Microwave assisted amberlite-IRA-402 (OH) ion exchange resin catalyzed synthesis of new benzoxazole scaffolds derived from antiinflammatory drugs aceclofenac and mefenamic acid as potential therapeutic agents for inflammation

Article abstract of DOI:10.1016/j.molstruc.2019.127092

An efficient microwave assisted synthesis of 2-substituted benzoxazole derivatives from antiinflammatory drugs aceclofenac and mefenamic acid using amberlite-IRA-402 (OH) ion exchange resin as a base catalyst were reported. The synthesized compounds were

Full text of DOI:10.1016/j.molstruc.2019.127092

Journal of Molecular Structure 1200 (2020) 127092
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Microwave assisted amberlite-IRA-402 (OH) ion exchange resin
catalyzed synthesis of new benzoxazole scaffolds derived from
antiinflammatory drugs aceclofenac and mefenamic acid as potential
therapeutic agents for inflammation
,
Gangadhara Angajala a *, Radhakrishnan Subashini b, Valmiki Aruna a
a Department of Chemistry, Kalasalingam Academy of Research and Education (Deemed to be University), Anand Nagar, Krishnankoil, 626126, Tamilnadu,
India
b Department of Chemistry, Arignar Anna Government Arts College for Women, Walajapet, 632513, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient microwave assisted synthesis of 2-substituted benzoxazole derivatives from antiin-
flammatory drugs aceclofenac and mefenamic acid using amberlite-IRA-402 (OH) ion exchange resin as a
Received 27 May 2019
Received in revised form
15 September 2019
Accepted 17 September 2019
Available online 20 September 2019
base catalyst were reported. The synthesized compounds were purified and characterized by 1H NMR, 13
C
NMR and Mass spectroscopy. In silico molecular docking studies were carried out to predict the binding
affinity of the synthesized benzoxazole derivatives with COX-2 protein. Molecular Docking analysis
showed that compounds 4 and 7 possess excellent binding affinity towards COX-2 with a docking score
of ꢀ11.6 and ꢀ10.4 kcaL/mol respectively. The results obtained from in vitro antiinflammatory studies
towards membrane stabilization and proteinase inhibitory activities showed that the synthesized ben-
zoxazole compounds 4 and 7 possess better efficacy when compared to that of standards aceclofenac and
etodolac with a percentage inhibition of 74.22 0.15, 70.64 0.24 for membrane stabilization and
Keywords:
Benzoxazole
Amberlite-IRA-402 (OH)
Anti-inflammatory
COX-2
75.19 0.12, 71.80 0.49 for proteinase enzyme assay at 100
m
moL/L. The synthesized compounds 4 and
Antioxidant
7
were also evaluated for antioxidant activity which showed good inhibition (70.16 0.31 and
68.25 0.49) at 100
m
moL/L which was on Par to that of standard ascorbic acid.
© 2019 Elsevier B.V. All rights reserved.
1. Introduction
cells [3e5]. The rate of ROS induced DNA damage is more during
chronic inflammation and this process substantially causes deple-
tion of cellular antioxidants. Currently used non-steroidal anti-in-
flammatory drugs (NSAIDS) have the risk of acute myocardial
infarction and other serious coronary heart diseases [6]. Though
numerous effective anti-inflammatory agents are available in
market it is still the challenge of the chemist to develop more
effective and less toxic agents to treat the signs and symptoms of
acute inflammation, long-term consequences of chronic inflam-
matory diseases and effective in the prevention of free radical-
mediated damage [7,8].
Over the past decades benzoxazole derivatives have gained a lot
of significance because of their versatile applications as in-
termediates for the design and synthesis of new pharmacologically
active compounds [9e11]. Benzoxazoles are the structural isosteres
of nucleic bases adenine, guanine which allow them to interact
easily with the biological receptors. A slight change in the substi-
tution pattern of benzoxazole nucleus causes distinguishable
Inflammation due to exposure of tissues and cells to harmful
stimuli initiates the release of chemicals from tissues, migrating
cells and so on results in inflammatory diseases and may leads in
neurodegenerative disease or may progress into cancer [1,2]. In
recent years chronic inflammatory diseases represents one of the
most significant causes of death throughout the world. The prev-
alence of diseases like heart disorders, cancer, stroke, chronic res-
piratory diseases, obesity and diabetes associated with chronic
inflammation is estimated to rise in the next 25 years [Fig. 1].
