw edema
Analogs 3a, 3d, and 3g possessing in vivo anti-inflammatory activity
greater than standard drug ibuprofen were further screened for their
ulcerogenic activity. The results (Table 3) (Supplementary Figure S2)
showed that the tested compound showed better GI safety profile
equivalent or near to standard ibuprofen. However, more studies
are required to confirm the anti-inflammatory activity of the
synthesized compounds.

KAUR ET AL.
| 5 of 14
docked molecules, hydrogen bonds with Arg120 and π–π interaction
with Tyr355 is conserved with COX-2 active site (Table 4). Compounds
3
d, 3a, and 3g showed the most promising in vitro, in vivo, ulcerogenic
potential, and docking score among all the compounds. In addition, the
hydrophobic cloud was contributed by Val89, Leu93, Val116, Val349,
Leu352, Leu359, Leu384, Tyr385, Trp387, Phe518, Val523, Ala527,
and Leu531 as shown in Figure 3. The benzoxazole moiety found to
play remarkable role in capturing H-bond with Arg120 (with N-atom of
benzoxazole ring) and π–π interaction with both aromatic rings of
benzoxazole moiety. Apart from above-mentioned residues, some
other residues (Tyr385–3k; Ser530–3k, 3j; Met522–3j) were also
found to be involved in interaction and those compounds were found
to show moderate in vivo and in vitro activities. The docking score
showed that unsubstituted phenyl ring (3a) and ortho-substituted
phenyl ring (3d and 3g) leads to increase in activity. The compounds
with electron withdrawing group at para position of phenyl ring (3b, 3j,
and 3k) showed moderate activity whereas electron donating group at
para position (3h and 3i) leads to considerable decrease in activity. All
the compounds showed comparable docking score to celecoxib. The
celecoxib possessed van der Waals interactions with amino acid
Val349, Leu384, Trp387, Leu352, Tyr385, Phe518, Val523, and
Ala527 and hydrogen bond with Gln192, Ser353, Arg513, and Phe518
FIGURE 2 In vitro percentage inhibition of COX-2 versus log
concentration curve of most potent compounds (3a, 3b, 3d, 3g, 3j,
and 3k)
with severity index ranging from 1.00 to 1.90, in comparison to
standard drug ibuprofen (2.20 ± 0.44). Most potent compound (3d)
showed severity index of 1.00 ± 0.50 which was very low in
comparison to the standard drug. Hence, these compounds may
ascertain to have better safety margin on gastric mucosa than
ibuprofen.
(
Figure 3e). The non-selective inhibitor ibuprofen showed no H-bond
2
.2.4 Acute toxicity study
|
with COX-2 but salt bridge with Arg120 (Figure 3d).
A dose of 2000 and 200 mg/kg resulted in death of animals under test
and dose of 20 mg/kg was found to be safe as no mortality and
behavioral changes were observed.
2
.3.2 Absorption, distribution, metabolism, and
|
excretion (ADME) study
The ADME parameters for all synthesized ligands were calculated
using Qikprop 4.0 (Table 5). Assessment of ADME properties is
imperative because they exclude weak or toxic molecule at an early
stage of drug discovery and development process. The desirable
ADME properties of these compounds make them promising
candidates as COX-2 inhibitors.
2
.3
|
Computational studies
Docking studies
2
.3.1
|
The docking study was performed using resolved crystal structure of
human COX-2 (PDB ID: 5F19). The results showed that among all the
TABLE 2 In vivo anti-inflammatory activity of the most potent compounds using carrageenan-induced rat paw edema method
Paw edema volume (mL)
a
b
Compound
0 h
3 h
Increase in paw edema (mL) (mean ± SEM)
0.13 ± 0.009
% Inhibition
70.45
63.63
84.09
79.54
63.63
65.90
–
3
3
3
3
3
3
a
b
d
g
j
0.67
0.69
0.73
0.69
0.67
0.66
0.7
0.80
0.85
0.80
0.78
0.83
0.81
1.14
0.8
0.16 ± 0.024
0.07 ± 0.016
0.09 ± 0.008
0.16 ± 0.024
k
0.15 ± 0.14
Control
0.44 ± 0.048
Ibuprofen
0.65
0.15 ± 0.022
65.90
–
, not applicable. p-Values were compared with control group (3 h after inducing edema) (Tukey's test). Number of animals (rats) in each group = 5.
a
Values are determined after 3 h and are expressed as mean ± SEM.
b
p < 0.05 (significant difference).

6
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KAUR ET AL.
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TABLE 3 Ulcerogenic activity of the most active compounds in rat
model
Elemental analyses were carried out on Flash 2000 organic
elemental analyzer.
a
Ulcerogenic activity
The InChI codes of the investigated compounds together with
some biological activity data are provided as Supporting Information.
b
Compound
(severity index) (mean ± SD)
3
3
3
a (60 mg/kg)
d (60 mg/kg)
g (60 mg/kg)
1.30 ± 0.45
1.00 ± 0.50
1.90 ± 0.42
2.20 ± 0.44
–
4
.1.2
|
Synthesis of 2-(3,5-dimethoxyphenyl)-
benzoxazol-5-amine (1)
Ibuprofen (60 mg/kg)
Control (normal saline)
2
-(3,5-Dimethoxyphenyl)benzoxazol-5-amine (1) was prepared by
heating equimolar mixture of 2,4-diaminophenol dihydrochloride
1 mmol) and 3,5-dimethoxybenzoic acid (1 mmol) in presence of
a
Number of animals in each group = 5.
(
b
p < 0.05 (significant difference).
cyclizing agent polyphosphoric acid (PPA) (24 g). The mixture was
heated at 80–95°C for 5–6 h. After the completion of reaction
(
monitored by TLC), mixture was cooled to room temperature and
3
|
CONCLUSIONS
poured into ice cold water, neutralized with an excess of 10 N NaOH
solution, and extracted with toluene, dried over anhydrous sodium
sulfate, and evaporated under vacuum. After evaporation, the product
obtained was boiled in charcoal and recrystallized from ethanol to give
In summary, we have reported a simple and efficient method for the
synthesis of N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)benzamide
derivatives (3a–m) with good yield. All the prepared analogs were
screened for their in vitro activity and selected compounds for in vivo
activity. All compounds exhibited in vitro selective inhibition of COX-2
than COX-1. Among the series of newly synthesized compounds, 3a,
pure compound (1).
−1
Yield: 84%. m.p.: 190–192°C. ATR-FTIR (cm ): 3325.2 (NH
2
),
2
825.8 (-CH-), 1682.3, 1452 (aromatic CC), 1600.20 (-NH ), 1200.5
2
1
(
C-N), 1111.2 (C-O), 720.32 (out-of-plane, bend). H NMR (300 MHz,
3
d, and 3g were found to have significant anti-inflammatory and less
3 3 2
CDCl ): δ 3.82 (s, 6H, 2 × -OCH ), 4.21 (s, 2H, -NH ), 6.22 (s, 2H, Hd’),
ulcerogenic activity than ibuprofen. The overall study concludes
compound 3d as the most potent compound of the series with
improved gastric safety profile. The in silico studies also suggest the
similar binding and activity profile of the compounds as observed by
the in vitro and in vivo activities. The compounds 3a, 3d, and 3g can
further be explored for development of more safer and active anti-
inflammatory agents.
