Synthesis of novel of 2, 5-disubstituted 1, 3, 4- oxadiazole derivatives and their in vitro anti-inflammatory, anti-oxidant evaluation, and molecular docking study

Article abstract of DOI:10.1016/j.bmcl.2020.127136

A series of novel 2, 5-disubstituted 1, 3, 4-Oxadiazole derivatives as a potential anti-inflammatory, and anti-oxidant agent were synthesized via cyclisation. Hydrazide molecule treated with substituted acids in the presence of phosphorus oxychloride (POCl₃) as an efficient reagent as well as solvent by conventional method with shorter reaction time and excellent yield. The newly synthesized 1, 3, 4- oxadiazole derivatives exhibited excellent to good anti-inflammatory and anti-oxidant activities compaired to the standard drugs. Molecular docking study on the crucial anti-inflammatory target–cyclooxygenase-2 (COX-2) revealed the ability of the scaffold to correctly recognize the active site and achieve significant bonded and non-bonded interactions with key residues therein. This study could identify potential compounds which can be pertinent starting points for structure-based drug design to obtain newer anti-inflammatory agents.

Full text of DOI:10.1016/j.bmcl.2020.127136

Journal Pre-proofs
Synthesis of Novel of 2, 5-disubstituted 1, 3, 4- Oxadiazole derivatives and
their In Vitro anti-inflammatory, anti-oxidant evaluation, and Molecular
Docking Study
Bharat B. Kashid, Pravin H. Salunkhe, Balasaheb B. Dongare, Kishor R.
More, Vijay M. Khedkar, Anil A. Ghanwat
PII:
S0960-894X(20)30229-8
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127136
BMCL 127136
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
5 October 2019
17 March 2020
20 March 2020
Please cite this article as: Kashid, B.B., Salunkhe, P.H., Dongare, B.B., More, K.R., Khedkar, V.M., Ghanwat,
A.A., Synthesis of Novel of 2, 5-disubstituted 1, 3, 4- Oxadiazole derivatives and their In Vitro anti-
inflammatory, anti-oxidant evaluation, and Molecular Docking Study, Bioorganic & Medicinal Chemistry Letters
(2020), doi: https://doi.org/10.1016/j.bmcl.2020.127136
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Synthesis of Novel of 2, 5-disubstituted 1, 3, 4- Oxadiazole derivatives and their In Vitro anti-
inflammatory, anti-oxidant evaluation, and Molecular Docking Study
Keyuan Pharmaceutical Co. Ltd Keyuan Street, Shandong Shanghe
a
ab
a
c
Bharat B. Kashid , Pravin H. Salunkhe , Balasaheb B. Dongare , Kishor R. More
d
a,
Vijay M. Khedkar , Anil A. Ghanwat *
a
Chemistry Research Laboratory, School of Chemical Sciences, Solapur University,
Solapur, 413255, India.
b
CSIR- National Chemical laboratory, Dr. Homi Bhabha Road, Pune 411008, India
c
Shandong Economic Development Zone, Jinan, Shandong, China.
d
Department of Pharmaceutical Chemistry, Shri Vile Parle Kelavani Mandal's Institute of Pharmacy,
Mumbai - Agra National Hwy, Dhule, Maharashtra 424001, India.
Email:anil_ghanwat@yahoo.com, bharatkasid@gmail.com
ABSTRACT
A series of novel 2, 5-disubstituted 1, 3, 4- Oxadiazole derivatives as a potential anti-inflammatory, and
anti-oxidant agent were synthesized via cyclisation. Hydrazide molecule treated with substituted acids
in the presence of phosphorus oxychloride (POCl ) as an efficient reagent as well as solvent by
3
conventional method with shorter reaction time and excellent yield. The newly synthesized 1, 3, 4-
oxadiazole derivatives exhibited excellent to good anti-inflammatory and anti-oxidant activities
compaired to the standard drugs. Molecular docking study on the crucial anti-inflammatory target–
cyclooxygenase-2 (COX-2) revealed the ability of the scaffold to correctly recognize the active site and
achieve significant bonded and non-bonded interactions with key residues therein. This study could
identify potential compounds which can be pertinent starting points for structure-based drug design to
obtain newer anti-inflammatory agents.
Keywords: 1, 3, 4- Oxadiazole, anti-inflammatory, anti-oxidant, Biological activity, Computational
Chemistry.
Compounds containing heterocyclic ring systems are of great importance both medicinally and
industrially. During the last few decades, biological activities, synthesis and transformations of five
membered heterocyclic compounds have received considerable attention and importance due to their
remarkable and wide variety of applications. Oxadiazole are frequently occurring motifs in drug like
molecules. Due to their remarkable unique properties and have been frequently employed in drug
synthesis such as including raltegravir, butalamine, fasiplon, oxolamine, and pleconaril.
Substituted oxadiazole and its derivatives constitute an important family of heterocyclic compounds
with biological and pharmacological properties like antibacterial , fungicidal , antimicrobial10-13,
1
-6
7-9
anti-inflammatory14,15, anticonvulsant16,17, anticancer18,19, antimalerial , and antidepressant . They
20
21
have also attracted interest in medicinal chemistry as surrogates (bioisosteres) for carboxylic acids,