Sustained vigorous inflammation can sometimes lead to cellular
damage or hyperplasia which subsequently leads to the over-
production of reactive oxygen species (ROS) from inflammatory
* Corresponding author.
E-mail address: gangadharaangajala@gmail.com (G. Angajala).
https://doi.org/10.1016/j.molstruc.2019.127092
0022-2860/© 2019 Elsevier B.V. All rights reserved.

2
G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
and are corrected with standard benzoic acid. The NMR spectra
were recorded on a Bruker Avance IIIe400 MHz spectrometer using
TMS as internal standard (chemical shifts in ppm). Mass was
d
recorded on Finnigan Mat 8230 Mass Spectrometer.
The synthetic strategy leading to the target compounds 4 and 7
from aceclofenac and mefenamic acid bulk drugs is illustrated in
Scheme: 1-2. The compounds 2-((2-(benzo[d]oxazol-2-yl) phenyl)
amino)-2-oxoethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)ace-
tate
4
and
N-(2-(benzo
[d]oxazol-2-yl)phenyl)-2-((2,3-
dimethylphenyl)amino)benzamide 7 were prepared by dissolving
aceclofenac 1 and mefenamic acid 5 in THF and the corresponding
acid chloride formation was carried out in a microwave by using
thionyl chloride followed by the reaction of 2-(benzo [d] oxazol-2-
yl)aniline 3 in the presence of amberlite-IRA-402 (OH) ion ex-
change resin as a base catalyst.
2.2. General procedure for the synthesis of benzoxazole scaffolds 4
and 7
Synthesis of 2-((2-(benzo[d]oxazol-2-yl) phenyl)amino)-2-
oxoethyl 2-(2-((2,6-dichlorophenyl) amino)phenyl)acetate, 4 and
Fig. 1. Inflammation and its associated diseases.
N-(2-(benzo
amino) benzamide, 7.
[d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl)
difference in their pharmacological activities [12]. Recent studies
clearly reveal the biological importance of benzoxazoles and its
related analogues like antiinflammatory [13e15], anti-cancer [16],
diuretic [17], herbicidal [18], hypoglycemic [19], anti-histaminic
[20], antiviral [21], antimicrobial [22], antiallergic [23], anti-
convulsants [24], elastase inhibitors [25], antitubercular agents
[26], antifungal [27], 5-HT3 receptor agonists [28], melatonin re-
ceptor agonists [29], amyloid fibril inhibitors [30] and Rho kinase
inhibitors [31]. These examples highlights the level of interest in
the synthetic approaches of new benzoxazole derivatives and have
prompted many researchers to explore the potential applicability of
this important pharmacophoric scaffold.
Among the widely used therapeutic drugs, NSAIDS are consid-
ered as significant agents primarily used for the treatment of
inflammation and arthritis. Antiinflammatory drugs presently
available for the treatment of various inflammatory disorders have
more adverse or undesirable side effects [32]. In recent years
therapeutically active substitutions have been incorporated in
benzoxazole scaffold to yield antiinflammatory drug candidates
and these hybrid molecules displays significant pharmacological
and biological activity [Fig. 2] [33e36]. The high therapeutic effi-
cacy of benzoxazole related drugs have encouraged medicinal
chemists to synthesize large varieties of novel anti-inflammatory
agents [37]. The incorporation of benzoxazole nucleus is an
important strategy in drug discovery research [38]. This class of
molecules has broadened the scope in remedying various disposi-
tions in clinical medicine. In the present work new potential ther-
apeutic benzoxazole scaffolds were synthesized by incorporating
two antiinflammatory drugs aceclofenac and mefenamic acid un-
der microwave irradiation in the presence of amberlite-IRA-402
(OH) ion exchange resin as a base cum catalyst [39].