6
.45 (s, 1H, H4 of benzoxazole), 6.46 (d, 1H, J = 6 Hz, H6 of
benzoxazole), 6.64 (s, 2H, Hb’, Hf’), 7.02 (d, 1H, J = 6 Hz, H7 of
13
3
benzoxazole). C NMR (75 MHz, CDCl ): δ 56.20, 60.12, 101.45,
1
04.32, 107.11, 111.42, 128.54, 141.25, 144.62, 163.34. (+) ESI-MS
+
(m/z): 271.2 [M+H] . Anal. calcd. for C15
14 2 3
H N O : C, 66.66; H, 5.22; N,
1
0.36. Found: C, 66.67; H, 5.21; N, 10.35.
4
.1.3 General procedure for the synthesis of
|
4
4
4
|
EXPERIMENTAL
Chemistry
anhydrides 2a–m
To 50 mL of methylene chloride (DCM), substituted acid derivative
.1
|
(
0.02 mol) and dicyclohexylcarbodiimide (DCC) (0.01 mol) were added
and stirred at room temperature for 3–4 h. After then the solvent was
separated (2a–m), the reaction mixture was filtered to remove
precipitate of dicyclohexylurea and the filtrate was evaporated to
.1.1 General
|
The chemical and solvents used were purchased from Merck Co. and
Sigma by commercial vendors and used in the experiments without
purification. COX (ovine/human) inhibitor screening assay kits
[37]
get the oily product (2a–m).
(
catalog no. 560131) were procured from Cayman Chemicals Inc.,
Benzoic anhydride (2a)
−
1
Ann Arbor, MI, USA. The progress of the chemical reaction was
monitored by thin layer chromatography (TLC) on pre-coated plates
and compounds were purified using column chromatography on
silica gel (100–200 mesh). Iodine vapors were used for detection of
spots on TLC plates. The melting points of the synthesized
compounds were determined on LAB-India MR-VIS visual melting
point apparatus and are uncorrected. The infrared (IR) spectra were
Yield: 72%. m.p.: 44–46°C. ATR-FTIR (cm ): 3064.2 (-CH- aromatic),
1789.12, 1711.10 (CO), 1607.12, 1472.2 (CC), 732.20 (out-of-plane,
1
bend). H NMR (300 MHz, CDCl ): δ 7.44–7.49 (m, 4H, Ar-H), 7.68 (d,
3
1
3
J = 7.5 Hz, Ar-H), 8.13(d, 4H, J =7.5 Hz, Ar-H). C NMR (75 MHz, CDCl3):
+
δ 128.80, 134.52, 162.40. (+) ESI-MS (m/z): 227.5 [M+H] . Anal. calcd. for
C14H10O : C, 74.33; H, 4.46. Found: C, 74.35; H, 4.47.
3
1
13
recorded on a Bruker Optics spectrophotometer. H and C NMR
were recorded in CDCl on Bruker, Advance DPX-300 spectrometer.
4-Chlorobenzoic anhydride (2b)
−1
3
Yield: 84%. m.p.: 182–184°C. ATR-FTIR (cm ): 3020.42 (-CH-
aromatic), 1800.18, 1722.20 (CO), 1600.24, 1478.6 (CC),
Tetramethylsilane (TMS) was used as internal standard and chemical
1
shifts (δ) were determined in parts per million (ppm). Mass spectra
784.20 (out-of-plane, bend). H NMR (300 MHz, CDCl ): δ7.41 (t,
3
(
ESI-MS) were recorded on API 2000 LCMS/MS Applied Biosystems.
J = 7.2 Hz, 2H, Ar-H), 7.62 (d, 2H, J = 8.4 Hz, Ar-H), 8.02 (d, 4H,

KAUR ET AL.
| 7 of 14
TABLE 4 Glide score (kcal/mol), type of interactions, and interacting residues of the COX-2 protein with synthesized compounds
Type of interactions
Hydrogen bonds
π-Interactions
Comp.
Glide score (kcal/mol)
Atom of ligand
Amino acids
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Arg120
Met522
Ser530
Arg120
Arg120
Tyr385
Ser530
Arg120
Arg120
Arg120
Arg120
–
Dist (Å)
2.23
1.69
2.22
1.7
Type
Ring/group
Amino acids
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Tyr355
Dist (Å)
3
3
3
3
3
3
3
3
a
b
c
d
e
f
−10.78
N
π-Stacking
Benzoxazole
5.05
5.23
5.16
5.33
5.09
5.32
5.04
5.21
5.04
5.72
5.06
5.26
5.02
5.21
5.39
5.26
5.29
N
−10.00
−9.83
−11.11
−9.75
−9.81
−10.52
−8.62
N
π-Stacking
π-Stacking
π-Stacking
π-Stacking
π-Stacking
π-Stacking
π-Stacking
Benzoxazole
Benzoxazole
Benzoxazole
Benzoxazole
Benzoxazole
Benzoxazole
Benzoxazole
N
N
2.16
1.73
2.16
1.63
2.26
2.72
2.22
2.7
N
N
N
N
N
N
N
g
h
N
2.19
1.72
2.18
2.72
2.55
2.24
2.69
2.72
3.02
2.16
2.73
3.62
2.65
2.17
2.73
2.22
2.71
–
N
N
N
3
i
j
−8.38
−9.75
−*CO−
N
π-Stacking
π-Stacking
Benzoxazole
Benzoxazole
3
N
Tyr355
Tyr355
5.35
5.21
NO
NO
N
2
2
3k
−9.79
π-Stacking
Benzoxazole
N
Tyr355
5.3
NO
NO
N
2
2
3
3
l
−9.67
−9.62
π-Stacking
π-Stacking
Salt bridge
Benzoxazole
Benzoxazole
COOH
Tyr355
Tyr355
Tyr355
5.31
5.05
5.19
N
m
N
N
Ibuprofen
Celecoxib
−6.97
Arg120
3.48
−10.49
NH
NH
2
2
Gln192
Ser353
Arg513
Phe518
3.55
2.09
2.80
2.69
SO
SO
2
2
1
3
13
J = 8.4 Hz, Ar-H). C NMR (75 MHz, CDCl
3
): δ 128.31, 130.92, 138.8,
Cl : C,
C NMR (75 MHz, CDCl
3
): δ 128.42, 130.12, 130.42, 134.8, 152.70.
+
+
1
67.20. (+) ESI-MS (m/z): 295.4 [M+H] . Anal. calcd. for C14
H
8
2
O
3
(+) ESI-MS (m/z): 294.7 [M+H] . Anal. calcd. for C14
H
8
Cl
2
O
3
: C, 56.98;
5
6.98; H, 2.73. Found: C, 56.99; H, 2.71.
H, 2.73. Found: C, 56.97; H, 2.72.
