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org/journal/acsodf Article

Conventional and Microwave-Assisted Synthesis, Antitubercular

Activity, and Molecular Docking Studies of Pyrazole and Oxadiazole
Hybrids
Nisheeth C. Desai,* Kandarp Bhatt, Jahnvi Monapara, Unnat Pandit, and Vijay M. Khedkar
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ABSTRACT: Microwave-assisted organic reaction enhancement (MORE)

has become more important in synthetic organic chemistry for efficient
resource utilization. In this study, we synthesized bioactive compounds
Downloaded via 175.100.128.2 on March 10, 2022 at 05:49:41 (UTC).

using both traditional and microwave methods. Microwave-assisted

synthesis takes less time and produces higher yields and quality than
conventional approaches. We reported the synthesis of N′-(1-(2-(3-(4-
chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-
yl)ethylidene) substituted hydrazides (4a−t). We also tested them against
two strains: M. tuberculosis H37Ra and M. bovis BCG. Against M. tuberculosis
H37Ra, the compounds 4e, 4h, 4k, 4p, and 4s were the most effective.
Compounds 4f, 4g, and 4s showed significant activity against M. bovis BCG.
The structures of newly synthesized molecules were determined using
spectral methods. Furthermore, molecular docking investigations into the
active site of mycobacterial InhA yielded well-clustered solutions for these
compounds’ binding modalities producing a binding affinity in the range of −10.366 to −8.037. Theoretical results were in good
accord with the observed experimental values. The docking score of compound 4e was −10.366, and the Glide energy was −66.459
kcal/mol.

■ INTRODUCTION
In the recent past, 10 million new cases of tuberculosis were
reported worldwide.1 Despite the fact that medications to treat
tuberculosis are available in the market, bacteria started
developing resistance toward drugs like isoniazid and
rifampicin. Due to this, there is a continuous need to search
for improved medicines. Pyrazole is an interesting heterocycle
to investigate. It has also gotten a lot of interest because it is
being studied for a broad-spectrum biological property.2−14
The 1,3,4-oxadiazole is being studied because of its potentially
relevant pharmacological activity.15−26
To improve antitubercular activity, an efficient synthetic
protocol for combining the pyrazole moiety with oxadiazole
has been established. Figure 1 depicts commercially accessible
pharmaceuticals with pyrazole and 1,3,4-oxadiazole motifs. We
present the synthesis of certain novel structural hybrids of
pyrazole and 1,3,4-oxadiazole pharmacophores in a single
molecular framework to investigate their antitubercular efficacy
in vitro. Scheme 1 depicts the traditional and microwave-
assisted synthesis pathways for named compounds.
Microwave-assisted organic reaction enhancement (MORE)
has gained popularity because microwave-assisted procedures
offer the advantage of maximizing resource utilization and
providing a pure product with fewer undesirable side
© 2021 The Authors. Published by
American Chemical Society
28270
products.27 Microwave-assisted synthesis takes less time and
produces higher yields of derivatives.
Strategically constructed innovative antitubercular drugs can
exemplify two or more active scaffolds to create a single
molecule with improved biological potency in the hybrid
strategy to integrate physiologically active heterocycles. The
novel pyrazole and oxadiazole hybrids described in this paper
could be a valuable addition for the development of new
antitubercular agents with a novel mechanism of action. We
created scaffolds 4a−t by incorporating the pharmacophore
feature of thioacetazone (antitubercular antibiotic), furamizole
(antibiotic), and lonazolac (anti-inflammatory) in pursuit of
novel heterocycles with potency to deal with tuberculosis
resistance. The structure−activity relationship (SAR) of the
various pharmacophores was taken into account when
designing the molecule (Figure 1). By changing the side
chain of thioacetazone and altering the dihydrooxadiazole ring
of furamizole, the novel scaffolds 4a−t were created. The
Received: August 15, 2021
Accepted: September 24, 2021
Published: October 11, 2021
https://doi.org/10.1021/acsomega.1c04411
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Figure 1. Design concept based on commercially available drugs comprising the heterocycles pyrazole and oxadiazole.