A mixture of aceclofenac (6 mmol, 2.12 g) and thionyl chloride
(7 mmol, 3.5 mL) was taken in a reaction vessel mixed thoroughly
in THF and then irradiated in a microwave oven at 420 W for 90 min
afforded 2-chloro-2-oxoethyl 2-(2-((2,6-dichlorophenyl)amino)
phenyl)acetate, 2. Similarly a mixture of mefenamic acid (6 mmol,
1.45 g) and thionyl chloride (7 mmol, 3.14 mL) was taken in a re-
action vessel mixed thoroughly in THF and then irradiated in a
microwave oven at 340 W for 45 min afforded 2-((2,3-
dimethylphenyl)amino)benzoyl chloride, 6. Completion of the re-
action was determined by the stoppage of SO2 gas. Removal of
excess of thionyl chloride was carried out by distillation under
reduced pressure. Further a base trap was connected in order to
neutralize the excess vapour evolved. To the compounds 2 and 6
(in-situ) 2-(benzo [d] oxazol-2-yl)aniline 3 (6 mmol, 1.26 g) and
amberlite-IRA-402 (OH) ion exchange resin (20 mg) was added and
subjected to microwave oven at a power of 340 W for 2 h. The
completion of the reaction was monitored by thin layer chroma-
tography (TLC) using Petroleum ether: EtOAc (3:1). After comple-
tion, the catalyst was filtered off and the mixture was diluted with
EtOAc, washed with water followed by brine and dried over
anhydrous Na2SO4. The solvent was removed under vacuum and
the resulting solid was filtered, dried and purified using column
chromatography to afford compounds 4 and 7.
2.3. Spectral data of the synthesized compounds 4 and 7
2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl 2-(2-((2,6-
dichlorophenyl) amino) phenyl) acetate, 4 light brown solid, 84.2%
yield, mp 216e218 ꢁC. IR (KBr pellets, cmꢀ1
)
y
: 751.22, 790.76,
1123.46, 1191.93, 1277.75, 1356.83, 1608.52, 1672.17, 1756.07,
3315.41. 1H NMR (CDCl3, ppm, 400 MHz)
: 3.76 (2H, s, CH2), 4.54
d
2. Experimental
(2H, s, CH2), 4.99 (1H, s, NH), 6.37e6.39 (1H, d, J ¼ 8.0 Hz, CH), 6.45
(1H, s, NH), 6.63e6.67 (1H, t, J ¼ 8.4 Hz, CH), 6.78e6.80 (2H, d,
J ¼ 8.4 Hz, CH), 6.94e6.98 (2H, m, CH), 7.07e7.09 (3H, m, CH),
7.14e7.17 (3H, m, CH), 7.48e7.51 (2H, d, J ¼ 8.4 Hz, CH), 7.71e7.75
2.1. Materials and method
Reagents and solvents were sourced commercially and used
without additional purification. Thin layered chromatography (TLC)
was carried out on preparative plates of silica gel. Visualization was
made using iodine chamber. Purification of the synthesized com-
pounds were performed by column chromatography using silica gel
(100e200 mesh). Melting points were measured on Elchem
Microprocessor based DT apparatus using an open capillary tube
(1H, m, CH). 13C NMR (CDCl3, ppm, 100 MHz)
d: 34.06, 43.72, 114.79,
124.71, 125.72, 126.02, 127.81, 129.61, 130.06, 130.77, 131.05, 131.95,
132.17, 133.07, 133.42, 134.07, 143.43, 146.60, 156.25, 167.63, 172.46.
HRMS [EIþ] Calcd for C29H21Cl2N3O4 m/z 545.0909 [Mþ], found
545.0994.
N-(2-(benzo
[d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl)
amino) benzamide, 7 pale brown solid, 88.4% yield, mp 262e265 ꢁC.

G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
3
Fig. 2. Various drugs possessing benzoxazole nucleus.
Scheme: 1. Synthesis of 2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl 2-(2-((2,6-dichloro phenyl)amino)phenyl)acetate, 4.