3
-Chlorobenzoic anhydride (2c)
2-Chlorobenzoic anhydride (2d)
−
1
−1
Yield: 68%. m.p.: 153–157°C. ATR-FTIR (cm ): 3015.52 (-CH-
Yield: 81%. m.p.: 63–68°C. ATR-FTIR (cm ): 3010.48 (-CH- aromatic),
aromatic), 1808.12, 1730.40 (CO), 1620.40, 1475.38 (CC), 790.85
1783.26, 1721.11 (CO), 1618.15, 1472.18 (CC), 1074.2 (out-
1
1
(
out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 7.51 (d, 4H,
of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 7.36–7.42 (m, 2H, Ar-H),
13
J = 8.4 Hz, Ar-H), 8.02 (d, 2H, J = 6 Hz, Ar-H), 8.14 (s, 2H, Ar-H).
7.49–7.54 (m, 4H, Ar-H), 8.02 (d, 2H, J = 7.5 Hz, Ar-H). C NMR

8
of 14
KAUR ET AL.
|
FIGURE 3 Docked pose of compound (A) 3a, (B) 3d, (C) 3g, (D) ibuprofen, (E) celecoxib in the catalytic cavity of COX-2
(
75 MHz, CDCl
3
): δ 126.90, 132.54, 133.60, 134.12, 135.10, 160.28.
6H, 2 × -CH
3
1
), 7.32 (d, 4H, J = 7.8 Hz, Ar-H), 8.02 (dd, 4H, J = 7.8 Hz,
+
13
(
+) ESI-MS (m/z): 294.2 [M+H] . Anal. calcd. for C14
H
8
Cl
2
O
3
: C, 56.98;
J
2
= 5.1 Hz, Ar-H). C NMR (75 MHz, CDCl
3
): δ 22.6, 126.4, 129.68,
+
H, 2.73. Found: C, 56.96; H, 2.74.
130.21, 145.54, 162.60. (+) ESI-MS (m/z): 255 [M+H] . Anal. calcd. for
16 14 3
C H O : C, 75.57; H, 5.55. Found: C, 75.56; H, 5.56.
4
-Methylbenzoic anhydride (2e)
−
1
Yield: 59%. m.p.: 79–81°C. ATR-FTIR (cm ): 3113.25 (-CH- aromatic),
3-Methylbenzoic anhydride (2f)
−1
2
843.40 (-CH- aliphatic), 1800.12, 1785.10 (CO), 1625.84, 1480.01
Yield: 48%. m.p.: 64–66°C. ATR-FTIR (cm ): 3010.01 (-CH- aromatic),
2845.84 (-CH- aliphatic), 1810.09, 1795.21 (CO), 1630.21, 1452.65
1
(
CC), 810 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 2.38 (s,

KAUR ET AL.
| 9 of 14
TABLE 5 Predicted absorption, distribution, metabolism, and excretion (ADME) properties of synthesized compounds
%
Human oral
Rule of
Comp
#rtvFG CNS mol_MW SASA
FOSA
185.4
185.4
273.5
185.4
273.6
273.5
256.8
315.7
361.8
185.4
185.4
185.4
278.2
278.8
FISA donorHB accptHB
QPlogPo/w QPPCaco QPlogBB #metab QPlogKhsa absorption
five
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
374.4
408.8
388.4
408.8
388.4
388.4
388.4
402.4
434.4
419.3
453.8
419.3
404.4
206.2
686.2
710.2
718.3
705.5
718.5
718.3
703.7
748.5
767.4
724.4
743.7
724.1
722.1
477.0
64.3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
6.0
6.0
6.0
6.0
6.0
6.0
6.0
6.0
7.5
7.0
7.0
7.0
6.7
2.0
4.2
4.7
4.5
4.7
4.5
4.5
4.6
4.9
4.4
3.5
4.0
3.5
4.3
3.5
2433.19
2434.04
2433.28
2873.88
2432.88
2433.28
3368.83
2432.91
2433.61
292.42
−0.36
−0.20
−0.38
−0.14
−0.38
−0.38
−0.20
−0.46
−0.52
−1.51
−1.30
−1.51
−0.44
−0.48
3
3
4
3
4
4
4
4
5
4
4
4
4
2
0.47
0.59
0.63
0.57
0.63
0.63
0.60
0.74
0.49
0.41
0.51
0.41
0.47
0.06
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
91.81
0
64.2
0
64.3
0
56.6
0
64.3
0
64.3
0
g
h
i
49.4
0
64.3
0
64.2
0
j
−2
161.3
153.7
161.4
64.21
91.23
0
k
l
−2
−2
0
345.20
95.95
0
291.65
91.77
0
m
2437.80
342.27
100.00
92.78
0
Ibuprofen
−1
0
Parameters: #rtvFG, number of reactive functional groups. The presence of these groups can lead to false positives in HTS assays and to decomposition,
reactivity, or toxicity problems in vivo (0–2); CNS, predicted central nervous system activity −2 (inactive) to 2 (active); mol_MW, molecular weight of the
molecule; SASA, total solvent accessible surface area (SASA) in square angstroms using a probe with a 1.4 Å radius (300.0–1000.0); FOSA, hydrophobic
component of the SASA (saturated carbon and attached hydrogen); FISA, hydrophilic component of the SASA (SASA on N, O, and H on heteroatoms);
donorHB, estimated number of hydrogen bonds that would be donated by the solute to water molecules in an aqueous solution; accptHB, estimated number
of hydrogen bonds that would be accepted by the solute from water molecules in an aqueous solution; QPlogPo/w, predicted octanol/water partition
coefficient; QPPCaco, predicted apparent Caco-2 cell permeability in nm/s (<25 poor >500 great); QPlogBB, predicted brain/blood partition coefficient
(range or recommended value for 95% of known drug −3 to 1.2); #metab, number of likely metabolic reactions (1–8); QPlogKhsa, prediction of binding to
human serum albumin (−1.5 to 15); % human oral absorption, predicted human oral absorption on 0–100% scale (25–80%). The prediction is based on a
quantitative multiple linear regression model. This property usually correlates well with human oral absorption, as both measure the same property; rule of
five, number of violation of Lipinski's rule of five. Compounds that satisfy these rules are considered drug-like (maximum is 4).
1
(
CC), 799.20 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ
3,4-Dimethoxybenzoic anhydride (2i)
−1
2
.36 (s, 6H, 2 × -CH
3
), 7.32–7.38 (m, 4H, Ar-H), 7.8 (s, 4H, Ar-H).
Yield: 67%. m.p.: 122–124°C. ATR-FTIR (cm ): 3010.42 (-CH-
1
3
C NMR (75 MHz, CDCl
3
): δ 21.30, 128.82, 128.88, 131.20, 135.28,
aromatic), 2581.10 (-CH- aliphatic), 1800.12, 1780.56 (CO),
+
1
1
38.80, 162.70. (+) ESI-MS (m/z): 255.6 [M+H] . Anal. calcd. for
1672.10, 1410.26 (CC), 810 (out-of-plane, bend).
H NMR
C
16
H
14
O
3
: C, 75.57; H, 5.55. Found: C, 75.57; H, 5.54.
