Green synthesis of therapeutically active 1,3,4-oxadiazoles as antioxidants, selective COX-2 inhibitors and their in silico studies

Article abstract of DOI:10.1016/j.bmcl.2021.128112

A modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The biological outcomes as well as computational study suggested that the compounds originated to have elevated resemblance towards COX-2 enzyme than COX-1. The compounds 8i, 8l, 8q, 8r, 8s and 8t emerged as most potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l, 8n and 8r was respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Interestingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents.

Full text of DOI:10.1016/j.bmcl.2021.128112

Bioorg. Med. Chem. Lett. 43 (2021) 128112
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Green synthesis of therapeutically active 1,3,4-oxadiazoles as antioxidants,
selective COX-2 inhibitors and their in silico studies
,
Aravind R. Nesaragia, Ravindra R. Kamblea *, Shruti Dixitb, Barnabas Kodasia,
Swati R. Hoolageria, Praveen K. Bayannavara, Jagadeesh Prasad Dasappac,
Shyamkumar Vootlab, Shrinivas D. Joshid, Vijay M. Kumbare
a Department of Studies in Chemistry, Karnatak University, Dharwad 580003, India
b Department of Biotechnology and Microbiology, Karnatak University, Dharwad 580003, India
c Department of Chemistry, Mangalore University, Mangalagangothri, Konaje 574199, India
d Novel Drug Design and Discovery Laboratory, Department of Pharmaceutical Chemistry, S.E.T.’s College of Pharmacy, Dharwad 580002, India
e Central Research Laboratory, Maratha Mandal’s NGH Institute of Dental Sciences and Research Centre, Belagavi 590010, India
A R T I C L E I N F O
A B S T R A C T
modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-
Keywords:
A
Antioxidant
mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the
compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The
biological outcomes as well as computational study suggested that the compounds originated to have elevated
resemblance towards COX-2 enzyme than COX-1. The compounds 8i, 8l, 8q, 8r, 8s and 8t emerged as most
potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l, 8n and 8r was
respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Inter-
estingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents.
COX-2 inhibitors
Coumarin
Microwave
Molecular docking
Mercapto benzoxazole
1,3,4-Oxadiazole
Inflammation is a multifarious occurrence concerning humoral and
(coxibs) had been evolved.3 While, the selective COX-2 inhibitors have
not exhibited any gastrointestinal side effects, they endure from the
drawbacks of cardiovascular complications that preceded to the with-
drawal of Rofecoxib (Vioxx) and Valdecoxib (Bextra) from the market in
2004 and 2005, respectively.4,5
cellular reactions through innumerable inflammatory mediators.1
A
great deal of attentiveness has been attracted by Cyclooxygenase (COX)
enzymes as significant targets for drug pioneering due to their crucial
role in prostaglandin biosynthesis. Inhibition of COX enzymes is a
promising approach for the pharmacological intervention in inflamma-
tion. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most
recurrently stipulated clinical tools due to their superior anti-
inflammatory, analgesic and antipyretic effects which employ through
the inhibition of COX-1 and COX-2 however, COX-1 is inhibited more
vigorously than COX-2. NSAIDs are predominantly used for diminishing
pain and inflammation in osteoarthritis, rheumatoid arthritis and
arthritis of systemic lupus erythematosus, psoriasis and other seroneg-
ative spondyloarthropathies.2 Nevertheless, their therapeutic benefit is
habitually limited by troublesome side effects at the gastrointestinal
level (mucosal damage, bleeding). Profound investigation divulged that
inhibition of COX-2 is associated with anti-inflammatory and analgesic
properties, whereas COX-1 executes a significant role in physiological
homeostasis. Subsequently, a new genre of selective COX-2 inhibitors
Heterocycles encompassing five-membered oxadiazole nucleus pro-
cure a miscellany of useful biological consequences such as anti-edema,
antioxidant and anti-inflammatory activities. 1,3,4-Oxadiazoles exhibit
anti-inflammatory activity by virtue of dual mechanism i.e., their
enzyme inhibiting properties for both cyclooxygenase and 5-lip-
ooxygenase to bring down gastric ulcer formation.6–9 During the last
decade 686 patent applications concerning to drug discovery program
have been filed on oxadiazole scaffold.3 For the treatment of cancer and
cystic fibrosis the valuable privileges of the oxadiazole scaffold such as
Zibotentan and Ataluren respectively are enduring clinical trials with
respect to the drug discovery.10 In recent years there has been a massive
analysis on the diverse set of oxadiazoles among which several such
scaffolds were found to possess an extensive spectrum of pharmaco-
logical activities.11
* Corresponding author.