IR (KBr pellets, cmꢀ1
1356.83, 1608.52, 1672.17, 1756.07, 3315.41. 1H NMR (CDCl3, ppm,
400 MHz) : 2.12 (3H, s, CH3), 2.34 (3H, s, CH3), 5.03 (1H, s, NH), 6.45
)
y
: 751.22, 790.76, 1123.46, 1191.93, 1277.75,
HRMS [EIþ] Calcd for C28H23N3O2 m/z 433.1790 [Mþ], found
433.9245.
d
(1H, s, NH), 6.69e6.70 (2H, d, J ¼ 5.6 Hz, CH), 6.94e6.98 (2H, t,
2.4. Pharmacology
J ¼ 7.2 Hz, CH), 7.38e7.41 (3H, m, CH), 7.48e7.51 (3H, m, CH),
8.38e8.40 (1H, d, J ¼ 8.0 Hz, CH). 13C NMR (CDCl3, ppm, 100 MHz)
d:
2.4.1. In-vitro anti-inflammatory studies
In the present work in-vitro anti-inflammatory studies were
carried out by two methods such as membrane stabilization test
17.92, 22.48, 116.35, 122.56, 124.83, 125.31, 126.12, 131.14, 133.48,
134.15, 136.51, 137.67, 141.81, 145.39, 147.20, 151.74, 162.31, 165.15.
Scheme: 2. Synthesis of N-(2-(benzo[d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl)amino) benzamide, 7.

4
G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
and proteinase inhibitory test as per the reported method [40,41].
Etodolac was taken as standard drug. The mixture was incubated at
37 ꢁC for 5 min and then 1 mL of 0.8% (w/v) casein was added. The
mixture was incubated for an additional 20 min. 2 mL of 70%
perchloric acid was added to terminate the reaction. Cloudy sus-
pension was centrifuged and the absorbance of the supernatant
was read at 210 nm against buffer as blank.
2.4.1.1. Membrane stabilization test. Preparation of red blood cells
(RBCs) suspension:
After the consent from a healthy volunteer fresh human blood
(10 mL) was collected and transferred to heparinized centrifuged
tubes. Collected blood was subjected to centrifugation at 3500 rpm
for 10 min and washed with equal volume of saline solution for
three times. The volume of blood was measured and reconstituted
to 10% by using normal saline.
Heat induced hemolysis:
Equal volume of test samples of various concentrations (25, 50
and 100 mmoL/L) and 10% v/v RBC suspension (2 mL) were trans-
ferred to centrifuged tubes. In control test tube instead of drug only
saline was added. Etodolac was taken as standard drug. All
centrifuge tubes were incubated in water bath at 56 ꢁC for 30 min.
Reaction mixture was then centrifuged at 2500 rpm for 5 min and
absorbance of the supernatant was taken at 560 nm. The experi-
ment was performed in triplicates and the Percent membrane
stabilization activity was calculated by:
The experiment was performed in triplicate and the percentage
inhibition of proteinase inhibitory activity was calculated by:
I%ðpercentage inhibitionÞ ¼ ½AB ꢀ AA=ABꢂ ꢃ 100
Where AB ¼ absorption of blank sample
AA ¼ absorption of sample
2.4.2. Antioxidant studies
The generation of different reactive oxidant species during
inflammation generally stimulates the progress of a state of
oxidative stress, with major biological implications. Oxidative
stress plays an essential role in the development and perpetuation
of inflammation, and thus contributes to the pathophysiology of a
number of debilitating illnesses, such as diabetes, cancer, cardio-
vascular diseases and neurodegenerative processes. Oxidants affect
all stages of the inflammatory response, including the release by
damaged tissues of molecules acting as endogenous danger signals.
So there is a need for antioxidants which effectively terminate
these signals by removing free radical intermediates, and inhibit
cell death and other oxidation reactions during inflammatory
processes. In present study the antioxidant efficacy of benzoxazole
derivatives were screened for their free radical scavenging activity
I%ðpercentage inhibitionÞ ¼ ½AB ꢀ AA=ABꢂ ꢃ 100
Where AB ¼ absorption of blank sample
AA ¼ absorption of sample
2.4.1.2. Proteinase inhibitory activity. The reaction mixture (2 mL)
containing 0.06 mg trypsin, 1 mL of 20 mM Tris HCl buffer (pH 7.4)
and 1 mL test sample of different concentrations was added.
Table: 1
Screening of effective base and solvent combination in the synthesis of 2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl2-(2-((2,6-dichlorophenyl)amino)phenyl) ace-
tate, 4 under the presence and absence of microwave irradiationa.