Scheme 1. Synthetic Pathway of Titled Compounds 4a-t

inclusion of an active pharmacophore was linked to the
introduction of a 1,3,4-substituted pyrazole ring from
lonazolac. The phenyl ring of thioacetazone was replaced by
a five-membered heterocyclic ring (dihydro-1,3,4-oxadiazole),
and the side chain of thioacetazone was terminated by
28271
substituted phenyl rings containing distinct electron-donating
and electron-withdrawing groups.
We have reported several 1-(2-(1H-indol-3-yl)-5-(pyridin-4-
yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(aryl)prop-2-en-1-ones28 and
investigated their antitubercular efficacy in vitro. The results
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Figure 2. Comparison and structural modifications in our previous study based on oxadiazole hybrids with the reported work.
revealed that the compounds tested have antitubercular
activity. The antitubercular potency of 1-(2-(1H-indol-3-yl)-
5-(pyridin-4-yl)-1,3,4-oxadiazol-3(2H)-yl)-3-(2-nitrophenyl)-
prop-2-en-1-one with MIC and IC50 values against M. bovis
BCG in the active state was 1.03 and 0.48 μg/mL, respectively,
among the studied substances. The active molecule had a
docking score of −8.267 and a Glide energy of −54.856 kcal/
mol when it docked into the active site of the mycobacterial
enoyl reductase (InhA) enzyme. These findings piqued our
interest in developing new hybrids based on the oxadiazole
pharmacophore. Herein, we reported the synthesis of N′-(1-(2-
(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-
1,3,4-oxadiazol-3(2H)-yl)ethylidene) substituted hydrazides
(4a−t) and in vitro antitubercular efficacy. The structural
changes, such as replacing the indole moiety with a substituted
pyrazole ring, increased the pharmacological potency. The
Schiff base linker was used to replace the chalcone linker
between the nitrophenyl ring and the oxadiazole ring. At three
different concentrations, the synthesized compounds showed
substantial inhibition. In the active state, compound 4e had
excellent antitubercular activity against M. tuberculosis H37Ra,
with MIC and IC50 values of 0.92 and 0.52 μg/mL,
respectively. The docking score of compound 4e was
−10.366, and the Glide energy was −66.459 kcal/mol. Figure
2 shows the structural alterations, as well as a comparative
study of activity and molecular docking research.
■
RESULTS AND DISCUSSION
Chemistry. The traditional and microwave-assisted syn-
thesis pathways for novel N′-(1-(2-(3-(4-chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene) substituted hydrazides (4a−t) are shown in
Scheme 1. The chalcone derivative, N′-(3-(4-chlorophenyl)-
28272
Article
1-phenyl-1H-pyrazole−4-carbaldehyde)benzohydrazide (2),
was prepared by dissolving 3-(4-chlorophenyl)-1-phenyl-1H-
pyrazole-4-carbaldehyde (1) and benzohydrazide in 1,4-
dioxane and refluxing for 4 h. The generation of chalcone
derivative (2) is explained by the nucleophilic attack of
nitrogen on the carbonyl carbon of aldehyde followed by
proton transfer, protonation, removal of water molecule, and
deprotonation. The intermediate 1-(2-(3-(4-chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethenone (3) is produced by refluxing the chalcone derivative
(2) in acetic anhydride at 140 °C for 5 h. A well-dissolved
mixture of intermediate (3), appropriate benzohydrazides, and
a pinch of anhydrous ZnCl2 in ethanol is refluxed for 7−9 h to
yield N′-(1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene) substituted hy-
drazides (4a−t). Microwave-assisted synthesis of the identical
compounds reduces reaction time from 7−9 h to 9−10 min,
resulting in a 79−92% improvement in product yield (see
Table 1). In the experimental part, the details of microwave
synthesis are described.