(300 MHz, CDCl ): δ 3.79 (s, 12H, 4 × -OCH
3
3
), 6.65 (s, 2H, Ar-H),
1
3
7
.20 (s, 4H, Ar-H). C NMR (75 MHz, CDCl
3
): δ 55.90, 105.6, 106.88,
+
2
-Methylbenzoic anhydride (2g)
132.30, 152.79, 161.45, 161.80. (+) ESI-MS (m/z): 347 [M+H] . Anal.
−
1
Yield: 48%. m.p.: 85–87°C. ATR-FTIR (cm ): 2999.20 (-CH- aromatic),
18 7
calcd. for C18H O : C, 62.42; H, 5.24. Found: C, 62.43; H, 5.22.
2
680.35 (-CH- aliphatic), 1800.15, 1787.58 (CO), 1650.61, 1420.46
1
(
CC), 810.10 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ
4-Nitrobenzoic anhydride (2j)
−1
2
.62 (s, 6H, 2 × -CH
3
), 7.25 (d, 4H, J = 8.8 Hz, Ar-H), 7.40–7.45 (m, 2H,
Yield: 74%. m.p.: 92–94°C. ATR-FTIR (cm ): 2989.81 (-CH- aromatic),
1
3
Ar-H), 7.95 (d, 2H, J = 7.7 Hz, Ar-H). C NMR (75 MHz, CDCl
3
): δ
2780.11 (-CH- aliphatic), 1810.14, 1784.46 (CO), 1676.71, 1408.52
1
2
1.98, 126.16, 127.80, 131.42, 132.30, 133.60, 142.50, 162.98. (+)
(CC), 1535.52, 1398.4 (Ar-NO
(300 MHz, CDCl
(75 MHz, CDCl
2
), 790 (out-of-plane, bend). H NMR
+
13
ESI-MS (m/z): 255 [M+H] . Anal. calcd. for C16
H
14
O
3
: C, 75.57; H, 5.55.
3
): δ 8.39 (d, 4H, Ar-H), 8.40 (d, 4H, Ar-H). C NMR
Found: C, 75.55; H, 5.56.
3
): δ 121.01, 131.20, 136.46, 152.75, 153.68 (+) ESI-MS
+
(
m/z): 317.5 [M+H] . Anal. calcd. for C14
H
8
N
2
O
7
: C, 53.17; H, 2.55.
4
-Ethylbenzoic anhydride (2h)
Found: C, 53.19; H, 2.56.
−
1
Yield: 75%. m.p.: 96–98°C. ATR-FTIR (cm ): 3000.10 (-CH- aromatic),
2
590.17 (-CH- aliphatic), 1805.18, 1782.26 (CO), 1680.12, 1416.30
2-Chloro-4-nitrobenzoic anhydride (2k)
1
−1
(
CC), 900 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 1.24 (t,
), 7.33 (dd, 4H,
= 6.0 Hz, J = 6.0 Hz,
Yield: 74%. m.p.: 103–105°C. ATR-FTIR (cm ): 3312.6 (-CH-
6
3 2 3
H, J = 5.4 Hz, -CH ), 2.59 (q, 4H, J = 7.2 Hz, -CH *-CH
aromatic), 2910.58 (-CH- aliphatic), 1800.26, 1775.48 (CO),
1629.4, 1530.2 (CC), 1532.6 (Ar-NO
J
1
= 3.0 Hz, J = 3.3 Hz, Ar-H), 8.08 (dd, 4H, J
2
1
2
2
), 1472.2 (-CH bend),
1
3
1
Ar-H). C NMR (75 MHz, CDCl
3
): δ 14.60, 32.42, 127.51, 127.78,
1168.28 (Ar-Cl), 1112.40 (C-O), 790.2 (out-of-plane, bend). H NMR
+
1
44.18, 152.86. (+) ESI-MS (m/z): 283.6 [M+H] . Anal. calcd. for
3
(300 MHz, CDCl ): δ 8.28 (d, 2H, J = 3 Hz, Ar-H), 8.36 (d, 2H, J = 6.9 Hz,
1
3
C
18
H
18
O
3
: C, 76.57; H, 6.43. Found: C, 76.58; H, 6.44.
Ar-H), 8.41 (d, 2H, J = 5.4 Hz, Ar-H). C NMR (75 MHz, CDCl ): δ
3

10 of 14
KAUR ET AL.
|
1
19.12, 123.9, 132.62, 136.08, 137.18, 152.70, 155.06. (+) ESI-MS
3 3 3
(300 MHz, CDCl ): δ 3.84 (s, 3H, -OCH ), 3.86 (s, 3H, -OCH ), 6.09 (s,
+
(
m/z): 384.2 [M+H] . Anal. calcd. for C14
H
6
Cl
2
N
2
O
7
: C, 43.66; H, 1.57.
1H, Hd’), 6.69 (s, 2H, Hb’, Hf’), 7.02 (s, 1H, H7 of benzoxazole), 7.26 (d,
Found: C, 43.67; H, 1.54.
1H, J = 3.0 Hz, Hc), 7.36–7.43 (m, 2H, He, H6 of benzoxazole), 7.46–
1
3
7
3
.57 (m, 3H, Hb, Hf), 7.82 (s, 1H, -NH). C NMR (75 MHz, CDCl ): δ
3
-Nitrobenzoic anhydride (2l)
56.44, 56.72, 100.62, 104.24, 104.49, 106.72, 111.05, 112.62,
128.50, 128.92, 130.12, 130.32, 132.84, 135.52, 138.46, 141.28,
−
1
Yield: 58%; m.p.: 162–164°C. ATR-FTIR (cm ): 3300.74 (-CH-
aromatic), 2928.49 (-CH- aliphatic), 1799.52, 1756.64 (CO),
+
145.78, 162.86, 163.92, 164.62. (+) ESI-MS (m/z): 409.1 [M+H] . Anal.
1
626.2, 1530.4 (CC), 1539.80, 1376.8 (Ar-NO
2
), 790.68 (out-
calcd. for C22
2 4
H17ClN O : C, 64.63; H, 4.19; N, 6.85. Found: C, 64.60;
1
of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 7.73 (t, 2H, J = 6.4 Hz,
H, 4.18; N, 6.83.
1
3
Ar-H), 8.52 (d, 2H, J = 3 Hz, Ar-H), 9.08 (s, 2H, Ar-H). C NMR
(
75 MHz, CDCl
3
): δ 119.12, 123.9, 132.62, 136.08, 137.18, 152.70,
3-Chloro-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-
+
1
55.06. (+) ESI-MS (m/z): 317.8 [M+H] . Anal. calcd. for C14
H
8
N
2
O
7
: C,
benzamide (3c)
−1
5
3.17; H, 2.55. Found: C, 53.16; H, 2.56.