E-mail address: ravichem@kud.ac.in (R.R. Kamble).
https://doi.org/10.1016/j.bmcl.2021.128112
Received 24 March 2021; Received in revised form 7 May 2021; Accepted 9 May 2021
Available online 13 May 2021
0960-894X/© 2021 Elsevier Ltd. All rights reserved.

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
Scheme 1. Synthesis of 1,3,4-oxadiazole intermediates 5a,b.
Scheme 2. Synthetic strategy for the fabrication of compounds 8i-t.
Reactive oxygen species (ROS) such as superoxide, singlet oxygen,
hydroxyl radical and hydrogen peroxide produced under oxidative stress
damage the lipids, proteins and DNA, causing serious health problems
such as cancer, inflammation, cardiovascular and neurodegenerative
disorders.12 Besides, radical reactions play a considerable role in the
evolution of life confining habitual diseases such as cancer, ageing,
diabetes, arteriosclerosis and others. Antioxidants are molecules, natu-
ral or synthetic, accomplished of interrelating with free radicals and
impeding their chain reactions before imperative vital molecules are
harmed. Thus, they are lately formulated as the drug candidates to retort
these multifarious diseases such as carcinogenesis, inflammation,
atherogenesis and ageing in aerobic organisms.13 Interpretation of these
outcomes, it was deemed of concern to incorporate the synthesis of
1,3,4-oxadiazole derivatives, anticipating to seize promising antioxidant
activity.
reaction mixture, consequently reducing the reaction times. Often, a few
minutes of microwave irradiation is sufficient for a reaction that
conventionally requires several hours for accomplishment.20 Addition-
ally, it provides supremacy such as accelerating the inert trans-
formations, ecologically feasible conditions, higher yields and
vigorously encourage the cyclocondensation reaction.21
Results and discussion
The starting compounds 4a-b and the 5a-b were prepared according
to the Scheme 1. The title compounds (8i-t) were synthesized by
employing conventional (Scheme 2, Path A) as well as microwave
irradiation technique (Scheme 2, Path B). In routine way, the com-
pounds were obtained in a stepwise manner which incorporates the
preparation of 2-mercapto benzoxazole from substituted 2-amino phe-
nols. Mercacapto benzoxazole is then esterified by the treatment of
ethylchloroacetate followed by the reaction with hydrazine to produce
hydrazine carboxamide (acid hydrazide). Intramolecular cyclization of
4a-b under strong basic conditions with carbon disulfide furnished the
key intermediary 5a-b in good yields (68–70%). Ultimately, the reaction
of 5a-b with proper electrophilic halides yielded the title compounds 8i-
t in admirable yields.
Prior studies have revealed that pharmacophores comprising of
benzoxazole moiety have incredible biological activities encompassing
anti-inflammatory.14 Coumarins form an influential genre of com-
pounds, that manifest a range of therapeutic activities including anti-
inflammatory and antioxidant.15,16 A variety of coumarin-coupled de-
rivatives are predicted as controllers of the lipoxygenase and cyclo-
oxygenase pathways of arachidonate metabolism.17–19
Microwave irradiation (MWI) procedure has been the biggest
advantage in the target synthesis due to its direct transfer of heat into the
We were interested in exploring the most efficient and user-friendly
protocol. Hence, aiming to intensify the yield, we refluxed the reaction
2

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
Table 1
Title compounds 8i-t and the comparison of conventional and microwave methods.