2
2
esters and carboxamides . The therapeutic importance of these compounds prompted us to develop
selective molecules in which the substituent could be arranged in a pharmacophore pattern to display
higher pharmacological activities. In view of these observations and our continued interest in the
2
3
synthesis of biologically active heterocyclic compounds . Two examples of compounds containing the
, 3, 4-oxadiazole unit currently used in clinical medicine are: Raltegravir an antiretroviral drug and
1
Zibotentan an anticancer agent.
N
O
N
OH
F
S NH
O
N
O
CH3
N N
O
H
H
N
N
N
O
N
N
N
O
O
O
CH3
Raltegravir: antiretroviral
Zibotentan: anticancer
Structures of the API molecules with oxadiazole moieties
There are limited methodology exists for the synthesis of 1, 3, 4- oxadiazoles. A few one pot
methods have been reported as the use of acetohydrazides or its derivative, as a source of two
2
4
contiguous nitrogen atoms, and a variety of cyclizing agents . Typically, the reaction is promoted by
heat and anhydrous reagents including thionyl chloride , phosphorous pentoxide26,
2
5
2
7
28
29
triphenylphoshine , triflic anhydride , and phosphorous oxychloride . Alternative synthetic methods
3
0
comprise reaction of aceto hydrazides with keteneylidene triphenylphosphorane or base promoted
3
1
cyclization reaction of trichloroacetic acid hydrazones .
Compound 6 (Scheme I) obtained by esterification, rearrangement, acylation, cyclization,
hydrolyzation32-33, followed by hydrogenation with an overall low yield. Reported conditions were not
suitable for industrial application. Compound 3 synthesised by one pot Friedel Craft acetylation
followed by Fries rearrangement from 4-fluoro phenol 1. Base catalysed Claisen condensation of
diethyl oxalate of 3 followed by acid catalyed cyclisation to afford 5 in situ. Compound 7 obtained by
hydrogenation of compound 5 using Pd/C in acetic acid followed by esterification using H SO in
34
2
4
methanol. Compound 8 hydrazides obtained by hydrazinolysis of ester. Compound 8 was the key
materials for the synthesis of 2, 5 disubstituted 1, 3, 4 oxadiazole by refluxing in POCl with substituted
3
aromatic carboxylic acid derivatives to afford final products BK-12 to BK-23 with overall moderate
yield. Present process is mild, economic and industrially feasible using cheap raw materials. The effect
of different dehydrating agents were disclosed in Table 1 with respective to reaction time and yield
studied for BK-12 (Scheme II). Structures of final BK-12 to BK-23 disclosed in Table 2 with
corresponding aromatic acids.