The final structures of N′-(1-(2-(3-(4-chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene) substituted hydrazides (4a−t) were confirmed by
different spectroscopic analysis data. Compound 4c exhibited a
distinct absorption band at 1691 cm−1, which corresponded to
the presence of a carbonyl group in the structure. The Schiff
base’s N−H stretching (secondary amide stretching) and O−
H stretching of the −OH group linked to the phenyl ring
caused different vibrations at 3367 and 3447 cm−1. The
aromatic ring’s C−H stretching and the −CHCH− group
produced vibrations at 3066 and 3024 cm−1, respectively. The
C−O−C stretching of the oxadiazole nucleus and C−Cl
stretching caused absorptions at 1232 and 747 cm−1. A singlet
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Table 1. Optimization of Reaction Conditions for the hydroxyl proton, respectively. The presence of the −CONH−
Conventional and Microwave Methods group in the molecule’s arrangement was demonstrated by a
singlet peak at 12.30 ppm.
conventional method microwave method
The methyl carbon of the methyl group produced a signal at
yield reaction time yield reaction time 12.9 ppm in 13C NMR, while the carbon connected to the
entry -R (%) (min) (%) (min)
−CH3 group produced a signal at 147.3 ppm. Two signals
4a -C6H5 77 420 92 10 appeared due to carbons of the oxadiazole ring at 157.6 and
4b -2-OH-C6H4 65 450 80 9 78.4 ppm, proving the presence of the oxadiazole ring, while
4c -3-OH-C6H4 69 450 83 8
three signals appeared due to carbons of the pyrazole ring at
4d -4-OH-C6H4 61 450 80 9
117.9, 123.1, and 149.4 ppm, proving the presence of the
4e -4-NO2-C6H4 58 420 79 8
pyrazole ring in the structure of compound 4c. At 163.7 ppm,
4f -3-CH3-C6H4 73 450 90 9
the carbonyl carbon of the amide group produced a distinct
4g -4-CH3-C6H4 71 450 90 8
signal. In mass spectra, m/z = 577.17 corresponds to the
4h -4-OCH3-C6H4 62 450 85 9
molecular weight suggested. The details of spectral information
4i -3-Cl-C6H4 68 480 88 10
are given in the Supplementary Information.
4j -4-Cl-C6H4 74 480 92 10
4k -CH2-C6H5 57 450 79 9
Biological Evaluation. Antimycobacterial Activity. In
4l -CH2NHCO- 60 540 81 10
both active and dormant modes, the newly synthesized
C6H5 compounds demonstrated good effectiveness against M. bovis
4m -CH2-O-C6H4-2- 64 540 85 10 BCG and M. tuberculosis H37Ra. The antitubercular action of
CH3 the pyrazole and oxadiazole hybrids 4e, 4h, 4k, 4p, and 4s
4n -CH2-O-C6H4-3- 63 540 85 9 against M. tuberculosis H37Ra was described. The compounds
CH3
4e, 4k, and 4p had excellent MICs against M. tuberculosis
4o -CH2-O-C6H4-4- 70 540 90 9
CH3 H37Ra in an active state, ranging from 0.92 to 2.56 μg/mL.
4p -CH2-O-C6H4-2- 61 480 83 10 Compound 4e was shown to be the most effective against
NO2 active M. tuberculosis H37Ra, with an active MIC of 0.92 μg/
4q -CH2-O-C6H4-3- 55 480 80 9 mL and a dormant MIC of 1.26 μg/mL. In active and dormant
NO2
stages, compound 4k had MICs of 1.31 and 1.53 μg/mL,
4r -CH2-O-C6H4-4- 66 480 85 9
NO2 respectively, against M. tuberculosis H37Ra. Compound 4p was
4s -CH2-O-C6H4-2- 73 450 91 8 around 2 to 3 times less active against M. tuberculosis H37Ra
Cl than the most active compound 4e (active state MIC: 2.56 μg/
4t -CH2-O-C6H4-4- 69 450 87 8 mL, dormant state MIC: 2.32 μg/mL). In a dormant
Cl condition, compound 4s had an excellent MIC value of 1.03
μg/mL against M. tuberculosis H37Ra. Compounds 4e, 4h, 4k,
signal at 5.69 ppm in the 1H NMR spectra of compound 4c 4p, and 4s had MICs ranging from 1.03 to 2.32 μg/mL against
was attributable to the oxadiazole ring’s C2−H, while peaks at M. tuberculosis H37Ra in a dormant condition. Compounds 4f
2.17 and 5.30 ppm were three −CH3 group protons and one (active state MIC: 2.71 μg/mL, dormant state MIC: 2.47 μg/