Entry
Structures
Conventional
Time (hrs)
10
Microwave
Yield (%)
72
Time (min)
14
Yield (%)
92
8i
8j
11
11
66
65
16
15
85
86
8k
8l
12
68
14
82
8m
8n
11
12
70
65
15
15
87
90
8o
8p
12
12
67
64
15
14
92
78
8q
8r
12
11
68
63
14
13
84
80
8s
8t
10
11
67
72
15
15
88
90
3

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
Fig. 1. Interaction of 8l at the binding site of the enzyme (PDB ID: 5IKR).
mixture of the compounds 5a-b and 7c-h which resulted into the
reduced reaction time for completion of the reaction. The desired
product was obtained in 2–3 h with moderate yield. The diminished
reaction time encouraged us to proceed with the microwave synthesis
approach where the heat is directly transmitted to the contents of the
reaction mixture. Hence, a mixture of the compound 4a-b, carbon
disulphide and potassium hydroxide in ethanol were taken in a sealed
glass vial (10 ml) and irradiated under microwave (MW) at 100 W
(60 ◦C) for 10 min. The excess ethanol was distilled off to get 5a-b and
substituted bromomethyl coumarins 7c-h were added to the same re-
action mixture in acetone followed by anhydrous K2CO3 and irradiated
again at 100 W (40 ◦C). The desired product was formed with signifi-
cantly diminished reaction time and enhanced yield. The non-classical
reaction (MWI) rates were faster than usual heating conditions
(Table 1).
Compounds were docked into the active site of both the human COX-
2 enzyme (PDB: 5IKR) and the Ovine COX-1 (PDB code: 4O1Z) as a
means to elucidate the relationship between structure of the compounds,
Table 2
Surflex Docking score (kcal/mol) of the derivatives on PDB ID: 5IKR.
Compounds
C Scorea
Crash Scoreb
Polar Scorec
D Scored
PMF Scoree
G Scoref
Chem Scoreg
5IKR_Ligand
7.63
9.51
8.78
8.41
8.29
8.19
8.18
7.32
7.08
7.04
6.99
6.39
4.17
ꢀ 1.16
ꢀ 2.17
ꢀ 2.41
ꢀ 4.47
ꢀ 1.95
ꢀ 2.53
ꢀ 2.01
ꢀ 2.41
ꢀ 2.00
ꢀ 2.14
ꢀ 3.33
ꢀ 4.03
ꢀ 5.04
1.35
1.08
1.15
1.08
1.11
2.07
1.30
0.79
2.12
1.44
0.81
1.17
0.30
ꢀ 133.442
ꢀ 145.411
ꢀ 132.381
ꢀ 133.934
ꢀ 127.883
ꢀ 126.404
ꢀ 120.642
ꢀ 123.160
ꢀ 112.385
ꢀ 139.314
ꢀ 132.495
ꢀ 129.691
ꢀ 142.887
ꢀ 47.85
ꢀ 64.48
ꢀ 69.26
ꢀ 79.54
ꢀ 58.41
ꢀ 73.55
ꢀ 63.79
ꢀ 59.28
ꢀ 95.90
ꢀ 94.76
ꢀ 37.82
ꢀ 75.03
ꢀ 49.56
ꢀ 180.07
ꢀ 340.71
ꢀ 343.13
ꢀ 354.29
ꢀ 308.76
ꢀ 320.05
ꢀ 304.18
ꢀ 311.92
ꢀ 273.18
ꢀ 326.28
ꢀ 352.52
ꢀ 326.43
ꢀ 334.41
ꢀ 35.73
ꢀ 44.11
ꢀ 37.54
ꢀ 34.83
ꢀ 37.43
ꢀ 37.30
ꢀ 36.14
ꢀ 35.20
ꢀ 36.47
ꢀ 43.39
ꢀ 33.80
ꢀ 39.35
ꢀ 37.44
8l
8t
8n
8s
8p
8m
8i
8j
8r
8o
8k
8q
Negative numbers indicate penetration.
a
CScore (Consensus Score) integrates a number of popular scoring functions for ranking the affinity of ligands bound to the active site of a receptor and reports the
output of total score.
b
Crash-score revealing the inappropriate penetration into the binding site. Crash scores close to 0 are favorable.
c
Polar indicating the contribution of the polar interactions to the total score. The polar score may be useful for excluding docking results that make no hydrogen
bonds.
d
D-score for charge and van der Waals interactions between the protein and the ligand.
e
PMF-score indicating the Helmholtz free energies of interactions for protein–ligand atom pairs (Potential of Mean Force, PMF).
f
g
G-score showing hydrogen bonding, complex (ligand–protein), and internal (ligand–ligand) energies.
Chem-score points for H-bonding, lipophilic contact, and rotational entropy, along with an intercept term.
4

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
Fig. 3. COX-2 inhibition (%) of compounds 8i-t at different concentrations.