Scheme I: Schematic representation of route of synthesis of 2, 5-disubstituted 1, 3, 4
oxadiazole.
O
F
a
F
F
b
O
OH
O
OH
1
2 IN SITU
3
c
O
O
O
O
F
e
d
F
O
OH
O
OH
O
5
4 IN SITU
F
f
F
g
OH
O
O
O
O
O
6
7
R1
F
F
h
H
O
N NH
O
2
O
N N
8
O
1
BK-12 to BK-23 R = Substitution like, H, F, Cl, -NH2, -NO2, -OMe...etc
Reagents and conditions: a= Acetyl chloride, 40-45°C, b= AlCl /H O/HCl, 140-
3
2
1
8
45°C, methanol, c= Diethyl oxalate, Methanol, NaOMe, 65-70°C, d= HCl, water,
5-90°C, e= H Pd/C, Acetic Acid, 75-80°C, f= Methanol, H SO , reflux,
2
2
4
g= Hydrazine hydrate, ethanol reflux, h= Substituted Aromatic acids, POCl reflux.
3
,
Scheme II: Synthesis of 2, 5-disubstituted 1, 3, 4 oxadiazole BK-12.
F
O
F
N
N
F
F
H
OH
N NH2
N
N N
F
O
O
O
N
O
N N
POCl3
Reflux
F
8
BK-12

Table 1: Screening of different dehydrating agents and their effect on reaction time and
yield for synthesis of BK-12 (Scheme II).
Cyclizing / Dehydrating Agents Reaction time
in hrs
% Yield
for BK-12
Thionyl chloride
13 hrs
18 hrs
20 hrs
15 hrs
18 hrs
6 hrs
41
33
---
45
48
85
Phosphorus pentoxide
Triphenylphoshine
Triflic anhydride
Polyphosphoric acid
Phosphorus oxychloride
Table-2 Synthesized compounds of 2, 5-disubstituted 1, 3, 4-oxadiazole
Aromatic Acid R’
Product
F
O
F
F
N N
N
O
OH
N N
O
N
F
N
N
F
BK-12
O
F
F
F
F
F
F
F
F
OH
O
O
N N
F
BK-13
O
F
F
OH
O
O
O
O
N
N
F
BK-14
O
O
F
F
O
O
O
O
OH
N N
F
O
BK-15

O
OCH3
OCH3
F
H CO
3
OH
O
O
H CO
3
OCH3
N N
OCH3
BK-16
O
F
NO2
OH
O
O
O N
2
N N
BK-17
O
F
OH
O
O
N N
BK-18
O
O
F
Cl
OH
O
N N
O
Cl
Cl
BK-19
BK-20
F
OH
O
O
Cl
N N
Cl
O
O
F
Cl
OH
OH
O
O
N N
BK-21
F
N
N
O
N
O
N
N N
BK-22

O
F
NH2
OH
O
O
H N
2
N N
BK-23
Table 3. In vitro Anti-oxidant and anti-inflammatory activities result of compounds
BK-12 to BK-23 in tabular form.
Test Samples
Anti-oxidant
Anti-
inflammatory
IC50/μM
------
------
90.21 ± 0.77
DPPH
IC /μM
Nitric oxide
IC /μM
5
0
50
Control
Ascorbic acid
Diclofenac
sodium
BK-12
------
44.18 ± 0.78
------
------
42.63 ±0.64
------
23.07 ±0.27
28.99 ±0.68
28.99 ±0.79
34.91 ±0.81
43.19 ±0.95
28.69 ±0.63
28.69 ±0.70
17.15 ±0.12
40.82 ±0.50
23.07 ±0.61
73.37 ±0.80
34.91 ±089
88.04 ±0.71
85.86 ±0.21
86.95 ±0.34
73.91 ±0.45
86.95 ±0.61
84.78 ±0.24
85.86 ±0.77
85.86 ±0.85
88.04 ±0.66
84.78 ±0.68
86.95 ±0.72
89.13 ±0.70
86.23 ±0.91
99.82 ±0.94
74.31 ±0.74
56.70 ±0.31
62.21 ±0.59
78.72 ±0.85
72.30 ±0.94
90.65 ±0.88
58.54 ±0.26
69.55 ±0.70
73.22 ±0.63
45.69 ±0.37
BK-13
BK-14
BK-15
BK-16
BK-17
BK-18
BK-19
BK-20
BK-21
BK-22
BK-23
Compounds in bold blue shade showing excellent activities. All the compounds
having error bars in the range of IC /μM ( ± 0.10 to 0.95)
5
0
Chart-1: anti-oxidant and anti-inflammatory activities result of compounds
BK-12 to BK-23.
Antioxidant screening results