Entry
Base
Solvent
Conventional
Time (h)
Microwave
Time
Yield (%)b
Yield (%)b
1
2
3
4
5
6
7
8
Pyridine
Et3N
DIPEA
Amberlite IRA-402 (OH)
KOH
DMF
DMF
DMF
DMF
DMF
DMF
Acetonitrile
Toluene
THF
12
8
14
5
10
12
10
8
41
55
47
60
45
52
59
45
67
58
60
55
8 h
4 h
8 h
3 h
6 h
7 h
5 h
3 h
2 h
5 h
2 h
3 h
55
70
60
78
62
68
72
65
84
65
75
70
K2CO3
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
9
5
10
5
10
11
12
DCM
Ethanol
Acetone
8
a
Reaction conditions: Compound 2 - 1 mmol, Compound 3 - 1 mmol; Base: 1.5 mmol; Amberlite IRA-402 (OH): 50 mg.
isolated yield.
b

G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
5
Table 2
Screening of effective base and solvent combination in the synthesis of N-(2-(benzo [d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl) amino) benzamide, 7 under the presence
and absence of microwave irradiationa.
Entry
Base
Solvent
Conventional
Time (h)
Microwave
Time
Yield (%)b
Yield (%)b
1
2
3
4
4
5
6
7
8
9
10
11
Pyridine
Et3N
DIPEA
Amberlite IRA-402 (OH)
KOH
DMF
DMF
DMF
DMF
DMF
DMF
Acetonitrile
Toluene
THF
12
8
14
5
10
12
10
8
45
68
52
64
55
62
65
48
70
64
67
61
8 h
4 h
8 h
3 h
6 h
7 h
5 h
3 h
2 h
5 h
3 h
3 h
66
78
67
75
69
70
78
75
88
68
78
74
K2CO3
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
Amberlite IRA-402 (OH)
5
10
5
DCM
Ethanol
Acetone
8
a
Reaction conditions: Compound 6 - 1 mmol, Compound 3 - 1 mmol; Base: 1.5 mmol; Amberlite IRA-402 (OH): 50 mg.
Isolated yield.
b
by using the DPPH radical assay as per the reported method [42].
4, 7 along with standards etodolac, aceclofenac and mefenamic acid
were investigated using Autodock tools (ADT) v1.5.4 and Autodock
v4.2 program. The COX-2 protein (ID-5IKR) in complex with
mefenamic acid was taken from protein data bank. To run the
docking process, searching grid map extended over the selected
COX-2 protein was used and polar hydrogens were added to the
ligand moieties. Kollman charges were allocated and atomic sol-
vation parameters were added. Polar hydrogen charges of the
Gasteiger-type were assigned and the non-polar hydrogens were
merged with the carbons and the internal degrees of freedom and
torsions were set. In the present version COX-2 protein was kept
rigid, and ligand allowed to move freely. The rototranstional area in
to which the ligand is allowed to move freely around the active
2.4.2.1. DPPH radical scavenging assay. Free radical scavenging is
one of the familiar mechanisms through which antioxidants in-
hibits oxidation. In the present study, the radical scavenging ability
of all the synthesized compounds was determined spectrophoto-
metrically using the stable DPPH radical scavenging method. DPPH
assay is a quite simple and standard method for evaluating anti-
oxidant activity. One of the best advantages of this assay is the
commercial availability of DPPH radical, so there is no need of it to
be generated in advance like in other assays. Compound solutions
were prepared by dissolving an appropriate amount of each com-
pound in ethanol. The solution of DPPH in ethanol was prepared
just before UV measurements. 3 mL of sample and 1 mL of DPPH
solutions were mixed and kept in the dark for 30 min at room
temperature and then the decrease in absorption was measured at
517 nm. For the control absorption blank sample containing the
same amount of ethanol and DPPH solution was measured. Ascor-
bic acid was used as standard. The experiment was carried out in
triplicate. Radical scavenging activity was calculated by following
formula:
Table 3
Optimization of the amount of catalyst in the synthesis of in the synthesis of 2-((2-
(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl2-(2-((2,6-dichlorophenyl)amino)
phenyl) acetate, 4 and N-(2-(benzo [d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl)
amino) benzamide, 7 under the presence of microwave irradiation.