Yield: 76%. m.p.: 96–98°C. ATR-FTIR (cm ): 3302.8 (NH), 2916.4
-CH), 1662.9 (-CONH-), 1628.64, 1484.60 (aromatic CC), 1482.15
(
4
-Methoxybenzoic anhydride (2m)
(-CH), 1210.2 (C-N), 1162.20 (Ar-Cl), 1050.23 (C-O), 800.91 (out-
−1
1
Yield: 66%; m.p.: 88–90°C. ATR-FTIR (cm ): 3012.16 (-CH- aromatic),
of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 3.88 (s, 3H, -OCH
), 6.42 (s, 1H, Hd’), 6.61 (s, 2H, Hb’, Hf’), 7.09 (d, 1H,
J = 12 Hz, H7 of benzoxazole), 7.34–7.44 (m, 2H, He, Hd), 7.59 (dd, 3H,
3
),
2
959.62 (-CH- aliphatic), 1801.60, 1782.10 (CO), 1618.28, 1515.80
3.98 (s, 3H, -OCH
3
1
(
CC), 840 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): 3.98 (s,
6
H, 2 × -OCH
3
), 6.96 (d, 4H, J = 7.4 Hz, Ar-H), 8.08 (d, 4H, J = 7.4 Hz,
J
1
= 6.3 Hz, J
2
= 7.2 Hz, Hf, H4, H6 of benzoxazole), 7.98 (s, 1H, Hb),
13
13
Ar-H). C NMR (75 MHz, CDCl
3
): δ 55.62, 114.28, 121.34, 132.68,
3
8.09 (s, 1H, -NH). C NMR (75 MHz, CDCl ): δ 56.24, 57.62, 101.06,
+
1
62.36, 164.92. (+) ESI-MS (m/z): 287.3 [M+H] . Anal. calcd. for
104.26, 104.66, 106.84, 111.06, 112.68, 125.46, 128.64, 130.67,
C
16
H
14
O
5
: C, 67.13; H, 4.93. Found: C, 67.12; H, 4.94.
132.87, 135.14, 135.92, 141.90, 145.74, 162.50, 163.10, 164.70. (+)
+
ESI-MS (m/z): 409.5 [M+H] . Anal. calcd. for C22
H
2
17ClN O
4
: C, 64.63;
H, 4.19; N, 6.85. Found: C, 64.64; H, 4.20; N, 6.84.
4
.1.4 General procedure for the synthesis of
|
N-(2-(3,5-dimethoxyphenyl)benzoxazole-5-yl)-
substituted benzamides 3a–m
2
-Chloro-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-
benzamide (3d)
−1
A mixture of benzoxazolamine (1) (0.012 mol), respective anhydride
Yield: 71%. m.p.: 91–93°C. ATR-FTIR (cm ): 3327.44 (NH), 2909.8
(-CH stretching), 1662.4 (-CONH-), 1625.12, 1524.45 (aromatic CC),
2
a–m (0.01 mol), zinc dust (0.010 g), in glacial acetic acid and DCM
(
15 mL) was refluxed for 4–5 h at room temperature. After completion
1480.19 (-CH bend), 1210.2 (C-N), 1162.50 (Ar-Cl), 1110.62 (C-O),
1
of the reaction, mixture was poured into ice cold water and precipitate
obtained was further collected and recrystallized with ethanol to give
the pure compound 3a–m.
800.52 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 3.99 (s, 6H,
3
2 × -OCH ), 6.69 (s, 1H, Hd’), 7.02 (s, 2H, Hb’, Hf’), 7.36 (d, 1H, J = 6 Hz,
H7 of benzoxazole), 7.47 (t, 3H, J = 8.1 Hz, He, Hd), 8.01 (d, 2H,
J = 6 Hz, H4, H6 of benzoxazole), 8.13 (d, 1H, J = 9 Hz, Hf), 8.29 (s, 1H,
1
3
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)benzamide (3a)
3
-NH). C NMR (75 MHz, CDCl ): δ 56.36, 61.05, 100.87, 104.59,
−1
Yield: 72%. m.p.: 115–117°C. ATR-FTIR (cm ): 3285.6 (NH), 2920.6
104.83, 110.28, 127.70, 128.45, 130.09, 132.95, 133.69, 136.91,
(
-CH), 1680 (-CONH-), 1620.42, 1468 (aromatic CC), 1208.2 (C-N),
141.28, 142.67, 162.77, 162.94, 165.28. (+) ESI-MS (m/z): 409.4
1
+
1
3
1
110 (C-O), 732.4 (out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ
[M+H] . Anal. calcd. for C22
H
17ClN
2
O
4
: C, 64.63; H, 4.19; N, 6.85.
.94 (s, 6H, 2 × -OCH
H, J = 6.9 Hz, H7 of benzoxazole), 7.36–7.44 (m, 4H, Hc, Hd, He, H4
= 6 Hz, J = 6 Hz, H6 of benzoxazole
3
), 6.11 (s, 1H, Hd’), 6.50 (s, 2H, Hb’, Hf’), 6.80 (d,
Found: C, 64.62; H, 4.20; N, 6.84.
of benzoxazole), 7.72 (dd, 3H, J
1
2
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-4-
1
3
merge with Hb, Hf), 8.01 (s, 1H, -NH). C NMR (75 MHz, CDCl
3
): δ
methylbenzamide (3e)
−
1
5
1
1
6.32, 59.03, 101.26, 104.65, 104.82, 110.55, 111.85, 118.33,
Yield: 56%. m.p.: 150–151°C. ATR-FTIR (cm ): 3326.42 (NH),
27.27, 127.32, 130.39, 130.65, 131.77, 134.57, 141.22, 142.65,
2992.64 (-CH stretching), 1680.46 (-CONH-), 1630.12, 1474.20
+
62.82, 163.94, 164.65. (+) ESI-MS (m/z): 375.2 [M+H] . Anal. calcd.
(CC), 1458.42 (-CH bend), 1100.14 (C-O), 732.42 (out-of-plane,
1
for C22
H
18
N
2
O
4
: C, 70.58; H, 4.85; N, 7.48. Found: C, 70.57; H, 4.84;
bend). H NMR (300 MHz, CDCl
3
): δ 2.43 (s, 1H, -CH
), 6.45 (s, 1H, Hd’), 7.70 (s, 1H, Hb’), 7.20 (s,
H, Hf’), 7.41 (d, 2H, J = 2.4 Hz, Hc, Hd), 7.67 (dd, 2H, J = 5.1 Hz,
= 5.1 Hz, H6, H7 of benzoxazole), 7.82 (s, 2H, H4 of benzoxazole
3
), 3.84 (s, 3H,
N, 7.45.
3 3
-OCH ), 3.87 (s, 3H, -OCH
1
1
4
-Chloro-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-
benzamide (3b)
Yield: 82%. m.p.:104–106°C. ATR-FTIR (cm ): 3284.4 (NH), 2920.2
J
2
1
3
merge with -NH), 8.01 (d, 2H, J = 3.9 Hz, Hb, Hf). C NMR (75 MHz,
CDCl ): δ 24.58, 56.38, 58.46, 100.66, 104.82, 105.01, 106.92,
−
1
3
(
-CH), 1672 (-CONH-), 1628.40, 1464 (aromatic CC), 1220.2 (C-N),
111.05, 112.90, 127.82, 127.98, 128.40, 130.12, 131.40, 136.14,
141.18, 141.50, 145.78, 162.38, 12.89, 163.08, 164.80. (+) ESI-MS
1
1
152.20 (Ar-Cl), 1114 (C-O), 736.2 (out-of-plane, bend). H NMR

KAUR ET AL.