*STD- Mefenamic acid.
Fig. 2. RMSD of COX-2 enzyme and compound 8l.
compounds together, compound 8s and Mefenamic acid (standard) with
the enzyme (PDB ID: 5IKR; A-Chain), hydrophobic and hydrophilic
amino acids of the enzyme surrounding the compounds 8l and 8s are
provided in the supplementary information.
Table 3
COX-1/COX-2 inhibitory activity of the compounds 8i-t.
Compound
COX-1 (IC50 µg/mL)
COX-2 (IC50 µg/
Selectivity Index
We have executed the computation of Root Mean Square Deviation
(RMSD) which appraises resemblance flanked by two superimposed
atomic coordinates. The acquired plot of RMSD v/s simulation time of
COX-2 enzyme and compound 8l is embodied in Fig. 2, which suggested
that docking study was affirmative and our devised molecules man-
ifested significant affinity towards 5IKR _ligand.
mL)
8i
245.93 ± 1.36
104.24 ± 0.86
106.82 ± 1.16
435.26 ± 1.02
87.26 ± 3.52
506.80 ± 2.32
206.13 ± 2.62
576.87 ± 4.16
326.35 ± 1.53
283.58 ± 2.16
145.18 ± 1.08
245.32 ± 0.96
186.34 ± 1.21
19.95 ± 0.91
32.93 ± 1.35
24.59 ± 1.21
12.82 ± 0.98
23.74 ± 1.61
25.02 ± 1.14
54.42 ± 0.86
44.54 ± 2.10
17.70 ± 1.76
11.35 ± 1.52
13.67 ± 2.72
13.23 ± 1.04
25.21 ± 1.16
12.32
3.16
8j
8k
4.34
8l
33.95
3.67
8m
8n
20.25
3.78
8o
In vitro anti-inflammatory assay
8p
12.95
18.43
24.98
10.62
18.54
7.39
8q
8r
The synthesized molecules were evaluated for in vitro COX-1 and
COX-2 inhibition. The results obtained in the form of IC50 and are
tabulated in Table 3. All the compounds were active as COX-1 and COX-
2 inhibitors. It is evident from the obtained data that the synthesized
compounds are more selective as COX-2 inhibitors than COX-1 in cor-
relation with the docking studies, which revealed the title compounds
prompted better uniformity towards COX-2 than COX-1. The compounds
possessing halo substituent exhibited the most potent and discerning
inhibition of COX-2. The compounds 8i (methyl at C6 position of the
coumarin), 8l (benzo at C7,8 position of the coumarin), 8q (Cl at C5
position of benzoxazole and benzo at C5,6 position of the coumarin), 8r
(Cl at C5 position of benzoxazole and benzo at C7,8 position of the
coumarin), 8s (Cl at C5 position of benzoxazole and methyl at C7 posi-
tion of the coumarin) and 8t (Cl at C5 position of benzoxazole and
methyl at C5,7 position of the coumarin) emerged as most potent and
selective COX-2 inhibitors with IC50 values of 19.95, 12.82, 17.70,
11.35, 13.67 and 13.23 µg/mL respectively (Fig. 3). The selectivity
index of 8l, 8n and 8r was found to be 33.95, 20.25 and 24.98 respec-
tively, manifested their high selectivity against COX-2. Overall, this
study paves a way for the development of 2,5-substituted 1,3,4-oxa-
diazoles as potent and selective COX-2 inhibitors.
8s
8t
Mefenamic acid
COX-1 and COX-2 selectivity and their binding approaches. The com-
pounds were comprised in hydrogen bonding interactions with the hy-
droxyl group of SER530 which have been reported to play a vital part in
the inhibition of COX-2 enzyme.
The biological outcomes were well supported by the consequences of
the computational study where the docked compounds were instituted
to reinforce the examined inhibitory results. This suggests that the
compounds are originated to have elevated resemblance towards COX-2
enzyme than COX-1 thus exhibiting utmost selectivity towards COX-2.