Entry
Catalyst (mg)
Compound 4
Time (h)
Compound 7
Yield (%)b
Time
Yield (%)b
1
2
3
4
5
6
7
8
5.0
10.0
15.0
20.0
25.0
30.0
50.0
No catalyst
4.0
3.5
3.0
2.0
2.0
2.0
2.0
18.0
65
73
79
84
84
84
84
15
4.0
3.5
3.0
2.0
2.0
2.0
2.0
17.0
68
76
82
88
88
88
88
18
I%ðpercentage inhibitionÞ ¼ ½AB ꢀ AA=ABꢂ ꢃ 100
Where AB ¼ absorption of blank sample
AA ¼ absorption of sample
aReaction conditions: Compound 2, 6 - 1 mmol, Compound 3 - 1 mmol; THF; Mi-
crowave-340 W.
b
2.4.3. In silico molecular docking studies
Isolated yield.
The docking analysis of the synthesized benzoxazole derivatives

6
G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
Table 4
In silico molecular docking results for antiinflammatory efficacy of synthesized benzoxazole derivatives and standards.
Entry
Ligand
Autodock score
Lipophilicity
Hydrophobicity
1
2
3
4
5
4
ꢀ11.6
ꢀ10.4
ꢀ8.9
ꢀ3.6
ꢀ3.0
ꢀ3.3
ꢀ3.5
ꢀ2.9
ꢀ1.4
ꢀ0.5
ꢀ0.8
ꢀ0.6
ꢀ0.5
7
Stda
Stdb
ꢀ10.2
ꢀ9.2
Reference ligand (Stdc)
a
Etodolac.
Aceclofenac.
Mefenamic acid.
b
c
sphere is restricted to 10 Å. Affinity maps for the entire atom types
present, as well as an electrostatic map was computed with a grid
spacing of 0.375 Aꢁ. For each ligand, a docking experiment con-
sisting of 100 simulations was performed and the analysis was
based on binding free energies and root mean square deviation
(RMSD) values and the ligand molecules were then ranked in the
order of increasing docking energies. The analysis of hydrophobic
and lipophilic interaction of ligands towards COX-2 protein was
carried by using ALOGPS 2.1 and Biovia discovery studio visualizer
4.5.
3. Results and discussion
3.1. Synthesis
The synthesis of 2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-
oxoethyl-2-(2-((2,6-dichloro phenyl)amino)phenyl)acetate, 4 and
N-(2-(benzo
[d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl)
amino) benzamide, 7 as depicted in scheme 1-2 is hitherto unre-
ported in literature. Synthesis of compounds 4 and 7 was initially
carried out by conventional method through heating on a water
bath for 7 h but the conversion of the desired product was less. On
Fig. 3. In silico molecular docking studies of benzoxazole derivatives as COX-2 inhibitors. [A-C] The binding interactions of 2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl2-
(2-((2,6-dichlorophenyl)amino)phenyl)acetate, 4 [D-F] The binding interactions of N-(2-(benzo[d]oxazol-2-yl)phenyl)-2-((2,3-di methyl phenyl) amino) benzamide, 7 [G-I] The
binding interaction of standard mefanamic acid [J-L] The binding interaction of aceclofenac.

G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
7
Fig. 4. Various interactions of synthesized benzoxazole derivatives 4, 7 and standards with COX-2 amino acids. [A] 2-((2-(benzo[d]oxazol-2-yl)phenyl)amino)-2-oxoethyl2-(2-((2,6-
dichloro phenyl)amino)phenyl)acetate, 4 [B] N-(2-(benzo[d]oxazol-2-yl)phenyl)-2-((2,3-di methyl phenyl) amino) benzamide, 7 [C] Standard mefanamic acid [D] Standard ace-
clofenac [E] Standard etodolac.
the other hand when the same reaction was carried out in a mi-
crowave at an appropriate time leads to the formation of the
products 4 and 7 with high yield and purity. The formation of the
product 4 as confirmed from 1H NMR showed 16 protons in the
spectra of compound 7 shows 28 carbons in which the peaks ap-
pears at 165.15 corresponds to C]O group. The appearance of
peaks at 22.48, 17.92 ppm corresponds to the methyl groups of the
corresponding product 7 and the signals at 116.15e151.74 ppm
corresponds to aromatic carbons. Furthermore, the product 7 was
confirmed by HRMS, which gave the molecular ion peak at m/z
433.1790 which matches with the molecular formula C28H23N3O2
(see, Figs. S4eS6 in supporting information).