The results of the antioxidant activity screening of the tested compound for DPPH (2, 2-
diphenyl-1-picrylhydrazyl) and Nitric oxide radical scavenging activities were also
summarized in Table 3 and Chart 1. All the newly synthesized compounds BK-12 to BK-23
shows good to moderate antioxidant activity as compared to the standard drug Ascorbic acid
(
Table 3). According to the DPPH assay analysed in triplicate, compounds with IC values
50
of BK-19 (17.5), BK-12 (23.07), BK-21 (23.07), BK-17 (28.69), BK-18 (28.69), BK-13
28.99) and BK-14 (28.99) µM/mL respectively, exhibited promising radical scavenging
activities when compared with synthetic antioxidant ascorbic acid (IC = 44.18µM/mL).
(
5
0
From the synthesized compounds with IC values (17.5 to 28.99µM/mL) showed the best
5
0
DPPH radical scavenging activity, while compound BK-22 showed the lowest activity when
compared with ascorbic acid. From the IC data it is clear that presence of 4-chloro benzene
5
0
at 5 position of oxadiazole exhibit better activity as compaired to 2- chloro (BK-20) and 3-
chloro (BK-21) substituent and also hybrid molecule like BK-12 are excellent potent as
compaired to others for DPPH radical scavenging activity.
All the compounds BK-12 to BK-23 are showing very poor antioxidant activity for
Nitric oxide radical scavenging activity compared to reference standard drug ascorbic acid.
Anti inflammatory screening results
The results of the anti-inflammatory activity screening of the tested compound
were also summarized in Table 3 and Chart 1. 2, 5 di-substituted 1,3,4-oxadiaxole
derivatives BK-12 to BK-23 shows good to moderate anti-inflammatory as compared to the
standard drug diclofenac sodium. According to the anti-inflammatory activities data analysed
in triplicate, compounds with IC50 values of BK-23 (45.69), BK-15 (50.54), and BK-20
(56.70) µM/mL respectively, are exhibited promising anti-inflammatory activities when
compared with synthetic antioxidant diclofenac sodium (IC50 = 90.21µM/mL). From the
synthesized compounds BK-23, BK-15 and BK-20 showed the best anti-inflammatory
activity, while all the other compounds are showing comparable results to the standard drug
diclofenac sodium.
Molecular Docking
Promising level of anti-inflammatroy activity demonstrated by the 2, 5-disubstituted 1, 3, 4-
oxadiazole derivatives discussed herein motivated us to elucidate the plausible mechanism by
which they can exert the anti-inflammatroy activity. Furthermore to rationalize the obtained
biological potency and establish an SAR based on these molecular docking study against the
well known targets in the anti-inflammatory therapy i.e cyclooxygenase-2 (COX-2). COX-2