The docking study divulged that compound 8l acts as good inhibitor
of cyclooxygenase 2 enzyme. As portrayed in Fig. 1, compound 8l
fabricated five hydrogen bonding interactions at the dynamic location of
the enzyme (PDB ID: 5IKR; A-Chain) out of which nitrogen atom present
on the 3rd position of oxadiazole ring frames two bonding interactions
with hydrogen atoms of ARG120 (-N—— H-ARG120, 2.09 Å; 1.75 Å),
the nitrogen atom present on the 4th position of oxadiazole ring makes
two interactions with hydrogen atoms of ARG120 (-N—— H-ARG120,
2.23 Å; 2.76 Å) and oxygen atom present on the 2nd position of chro-
mene ring forms an interaction with hydrogen atom of SER530 (-O——
H-SER530, 2.55 Å).
In vitro anti-oxidant assay
The reactive oxygen species play conclusive role in inflammatory
provisions. Oxidative stress is essential for gastrointestinal ulceration.
The compounds possessing antioxidant activity besides anti-
inflammatory activity may offer a feasible direction to more secure
anti-inflammatory agents.22
The consensus score acquired in the range 4.17–9.51 implied that
docking study was optimistic and the devised molecules manifested
substantial affinity towards 5IKR_ligand. The docked poses revealed that
the studied compounds have demonstrated the same kind of interaction
with amino acid residue (SER530) as that of 5IKR_ligand. Eventually, we
conclude that synthesized molecules preferentially bind to enzyme in
comparison to the 5IKR_ligand (Table 2) which substantiates the
observed preferential in vitro COX-2 inhibition. The interaction of all the
Antioxidants that evince DPPH radical scavenging activity is pro-
gressively accepting consideration as they have been reported to
encompass interesting anticancer, anti-ageing and anti-inflammatory
activities. Accordingly, compounds with antioxidant property could be
5

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
and selective inhibition of COX-2. The compounds 8i, 8l, 8q, 8r, 8s and
8t emerged as most potent and selective COX-2 inhibitors with IC50
values of 19.95, 12.82, 17.70, 11.35, 13.67 and 13.23 µg/mL respec-
tively. The selectivity index demonstrated their high selectivity against
COX-2. The antioxidant assets of the synthesized compounds were
evaluated using the 1,1-diphenyl-2-picrylhydrazyl, DPPH, free radical
scavenging assay. The compounds which were active as COX-2 in-
hibitors were also active as antioxidant agents. Overall the study sets a
trend for the advancement of 2,5-substituted-1,3,4-oxadiazoles as latent
and selective COX-2 inhibitors.
Table 4
Antioxidant activity of the compounds 8i-t.
Compounds
IC50 (µg/mL)
Correlation coefficient
8i
24.04
63.09
45.86
23.71
49.87
33.47
48.69
52.85
26.78
23.95
27.73
26.98
25.74
0.989
0.995
0.986
0.996
0.995
0.978
0.989
0.978
0.990
0.995
0.992
0.996
0.989
8j
8k
8l
8m
8n
8o
8p
8q
8r
Declaration of Competing Interest
8s
8t
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Ascorbic acid
*Correlation is significant at 0.010 level.
Acknowledgements
The authors are obliged to DST-PURSE Phase-II, SAIF, University
Scientific Instrumentation Center (USIC), Karnatak University, Dharwad
and Institution of Excellence, University of Mysore, Mysuru, India for
providing the spectral data and facilities to conduct the experiments.
The authors acknowledge the NGH College of Dental Sciences and
Research Centre Belgaum, Karnataka, India for anti-tubercular activity.
One of the authors (ARN) is grateful to DST-KSTePS, Govt. of Karnataka
for providing the Fellowship.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.bmcl.2021.128112.
References
Fig. 4. Radical scavenging (%) of compounds 8i-t at different concentrations.
*AA-Ascorbic acid.
1 Kontogiorgis CA, Hadjipavlou-Litina DJ. Synthesis and anti-inflammatory activity of
coumarin derivatives. J Med Chem. 2005;48:6400–6408. https://doi.org/10.1021/
jm0580149.
anticipated to offer assurance in rheumatoid arthritis and inflammation
and to lead to possibly viable drugs. Indeed, numerous non-steroidal
anti-inflammatory drugs have been accounted to operate either as in-
hibitors of free radical fabrication or as radical scavengers.23 The
reducing abilities of the compounds 8i-t were assessed using DPPH free
radical scavenging assay in an iron free system. The scavenging activ-
ities of the compounds were determined and compared with standard
ascorbic acid. IC50 value is an essential parameter to evaluate the po-
2 Raju GN, SwathiSree KN, Padma K, Sravani Y, Rao NR. Recent advance in analgesic
and anti-inflammatory activity of oxadiazole derivatives. Asian J Pharm Analysis and
Med Chem. 2015;3:20–30.