11 of 14
|
+
(
m/z): 389 [M+H] . Anal. calcd. for C23
H
20
N
2
O
4
: C, 71.12; H, 5.19; N,
3,4-Dimethoxy-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-
7
.21. Found: C, 71.10; H, 5.18; N, 7.20.
benzamide (3i)
−
1
Yield: 62%. m.p.: 114–116°C. ATR-FTIR (cm ): 3355.42 (NH),
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-3-
2950.11 (-CH stretching), 1660.04 (-CONH-), 1610.11, 1465.10
methylbenzamide (3f)
(CC), 1464.52 (-CH bend), 1110.32 (C-O), 800.60 (out-of-plane,
−1
1
Yield: 51%. m.p.: 142–144°C. ATR-FTIR (cm ): 3324.26 (NH),
996.84 (-CH stretching), 1682.60 (-CONH-), 1636.20, 1475.20
bend). H NMR (300 MHz, CDCl
3
): 3.83 (s, 3H, -OCH
3
), 3.94 (s, 9H,
2
3 × -OCH
3
), 6.18 (s, 1H, Hd), 6.63 (s, 2H, Hd), 6.63 (s, 2H, Hb’, Hf’), 6.92
(
CC), 1460.82 (-CH bend), 1110.28 (C-O), 810.24 (out-of-plane,
(d, 1H, J = 8.4 Hz, He), 7.35 (d, 1H, J = 4.8 Hz, Hf), 7.78 (d, 2H,
13
1
bend). H NMR (300 MHz, CDCl
3
): δ 2.42 (s, 1H, -CH3), 3.89 (s, 6H,
J = 8.4 Hz, H4, H6 of benzoxazole), 8.06 (s, 1H, -NH). C NMR
2
1
1
8
× -OCH3), 6.26 (s, 1H, Hd’), 6.63 (s, 1H, Hb’), 7.02 (s, 1H, Hf’), 7.27 (d,
3
(75 MHz, CDCl ): δ 55.20, 56.32, 57.42, 57.64, 100.80, 104.20,
H, J = 22.8 Hz, H7 of benzoxazole), 7.45 (t, 1H, J = 8.1 Hz, He),7.63 (d,
104.82, 108.20, 110.82, 112.60, 116.52, 121.20, 128.14, 128.56,
H, J = 8.4 Hz, H6 of benzoxazole), 7.79 (s, 2H, Hb, H4 of benzoxazole),
136.02, 142.22, 146.14, 150.12, 153.60, 163.20, 163.51, 164.85. (+)
1
3
+
.07 (d, 1H, J = 18.9 Hz, Hf), 8.20 (s, 1H, -NH). C NMR (75 MHz,
): δ 24.42, 56.23, 57.18, 100.80, 104.14, 104.62, 106.34,
11.12, 112.67, 125.12, 127.58, 128.90, 132.57, 134.22, 135.10,
ESI-MS (m/z): 435 [M+H] . Anal. calcd. for C24
H
22
N
2
O
6
: C, 66.35; H,
CDCl
3
5.10; N, 6.45. Found: C, 66.36; H, 5.09; N, 6.46.
1
1
38.59, 142.15, 146.20, 162.50, 162.81, 163.12, 164.50. (+) ESI-MS
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-4-nitrobenzamide
+
(
m/z): 389.6 [M+H] . Anal. calcd. for C23
H
20
N
2
O
4
: C, 71.12; H, 5.19; N,
(3j)
−
1
7
.21. Found: C, 71.11; H, 5.21; N, 7.22.
Yield: 57%; m.p.: 149–151°C. ATR-FTIR (cm ): 3280.20 (NH), 2930.6
-CH stretching), 1664.6 (-CONH-), 1626.2, 1530.4 (CC), 1535.52,
(
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-2-
1398.4 (Ar-NO
2
), 1489.6 (-CH bend), 1012.32 (C-O), 810.32 (out-
1
methylbenzamide (3g)
of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 3.86 (s, 3H, -OCH
3
),
−
1
Yield: 36%. m.p.: 130–132°C. ATR-FTIR (cm ): 3320.52 (NH),
985.62 (-CH stretching), 1680.60 (-CONH-), 1624.26, 1476.28
3.90 (s, 3H, -OCH
3
), 6.11 (s, 1H, Hd’), 6.65 (s, 2H, Hb’, Hf’), 7.40 (d, 1H,
2
J = 2.1 Hz, H7 of benzoxazole), 7.60 (s/d, 2H, J = 1.8 Hz, H4, H6 of
benzoxazole), 7.72 (d, 1H, J = 7.8 Hz, Hb), 7.93 (s, 1H, -NH), 8.09 (d, 1H,
J = 7.8 Hz, Hf), 8.28 (d, 1H, J = 3.3 Hz, Hc), 8.32–8.35 (d, 1H, J = 9 Hz,
(
CC), 1450.22 (-CH bend), 1108.06 (C-O), 800.26 (out-of-plane,
1
bend). H NMR (300 MHz, CDCl
3
): δ 2.35 (s, 3H, -CH
), 6.63 (s, 1H, Hd’), 7.02 (s, 2H, Hb’, Hf’),
.20 (d, 2H, J = 4.2 Hz, Hc and H7 of benzoxazole), 7.27 (t, 2H,
J = 4.2 Hz, He, Hd), 7.64 (d, 1H, J = 4.2 Hz, H6 of benzoxazole), 7.78 (s,
H, H4 of benzoxazole), 7.91 (d, 1H, J = 4.8 Hz, Hf), 8.09 (s, 1H, -NH).
3
), 3.93 (s, 3H,
1
3
-
OCH
3
), 3.97 (s, 3H, -OCH
3
3
He). C NMR (75 MHz, CDCl ): δ 56.24, 56.69, 103.85, 104.12,
7
106.24, 110.01, 112.28, 121.26, 128.41, 128.95, 135.16, 140.34,
141.79, 145.60, 151.96, 162.19, 162.48, 164.62. (+) ESI-MS (m/z): 420
+
1
[M+H] . Anal. calcd. for C22
H
17
N
3
O
6
: C, 63.01; H, 4.09; N, 10.02.
1
3
C NMR (75 MHz, CDCl
3
): δ 18.12, 56.20, 57.36, 100.90, 104.42,
Found: C, 63.02; H, 4.13; N, 10.03.
1
1
1
04.84, 106.83, 110.72, 112.55, 126.17, 127.65, 128.24, 129.71,
32.43, 135.17, 135.54, 138.02, 142.20, 146.19, 162.18, 163.23,
2-Chloro-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-4-
+
63.67, 164.20. (+) ESI-MS (m/z): 389.8 [M+H] . Anal. calcd. for
nitrobenzamide (3k)
−1
C
23
H
20
N
2
O
4
: C, 71.12; H, 5.19; N, 7.21. Found: C, 71.11; H, 5.21; N,
Yield: 35%; m.p.: 115–117°C. ATR-FTIR (cm ): 3308.2 (NH), 2910.4
(-CH stretching), 1672.2 (-CONH-), 1629.4, 1530.2 (CC), 1532.6
7
.22.