aromatic region and the peak at 6.45
group whereas the singlet appears at 4.99
group of the aceclofenac. The appearance of two singlets at 3.76 and
4.54 respectively related to two methylene groups of the aceclo-
fenac. The change in the position of chemical shift towards
deshielding region 4.54 for the CH2 group was mainly attributed
d
corresponds to amide eNH
d
corresponds to eNH
d
d
3.2. Optimization of the reaction conditions
to the presence of neighboring electronegative oxygen atom. The
13C NMR spectra of compound 4 shows 30 carbons in which the
peaks appears at 172.46 and 167.63 ppm corresponds to C]O
groups. The appearance of peak at 156.25 ppm related to the CeCl
group of the aceclofenac and the peaks at 34.06, 43.72 ppm cor-
responds to the methylene groups of the corresponding product 4.
Furthermore, the product 4 was confirmed by HRMS, which gave
the molecular ion peak at m/z 545.0909 which matches with the
molecular formula C29H21Cl2N3O4 (see, Figs. S1eS3 in supporting
information).
To afford increased selectivity and improvise yields, microwave
Table 5
Membrane stabilizing inhibitory activity of benzoxazole derivatives and standards.
S.No
Compound
Concentration (
25
m
mol/L)
50
100
1.
2.
3.
4.
5.
4
7
25.78 0.69
22.36 0.14
21.28 0.20
24.92 0.75
20.86 0.11
39.26 0.72
74.22 0.15
70.64 0.24
65.42 0.36
72.18 0.39
58.79 0.45
35.17 0.41
32.64 0.22
37.63 0.15
31.48 0.52
Similarly the formation of the product 7 as confirmed from the
Stda
Stdb
Stdc
1H NMR showed 16 protons in the aromatic region and the peak at
6.45
pears at 5.03
The appearance of two singlets at 2.12 and 2.34
related to two methyl groups of the mefenamic acid. The 13C NMR
d
corresponds to amide eNH group whereas the singlet ap-
corresponds to eNH group of the mefenamic acid.
respectively
d
a
Etodolac.
Aceclofenac.
Mefenamic acid.
b
c
d

8
G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
Table 6
increase in the amount of catalyst failed to increase the yield;
therefore, 20 mg of amberlite IRA-402 (OH) was found to be the
optimal quantity for this reaction under the present experimental
conditions.
Proteinase inhibitory efficacy of benzoxazole derivatives and standards.
S.No
Compound
Concentration (
25
m
mol/L)
50
100
1.
2.
3.
4.
5.
4
7
27.64 0.35
23.95 0.84
22.87 0.25
26.14 0.98
21.90 0.66
40.10 0.55
75.19 0.12
71.80 0.49
69.04 0.51
72.48 0.55
67.02 0.48
3.3. Reusability of the catalyst
36.04 0.19
34.55 0.76
39.76 0.10
32.50 0.17
Stda
Stdb
Stdc
The recovery and reusability of amberlite-IRA-402 (OH) catalyst
are one of the important advantages which make it more suitable
for commercial applications. In this perspective, reusability and
recovery efficiency were examined in the synthesis of compound 4
and 7 under optimized conditions. After completion of the reaction
the catalyst was recovered by filtration, washed with hot ethanol
thoroughly, dried at 90 ꢁC for 5 h and reused as such for subsequent
model reaction under similar reaction conditions. Recovered
amberlite-IRA-402 (OH) exhibited good catalytic activity even up to
four cycles without any change in reaction time and only a minimal
decrease in the yield was observed which could be attributed to the
loss of catalyst during recycling.
a
Etodolac.
b
c
Aceclofenac.
Mefenamic acid.
irradiation has been established as an important technique. To find
appropriate reaction medium, various bases like Pyridine, Et3N,
KOH, DIPEA and K2CO3 were employed along with amberlite IRA-
402 (OH) in the synthesis of compounds 4 and 7 by using DMF as
a solvent. The reactions proceeded in the presence of all the bases
with yields ranging from 55 to 78% and the maximum yield of 78%
was observed with amberlite IRA-402 (OH)-DMF combination.