3 Grover J, Bhatt N, Kumar V, et al. 2,5-Diaryl-1,3,4-oxadiazoles as selective COX-2
inhibitors and anti-inflammatory agents. RSC Adv. 2015;5:45535–45544. https://
doi.org/10.1039/C5RA01428J.
4 Cannon CP, Cannon PJ. COX-2 inhibitors and cardiovascular risk. Science. 2012;336:
1386–1387. https://doi.org/10.1126/science.1224398.
5 Arora RK, Kaur N, Bansal Y, Bansal G. Novel coumarin-benzimidazole derivatives as
antioxidants and safer anti-inflammatory agents. Acta Pharm Sin B. 2014;4:368–375.
https://doi.org/10.1016/j.apsb.2014.07.001.
tency. The IC50 value existing between 10–50, 50–100, and >100 μg/mL
signifies strong, moderate and poor antioxidant activity respectively.24
The obtained radical scavenging activity results as exemplified in
Table 4 manifested that compounds 8i, 8l, 8q, 8r, 8s and 8t with the
substituents like halogen, alkyl and aryl groups are possessing very good
antioxidant activity with IC50 values of 24.04, 23.71, 26.78, 23.95,
27.73 and 26.98 µg/mL respectively in comparison to ascorbic acid with
an IC50 value of 25.74 µg/mL (Fig. 4). Accordingly, we can conclude
from the acquired IC50 values and correlation coefficient that all the
compounds exhibit strong antioxidant activity except 8j and 8p with
moderate activity.
6 Bala S, Kamboj S, Saini V, Prasad DN. Anti-inflammatory, analgesic evaluation and
molecular docking studies of N-phenyl anthranilic acid-based 1,3,4-oxadiazole
analogues. J Chem. 2013;2013:1–6. https://doi.org/10.1155/2013/412053.
7 Nampurath G, Durgashivaprasad E, Mathew G, Sebastian S, Reddy SAM, Mudgal J.
Novel 2,5-disubstituted-1,3,4-oxadiazoles as anti-inflammatory drugs. Indian J
Pharmacol. 2014;46:521. https://doi.org/10.4103/0253-7613.140584.
8 Jin L, Zhang B, Hua S, et al. Glycyrrhetinic acid derivatives containing
aminophosphonate ester species as multidrug resistance reversers that block the NF-
κB pathway and cell proliferation. Bioorg Med Chem Lett. 2018;28:3700–3707.
https://doi.org/10.1016/j.bmcl.2018.10.025.
9 Zhang B, Hu XT, Gu J, Yang YS, Duan YT, Zhu HL. Discovery of novel sulfonamide-
containing aminophosphonate derivatives as selective COX-2 inhibitors and anti-
tumor candidates. Bioorg Chem. 2020;105, 104390. https://doi.org/10.1016/j.
bioorg.2020.104390.
Anti-inflammatory agents are useful in relieving pain in many con-
ditions, ranging from menstrual and postoperative pain to arthritic pain.
In view of this and to wrap up the present work and results, we conclude
a modest, proficient and green synthesis of novel coumarinyl-1,3,4-
oxadiazolyl-2-mercaptobenzoxazoles 8i-t. Docking studies exemplified
strong binding interactions with enzyme (PDB ID: 5IKR; A-Chain) by
means of high C-score values acquired in the range 4.17–9.51. The
biological outcomes as well as the computational study revealed that the
title compounds have more affinity of inhibition towards COX-2 enzyme
than COX-1. The compounds possessing halogen entity showed potent
10 Bostrom J, Hogner A, Llinas A, Wellner E, Plowright AT. Oxadiazoles in medicinal
chemistry. J Med Chem. 2012;55:1817–1830. https://doi.org/10.1021/jm2013248.
11 Husain A, Ahmad A, Alam MM, Ajmal M, Ahuja P. Fenbufen based 3-[5-(substituted
aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones as safer anti-
inflammatory and analgesic agents. Eur J Med Chem. 2009;44:3798–3804. https://
doi.org/10.1016/j.ejmech.2009.04.009.