(
Ar-NO
2
), 1472.2 (-CH bend), 1168.28 (Ar-Cl), 1112.40 (C-O), 790.2
1
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-4-ethylbenzamide
3h)
Yield: 49%. m.p.: 122–124°C. ATR-FTIR (cm ): 3310.48 (NH),
898.16 (-CH stretching), 1690.26 (-CONH-), 1652.22, 1472.52
(out-of-plane, bend). H NMR (300 MHz, CDCl
3
): δ 3.88 (s, 3H, -OCH
3
),
(
3
3.89 (s, 3H, -OCH ), 6.61 (s, 1H, Hd’), 6.99 (s, 2H, Hb’, Hf’), 7.38 (d, 1H,
−
1
J = 1.2 Hz, H7 of benzoxazole), 7.64 (s/d, 2H, J = 6.6 Hz, H4, H6 of
2
benzoxazole), 8.04 (s, 1H, -NH), 8.17 (d, 1H, J = 1.8 Hz, Hf), 8.25 (d, 1H,
1
3
(
CC), 1462.74 (-CH bend), 1106.28 (C-O), 790.82 (out-of-plane,
3
J = 1.8 Hz, He), 8.41 (s, 1H, -NH). C NMR (75 MHz, CDCl ): δ 55.89,
1
bend). H NMR (300 MHz, CDCl
3
): 1.76 (t, 3H, J = 10.5 Hz, -CH
-), 3.77 (s, 3H, -OCH ), 3.80 (s, 3H,
), 6.56 (s, 1H, Hd’), 6.95 (s, 2H, Hb’, Hf’), 7.33 (d, 1H,
J = 1.8 Hz, H7 of benzoxazole), 7.41 (d, 2H, J = 7.8 Hz, Hc, He), 7.49
d, 1H, J = 7.8 Hz, H4 of benzoxazole), 7.59 (d, 1H, J = 4.8 Hz, H6 of
benzoxazole), 7.70 (d, 1H, J = 6.0 Hz, Hb), 7.96 (d, 1H, J = 7.8 Hz, Hf),
3
),
55.92, 100.44, 103.61, 103.63, 106.21, 110.60, 112.48, 119.39,
124.88, 128.33, 139.36, 133.21, 135.11, 138.46, 141.71, 145.68,
2
.65 (q, 2H, J = 7.5 Hz, -CH
2
3
-
OCH
3
153.21, 162.22, 162.23, 162.41, 164.80. (+) ESI-MS (m/z): 454.2
+
[M+H] . Anal. calcd. for C22
H
16ClN
3
O
6
: C, 58.22; H, 3.55; N, 9.26.
(
Found: C, 58.23; H, 3.57; N, 9.27.
1
3
8
5
1
1
.18 (s, 1H, -NH). C NMR (75 MHz, CDCl
3
): δ 14.72, 32.49, 56.38,
N-(2-(3,5-Dimethoxyphenyl)benzoxazol-5-yl)-3-nitrobenzamide
7.18, 100.29, 104.19, 104.64, 107.18, 111.20, 112.62, 127.49,
27.98, 132.20, 136.20, 142.10, 142.62, 143.20, 146.20, 162.9,
(3l)
−
1
Yield: 46%; m.p.: 132–134°C. ATR-FTIR (cm ): 3280.20 (NH), 2930.6
(-CH stretching), 1664.6 (-CONH-), 1626.2, 1530.4 (CC), 1535.52,
+
63.20, 163.62, 164.65. (+) ESI-MS (m/z): 403.2 [M+H] . Anal. calcd.
for C24
H
22
N
2
O
4
: C, 71.63; H, 5.51; N, 6.96. Found: C, 71.62; H, 5.53;
2
1398.4 (Ar-NO ), 1489.6 (-CH bend), 1012.32 (C-O) 810.32 (out-
1
N, 6.97.
3 3
of-plane, bend). H NMR (300 MHz, CDCl ): δ 3.98 (s, 6H, 2 × -OCH ),

12 of 14
KAUR ET AL.
|
6
3
2
.65 (s, 1H, Hd), 7.40 (d, 1H, J = 1.5 Hz, H7 of benzoxazole), 7.73 (m,
Center and were divided and housed in different cages at 25–28°C,
under well-maintained hygienic and environmental conditions with
relative humidity of 50–65%, under 12 h light and dark cycles. All
animals were acclimatized for a week before use. The food was
withdrawn on the day before the experiment but free access to water
was given. All experimental work was conducted according to ethical
guidelines and after receiving the approval from Institutional Animal
Ethics Committee (IAEC) via protocol no. IAEC/2015-I/Prot no. 09, 10
and IAEC/2016-I/Prot no. 10, Delhi Institute of Pharmaceutical
Sciences and Research, New Delhi. The animals were divided into
groups consisting of five rats each. Prepared compounds were
administered orally (20 mg/kg b.wt.) and the volume of paw was
determined plethysmographically (Ugo-Basyl, Italy). Control group
received equivalent volume of normal saline and ibuprofen (20 mg/kg
b.wt.) was administered orally to the reference group. Carrageenan
(0.1 mL, 1.0% w/v in 0.9% of normal saline) was injected after half an
hour into the sub-plantar tissue of the rat's hind paw. Difference in paw
volume was measured at hourly interval for 3 h (0–3 h). The mean value
of treated group was compared with those of control group and
analyzed using statistical methods. The percent inhibition of edema
was calculated using the following formula:
H, H4, H6 of benzoxazole merge with He), 8.00 (s, 1H, -NH), 8.32 (dd,
13
H, J
1
= 8.4 Hz, J
): δ 56.20, 57.12, 104.23, 104.84, 106.20, 110.86,
12.42, 122.48, 124.59, 128.21, 133.40, 135.18, 135.75, 141.72,
2
= 2.1 Hz, Hf, Hd), 8.84 (s, 1H, Hb). C NMR
(
75 MHz, CDCl
3
1
1
45.55, 148.47, 162.70, 163.14, 164.46; (+) ESI-MS (m/z): 420.5
+
[M+H] . Anal. calcd. for C22
H
17
N
3
O
6
: C, 63.01; H, 4.09; N, 10.02.
Found: C, 63.00; H, 4.11; N, 10.04.
4
-Methoxy-N-(2-(3,5-dimethoxyphenyl)benzoxazol-5-yl)-
benzamide (3m)
Yield: 54%. m.p.: 140–142°C. ATR-FTIR (cm ): 3304.26 (NH),
890.12 (-CH stretching), 1690.26 (-CONH-), 1638.42, 1479.18
−1
2
(
CC), 1473.12 (-CH bend), 1109.30 (C-O), 820.20 (out-of-plane,
1
bend). H NMR (300 MHz, CDCl
3
): δ 3.83 (s, 3H, -OCH
), 6.36 (s, 1H, Hd’), 6.63 (s, 2H, Hb’, Hf’), 7.02 (d, 2H,
J = 2.1 Hz, Hc, He), 7.40 (d, 1H, J = 1.5 Hz, H7 of benzoxazole), 7.64 (d,
3
), 3.89 (s, 9H,
3
× -OCH
3
2
8
1
1
1
6
H, J = 1.8 Hz, H4, H6 of benzoxazole), 7.89 (d, 2H, J = 8.7 Hz, Hb, Hf),
13
3
.03 (s, 1H, -NH). C NMR (75 MHz, CDCl ): δ 56.69, 57.12, 101.25,
04.60, 104.99, 111.02, 112.58, 114.41, 114.87, 126.52, 128.27,
29.40, 130.04, 135.21, 141.77, 145.69, 162.14, 162.72, 164.12,
+
64.84. (+) ESI-MS (m/z): 405 [M+H] . Anal. calcd. for C23
H
20
N
2
O
5
: C,
8.31; H, 4.98; N, 6.93. Found: C, 68.30; H, 4.97; N, 6.94.