is an oxido-reductase having a role in prostaglandin biosynthesis and is a key mediator of
inflammatory pathways owing to which it has gained special focus on anti-inflammatory
research since past few decades. An isoform of COX family, COX-2 is highly inducible in
response to proinflammatory stimuli, cytokines and consequential in exaggerated
prostaglandin release. In the absence of available resources to carry out target-based assays,
molecular docking has gained significant importance to identify the targets for ligands and
the associated thermodynamic interactions that govern the moduclation of the target.
Molecular docking study showed that all the 2, 5-disubstituted 1, 3, 4- oxadiazole
derivatives could snuggly fit in the active site cavity of COX-2 occupying energetically
favourable position at the co-ordinates close to the co-crystallized ligand. They produced
good to moderate binding affinities with docking scores ranging from -9.692 (glide binding
energy of -45.531 Kcal/mol) for the active compound BK-13 to -7.007 (glide energy -22.757
Kcal/mol) for a moderately active BK-23 with an average docking score of -8.063 (glide
energy -33.293 Kcal/mol) (Table 4 in SI). These binding affinity scores co-related well with
the experimentally observed anti-inflammatory activity. Furthermore to gain a deeper insight
into binding modes and nature of thermodynamic interactions influencing the anchoring of
these molecules into the target, a per-residue interaction analysis was carried out which is
elaborated in next section for the most active compound BK-13 and is summarized for others
in (Table 4 in SI).
The lowest energy docked conformation of BK-13 showed that the molecule is deeply
embedded into the active site of COX-2 (Figure 1) producing docking score of -9.692 (Glide
energy -45.531 Kcal/mol) which is attributed to a set of close bonded (H-bonding) and non-
bonded (steric and electrostatic) interactions with residues lining the active site.
Quantification of per-residue interactions showed that the molecule is engaged in an
extensive network of significant van der Waals interactions with Glu524 (-2.983 Kcal/mol),
Val523 (-2.985 Kcal/mol), Arg513 (-2.884 Kcal/mol), Leu359 (-2.879 Kcal/mol), Tyr355 (-
2
.913 Kcal/mol), Ser353 (-2.979 Kcal/mol), Tyr348 (-2.991 Kcal/mol), Arg120 (-2.957
Kcal/mol), Leu117 (-2.996 Kcal/mol), Val116 (-2.966 Kcal/mol), Val89 (-2.972 Kcal/mol)
through the 5-(2,3,4,5-tetrafluorophenyl)-1, 3, 4-oxadiazole component while the 6-fluoro-
3
2
,4-dihydro-2H-chromene component showed a similar type of interactions with Leu534 (-
.999 Kcal/mol), Leu531 (-2.988 Kcal/mol), Ser530 (-2.879 Kcal/mol), Ala527 (-4.379
Kcal/mol), Gly526 (-2.992 Kcal/mol), Met522 (-2.892 Kcal/mol), Phe518 (-2.980 Kcal/mol),
Trp387 (-2.911 Kcal/mol), Tyr385 (-2.909 Kcal/mol), Phe381 (-3.906 Kcal/mol), Leu352 (-

2
.969 Kcal/mol), Val349 (-2.995 Kcal/mol). The enhanced binding affinity of BK-13 is also
attributed to signifcant coloumbic inerations with Glu524 (-2.956 Kcal/mol), Val523 (-2.944
Kcal/mol), Met522 (-2.963 Kcal/mol), Arg513 (-2.991 Kcal/mol), Tyr355 (-2.987 Kcal/mol),
Ser353 (-2.936 Kcal/mol), Arg120 (-2.925 Kcal/mol) and His90 (-2.961 Kcal/mol) residues
of the active site. Such a balanced network of steric and van der Waals interactions were
observed for other molecules in the series as well (Table 4 and Figure 1S-S11 in SI). The
compound BK-13 was further stabilized into the active site of COX-2 through hydrogen bond
between the oxygen of chromene ring and Ser530 (2.55Å) and a very close pi-pi stacking
interactions with Tyr385 (2.618Å), which serve as "anchor" guiding the ligand into the active
site of the target and compliment the steric and electrostatic interactions.
Figure 1: Binding mode of compound BK-13 into the active site of cyclooxygenase 2 (COX-
2
) (on right side: green lines indicate π-π stacking interactions while the pink lines signify the
hydrogen bonding interactions)
Overall the per-residue ligand interaction analysis suggests that steric complementarities
along with electrostatic interactions with the residues lining active site of COX-2 contribute
significantly to the mechanical interlocking of these molecules which could be fruitfully
utilized to optimize these leads for obtaining tight binding candidates with high selectivity
and specificity.
In silico ADME properties
The success of a drug is determined by good efficacy and acceptable ADME (absorption,
distribution, metabolism and excretion) profile. In the present study, drug-likeness model
score (a collective property of physic-chemical properties, pharmacokinetics and
pharmacodynamics of a compound is represented by a numerical value) was computed by
3
5
MolSoft software . A computational study of all the synthesized compounds was performed