With amberlite IRA-402 (OH) as a base, the reactions were also
performed in different solvents like toluene, acetonitrile,
dichloromethane, tetrahydrofuran, ethanol and acetone (Tables 1
and 2). The dielectric constant of solvent molecules plays a major
role in the distribution of charges during the course of the reaction.
It generally measures the solvent ability to minimize strength of the
electric field associated with corresponding charged particle. Polar
solvents with high dielectric constant tend to donate hydrogens
more effectively and forms hydrogen bonding with the reactants
[43]. After screening different solvents and bases highest yield of 2-
((2-(benzo[d]oxazol-2-yl) phenyl) amino)-2-oxoethyl 2-(2-((2,6-
dichlorophenyl) amino)phenyl)acetate, 4 (84%) and N-(2-(benzo
[d]oxazol-2-yl)phenyl)-2-((2,3-dimethylphenyl) amino) benza-
mide, 7 (88%) was obtained with amberlite IRA-402 (OH) as a base
and tetrahydrofuran as a solvent.
3.4. Molecular docking simulations
The results obtained from molecular docking analysis of com-
pounds 4 and 7 along with standards showed that compound 4 and
7 possess good binding interaction towards COX-2 protein with
binding energy of ꢀ11.6 and ꢀ10.4 k cal/mol which was greater
than standard etodolac (ꢀ8.9 k cal/mol), aceclofenac (ꢀ10.2 k cal/
mol) and mefanamic acid (ꢀ9.2 k cal/mol) (Table 4 and Fig. 3). The
binding interactions of ligands 4, 7 and standards with various
amino acids of COX-2 protein was illustrated using Biovia discovery
studio visualizer 4.5. (Fig. 4). The effective binding affinities of
compound 4 and 7 was mainly attributed due to the synergistic
efficacy of both benzoxazole and antiinflammatory drugs (Aceclo-
fenac and Mefenemic acid) which further increases the hydro-
phobic and lipophilic interactions of the ligands. The hydrophobic
interaction is very important interaction in the binding site because
most interaction in the binding site are hydrophobic even less
stronger than hydrogen bonding and ionic interaction. Increase in
lipophilic nature makes the molecule more polarized and accord-
ingly the London dispersion forces increases which are quite
necessary for the lipophilic substances to interact within
In a pursuit to increase the yields, efforts were done to optimize
catalyst loading in the reaction under microwave irradiation at
340 W. Results obtained clearly indicated that increase in the
concentration of the catalyst loaded the yield in the formation of
the product increased gradually and maximum yield was obtained
when 20 mg of the catalyst used (Table 3). Moreover, further
Fig. 5. Membrane stabilization efficacy of synthesized benzoxazole derivatives 4, 7 and standards.

G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
9
Fig. 6. Proteinase inhibitory efficacy of synthesized benzoxazole derivatives 4, 7 and standards.
themselves and other amino acid residues in the receptor.
showed that the synthesized benzoxazole derivatives 4 and 7
showed good efficacy with percentage inhibition of 74.22 0.15,
70.64 0.24 for membrane stabilization and 75.19 0.12,
71.80 0.49 for proteinase enzyme assay at a concentration of
3.5. Pharmacology
100 mmoL/L which was on par to that of standard aceclofenac and
The results obtained from in vitro antiinflammatory activity
Fig. 7. Plausible antiinflammatory mechanism of synthesized benzoxazole derivatives.

10
G. Angajala et al. / Journal of Molecular Structure 1200 (2020) 127092
Table 7
Appendix A. Supplementary data
DPPH radical scavenging efficacy of benzoxazole derivatives and standard.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2019.127092.
Compound
Percentage Inhibition
Concentration (
10
m
mol/L)
50
100
IC50
References
4
12.27 0.29
10.64 0.15
16.65 1.29
34.29 0.10
32.55 0.72
40.20 0.33
70.16 0.31
68.25 0.49
79.05 0.14
1.88
1.91
1.72
7
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In conclusion novel benzoxazole derivatives were synthesized
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