% inhibition ¼ ð1 ꢀ ðVs=VcÞ ꢁ 100Þ
s c
where V is the paw volume in the sample-treated group and V is the
4
.2
|
Biological evaluation
In vitro cyclooxygenase inhibition assay
paw volume in the control group.
4
.2.1
|
Acute ulcerogenic activity
The in vitro inhibition of newly synthesized compounds against COX-1
and COX-2 enzyme was determined using COX (ovine/human)
inhibitor screening assay kit (catalog no. 560131). This assay was
performed as per the reported literature procedures and manufac-
The ulcerogenic activity of the prepared analogs was performed
[40]
according to the reported procedure of Cioli et al.
Each study group
consisted of five Wistar albino rats. Ibuprofen was used as reference
anti-inflammatory drug. The animals were fasted for 18 h before the
administration of the test compound, while water was given
continuously. The dose quantity was three times (60 mg/kg) of the
administered dose for anti-inflammatory studies (20 mg/kg). The
control group received only normal saline. After 6 h of the drug
administration the rats were sacrificed, stomach was removed and
opened around the greater curvature. Inner lining was washed
properly with distilled water followed by normal saline. The mucosal
damage was inspected and number of ulcers and severity index was
calculated on a scale of 0–3, where 0 = no lesions; 0.5 = redness;
1.0 = spot ulcers; 1.5 = hemorrhagic streaks; 2.0 = ulcers > 3 but ≤5;
3.0 = ulcers > 5.
[38]
turer's assay instructions.
The kit is based on the principle of
enzyme immunoassay which directly measures PGF2α from PGH
2
produced by reduction with stannous chloride. At the end, the product
of enzymatic reaction produces distinct yellow color which absorbs
strongly at 412–415 nm. The intensity of the color was determined
spectrophotometrically (Bio-Rad ELISA), which is proportional to the
amount of PG tracer bound to the well and is inversely proportional to
the quantity of free PG's present in the well during incubation. The
inhibitory efficacy of novel derivatives was calculated by comparison
with various control incubations. The efficiencies of the test
compounds that causes 50% inhibition of COX-2 was calculated as
IC50 from the log concentration versus % inhibition curve.
Acute toxicity study
Acute oral toxicity test was carried out according the Organization for
Economic Co-operation and Development (OECD) guideline for
testing of chemicals number 423. Female Wistar rats were used in
this procedure. They were randomly divided into groups containing
three rats each. First group served as a control and was given
equivalent volume of normal saline. The selected analogue was taken
at a dose of 2000, 200, and 20 mg/kg body weight and was given orally
to the remaining groups. All the animals were observed continuously
4
.2.2 In vivo activity
|
Anti-inflammatory activity
The anti-inflammatory activity of the synthesized compounds was
evaluated on Wistar albino rat by carrageenan-induced rat paw edema
[39]
as described by Winter et al.
Albino rats weighing 200–250 g were
used in the study. The animals were procured from Animal House

KAUR ET AL.
13 of 14
|
for first 30 min, periodically during the first 24 h and daily thereafter
water partition coefficient and violations related to Lipinski's
[46]
1
4 days for behavioral changes and/or death.
“Rule of 5.”
4
.4
|
Statistical analysis
4
.3
|
Computational studies
Software
Experimental data are expressed as mean. Statistical difference
between the treated and control group was evaluated by one way
analysis of variance (ANOVA) followed by Tukey's test as a post
ANOVA (GraphPad Prism 5, San Diego, USA) to determine the
statistical significance. p-Value <0.05 was considered statistically
significant.
4
.3.1
|
The in silico experiments were performed on Fujitsu Linux workstation
Xeon quad-core E3-1220 processor). Docking and ADME analyses
were carried out using LigPrep 3.0, Impact 6.3, Glide 6.3, and QikProp
.0 modules of Maestro 9.8 (Schrödinger, LLC, New York, NY, 2014).
The ligand and protein interacting behavior was studied using Protein-
(
4
[41]
ligand profiler server.
COX-2 were retrieved from RCSB data bank (PDBID-5F19, resolution-
.04 Å).
The highly resolved coordinates of human
ACKNOWLEDGMENTS
The authors are thankful to Delhi Institute of Pharmaceutical Sciences
and Research for providing infrastructure and other necessary
facilities. One of the author, Avneet Kaur is indebted to Department
of Science and Technology (DST), New Delhi for award of fellowship to
carry out this work (INSPIRE_CODE: IF130575, No. DST/INSPIRE
Fellowship/2013/495).
2
4
.3.2 Docking study
|
The crystal structure of human COX-2 (PDB ID: 5F19) was used for
molecular docking studies. There are nine Homo sapiens COX-2
structures available in RCSB PDB. Among these structures, 5F19 has
highest resolution of 2.04 Å and therefore was considered in this
study. This structure is aspirin-acetylated human COX-2 in which
CONFLICT OF INTEREST
[42]
The authors have declared no conflict of interest.
Ser530 was acetylated.
So we mutated this acetylated Ser530 to
serine. This protein structure was prepared using Protein Preparation
[43]
[44,45]
Wizard (Impact 6.3, Schrodinger)
as previously described.
In
ORCID
brief, the structure was processed for addition of hydrogen atoms,
formal charges treatment, and assignment of correct bond orders.
Structures of the molecules were sketched and prepared using LigPrep
Avneet Kaur
http://orcid.org/0000-0001-7469-1922
http://orcid.org/0000-0003-1408-1019
Sharad Wakode
3
.0 with Epik 2.8 and tautomeric state and protonation states were
expanded at 7.0 ± 2.0 pH units. The OPLS 2005 force field was used
for both molecules and protein minimization. The Glide grid was
generated by specifying the centroid of the residues His90, Thr94,
Arg120, Gln192, Tyr348, Val349, Leu352, Ser353, Gly354, Tyr355,
Leu359, Phe381, Leu384, Tyr385, Trp387, Arg513, Ala516, Ile517,
Phe518, Gly519, Met522, Val523, Gly526, Ala527, Ser530, and
Leu531. Prepared and minimized small molecules were docked into the
minimized protein structure using Glide 6.3 XP docking. The 3D
complex structures of all molecules were analyzed for Glide score
H-bonding, salt bridge, π–π and π–cation interactions.
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4
.3.3 ADME study
|
The ADME properties are imperative to decide the role of a new
molecule in drug development process and so are considered as crucial
for rational drug design. The lack of best fit ADME parameters of a
molecule leads to its denunciation in the progressive stages of drug
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1
09, 99.
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9] D. Adebayo, I. Bjarnason, Postgrad. Med. J. 2006, 82, 186.
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