for prediction of ADME properties and the value obtained is presented in Table 5. Absorption
3
6
(
% ABS) was calculated by: % ABS= 109-(0.345×TPSA) . It is observed that compounds
exhibited a good % ABS (% absorption) ranging from 76.58 to 92.39%. Furthermore, none of
the synthesized compounds BK-12 to BK-23 violated Lipinski’s rule of five (miLog P ≤ 5).
A molecule likely to be developed as an orally active drug candidate should not show more
than one violation of the following four criteria: miLog P (octanol-water partition coefficient)
≤
5, molecular weight ≤ 500, number of hydrogen bond acceptors ≤ 10 and number of
3
7
hydrogen bond donors ≤ 5 .
The larger the value of the drug likeness model score, the higher is also probability
that the particular molecule will be active. All the tested compounds BK-12 to BK-23
followed the criteria for orally active drug (Table 5) and therefore, these compounds may
have a good potential for eventual development as oral agents.
Table 5. Pharmacokinetic parameters important for good oral bio-availability and drug
likeness model score of the synthesized compounds BK-12 to BK-23.
Drug
Lipinski likeness
TPS
n-
RO
n-
OH
NH
%
ABS
miLog n-
Entry
A
MV
MW
P
ON
violation
model
score
2
(
A ) TB
Rule
-
-
-
-
<500
≤5
<10 <5
≤1
BK-12 81.79 78.88
BK-13 92.39 48.16
4
328.75 413.36
3.27
7
0
0
0
.78
2
2
2
5
3
2
2
2
2
2
2
273.35 368.26
307.13 370.36
303.10 382.32
330.26 386.38
276.95 341.30
253.62 296.30
267.16 330.75
267.16 330.75
267.16 330.75
245.31 298.28
264.91 311.32
4.09
3.57
2.82
3.28
3.61
3.65
4.33
4.30
4.28
1.82
2.73
4
5
6
7
7
4
4
4
4
6
5
0
0
0
0
0
0
0
0
0
0
2
0
0
0
0
0
0
0
0
0
0
0
-0.05
0.16
1.12
0.31
0.16
0.32
0.36
0.19
0.53
0.53
0.32
BK-14
89.2 57.39
BK-15 81.97 78.37
BK-16 82.83 75.86
BK-17 76.58 93.98
BK-18 92.39 48.16
BK-19 92.39 48.16
BK-20 92.39 48.16
BK-21 92.39 48.16
BK-22
83.5 73.94
BK-23 83.41 74.18
%
ABS: percentage absorption, TPSA: topological polar surface area, n-ROTB: number of

rotatable bonds, MV: molecular volume, MW: molecular weight, milogP: logarithm of partition
coefficient of compound between n-octanol and water, n-ON acceptors: number of hydrogen
bond acceptors, n-OHNH donors: number of hydrogen bonds donors.
The preliminary In vitro anti-oxidant, and anti-inflammatory screening results of novel 2,
5
di-substituted 1, 3, 4-oxadiaxole derivatives BK-12 to BK-23 reported here have emerged
as highly potent anti-oxidant agents for DPPH, and very poor for Nitric oxide radical
scavenging activity.The possible improvements in the activity can be further slight
modifications in the substituents on the basic, 2, 5 di-substituted 1, 3, 4-oxadiaxole nucleus.
The hybrid molecule like BK-12 having both moieties oxadiazole and triazole has very good
activity and also compound BK-13 shows highly increased activity may be due to tetra fluro
substitution on aromatic ring as compared to other substituent on aromatic ring which are
present on novel 2, 5 di-substituted 1, 3, 4-oxadiaxole derivatives. All the other compounds
showing very poor to comparable results for anti-oxidant, and anti-inflammatory activities as
compared to the standard drug. Moreover, the molecular docking study showed that all the
compounds bonded well with good binding energies to COX-2 enzyme qualifying the
scaffold as a pertinent starting point for structure based drug design to for the development of
new series of derivatives with potent anti-inflammatory activity.
Acknowledgement
Authors are gratefully acknowledge the Director school of chemical sciences, Co-ordinator
Instrument Centre, Punyashlok Ahilyadevi Holkar, Solapur University Solapur and thankful
for their kind co-operation, inspiration, encouragement and constant support to complete this
work. Authors also thank Schrödinger Inc. for Small-Molecule Drug Discovery Suite (2018)
to carry out the molecular docking studies.
Supporting Data
Experimental procedure, characterisation data, spectral reports along with docking study table
4
and figures S1-S11 are provided in supporting information file.
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Declaration of interests
[
2
☐
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.
☐
The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
There are no known competing financial interests or personal relationships which may influence
the work reported in this paper.
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Graphical Abstract

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