12 Khanam R, Hejazi II, Shahabuddin S, Bhat AR, Athar F. Pharmacokinetic evaluation,
molecular docking and in vitro biological evaluation of 1, 3, 4-oxadiazole derivatives
as potent antioxidants and STAT3 inhibitors. J Pharm Anal. 2019;9:133–141. https://
doi.org/10.1016/j.jpha.2018.12.002.
6

A.R. Nesaragi et al.
Bioorganic & Medicinal Chemistry Letters 43 (2021) 128112
13 Mohana KN, Kumar CBP. Synthesis and antioxidant activity of 2-amino-5-methyl-
thiazol derivatives containing 1,3,4-oxadiazole-2-thiol moiety. ISRN Org Chem. 2013;
2013:1–8. https://doi.org/10.1155/2013/620718.
oesophagus and oesophageal adenocarcinoma. Gut. 2007;56:1512–1521. https://
doi.org/10.1136/gut.2007.121244.
20 Nesaragi AR, Kamble RR, Bayannavar PK, et al. Microwave assisted regioselective
synthesis of quinoline appended triazoles as potent anti-tubercular and antifungal
agents via copper (I) catalyzed cycloaddition. Bioorg Med Chem Lett. 2021;41:
127984–127994.
14 Kakkar S, Tahlan S, Lim SM, et al. Benzoxazole derivatives: design, synthesis and
biological evaluation. Chem Cent J. 2018;12:92. https://doi.org/10.1186/s13065-
018-0459-5.
15 Fylaktakidou K, Hadjipavlou-Litina D, Litinas K, Nicolaides D. Natural and synthetic
coumarin derivatives with anti-inflammatory/antioxidant activities. Curr Pharm Des.
2004;10:3813–3833. https://doi.org/10.2174/1381612043382710.
16 Rosskopf F, Kraus J, Franz G. Immunological and antitumor effects of coumarin and
some derivatives. Pharmazie. 1992;47:139–142.
21 Rayam P, Polkam N, Kuntala N, et al. Design and synthesis of oxaprozin-1,3,4-
oxadiazole hybrids as potential anticancer and antibacterial agents. J Heterocycl
Chem. 2020;57:1071–1082. https://doi.org/10.1002/jhet.3842.
22 Kuçukguzel S, Coskun I, Aydın S, et al. Synthesis and characterization of celecoxib
derivatives as possible anti-inflammatory, analgesic, antioxidant, anticancer and
anti-HCV agents. Molecules. 2013;18:3595–3614. https://doi.org/10.3390/
molecules18033595.
17 Koshihara Y, Neichi T, Murota S, Lao A, Fujimoto Y, Tatsuno T. Selective inhibition
of 5-lipoxygenase by natural compounds isolated from Chinese plants, Artemisia
rubripes Nakai. FEBS Lett. 1983;158:41–44. https://doi.org/10.1016/0014-5793(83)
80672-3.
23 Kovala-Demertzi D, Hadjipavlou-Litina D, Staninska M, Primikiri A, Kotoglou C,
Demertzis MA. Anti-oxidant, in vitro, in vivo anti-inflammatory activity and
antiproliferative activity of mefenamic acid and its metal complexes with manganese
(II), cobalt(II), nickel(II), copper(II) and zinc(II). J Enzyme Inhib Med Chem. 2009;24:
742–752. https://doi.org/10.1080/14756360802361589.
18 Yoshiyuki K, Hiromichi O, Shigeru A, Kimiye B, Mitsugi K. Inhibition of the
formation of 5-hydroxy-6,8,11,14-eicosatetraenoic acid from arachidonic acid in
polymorphonuclear leukocytes by various coumarins. Biochim Biophys Acta – Lipids
Lipid Metab. 1985;834:224–229. https://doi.org/10.1016/0005-2760(85)90159-6.
19 Song S, Guha S, Liu K, Buttar NS, Bresalier RS. COX-2 induction by unconjugated bile
acids involves reactive oxygen species-mediated signalling pathways in Barrett’s
24 Gasti T, Dixit S, Sataraddi SP, et al. Physicochemical and biological evaluation of
different extracts of edible Solanum nigrum L. leaves incorporated chitosan/poly
(vinyl alcohol) composite films. J Polym Environ. 2020;28:2918–2930. https://doi.
org/10.1007/s10924-020-01832-6.
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