Table 2. Results of Primary Screening against M. tuberculosis H37Ra and M. bovis BCG of N′-(1-(2-(3-(4-Bromophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene)-(aryl)-benzohydrazides

at dormant M. tuberculosis H37Ra at dormant M. bovis BCG

entry -R 30 μg/mL 10 μg/mL 3 μg/mL 30 μg/mL 10 μg/mL 3 μg/mL
4a -C6H5 61.72 51.64 32.34 40.34 34.70 20.43
4b -2-OH-C6H4 54.14 60.21 21.99 100.53 100.80 99.85
4c -3-OH-C6H4 37.94 46.17 14.61 0.29 6.92 7.51
4d -4-OH-C6H4 98.45 94.86 14.86 99.55 100.57 99.63
4e -4-NO2-C6H4 95.09 92.48 11.22 99.55 100.38 38.49
4f -3-CH3-C6H4 98.47 85.31 25.24 99.24 100.48 98.79
4g -4-CH3-C6H4 7.98 19.22 3.22 96.14 98.65 99.47
4h -4-OCH3-C6H4 95.44 91.47 86.22 97.25 99.82 100.25
4i -3-Cl-C6H4 46.72 26.60 18.61 99.03 81.67 15.34
4j -4-Cl-C6H4 28.24 3.92 35.08 75.22 19.21 20.53
4k -CH2-C6H5 98.74 93.71 96.13 97.77 89.29 56.75
4l -CH2NHCO-C6H5 3.09 −17.07 35.30 58.41 21.15 8.60
4m -CH2-O-C6H4-2-CH3 38.95 7.09 33.03 37.25 37.51 33.01
4n -CH2-O-C6H4-3-CH3 −22.83 −35.88 3.56 71.56 4.17 −18.98
4o -CH2-O-C6H4-4-CH3 85.53 78.95 0.75 81.96 48.21 −1.06
4p -CH2-O-C6H4-2-NO2 95.19 90.23 94.58 98.81 94.62 91.41
4q -H2-O-C6H4-3-NO2 34.13 31.12 13.95 7.79 0.04 −7.87
4r -CH2-O-C6H4-4-NO2 54.11 40.25 7.88 33.24 26.42 20.26
4s -CH2-O-C6H4-2-Cl 93.68 98.02 93.52 82.60 86.27 83.22
4t -CH2-O-C6H4-4-Cl 11.41 −1.79 −4.38 9.62 25.12 13.69

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Table 3. Antitubercular Screening Results of the Tested Compounds against Mycobacterium tuberculosis H37Ra and
Mycobacterium bovis BCG Strainsa,b

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Table 3. continued

a
MIC = minimum inhibitory concentration in μg/mL. bIC50 = 50% inhibitory concentration in μg/mL. cRifampicin = reference for Mycobacterium
tuberculosis H37Ra and Mycobacterium bovis BCG strains. dIsoniazid = reference for Mycobacterium tuberculosis H37Ra and Mycobacterium bovis BCG
strains.

mL) and 4g (active state MIC: 2.19 μg/mL, dormant state
MIC: 2.12 μg/mL) were found to have excellent MIC values
for M. bovis BCG. In the active state of M. bovis BCG,
28275
compound 4s had an excellent MIC value of 0.79 μg/mL. The
antitubercular action was greatly impacted by the substitution
pattern at the phenyl ring, as shown in Tables 2 and 3. The
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Figure 3. Primary and secondary antitubercular screening of pyrazole−oxadiazole hybrids (4a−t) revealed a structure−activity relationship.
antitubercular activity against M. tuberculosis H37Ra was
affected by electron-withdrawing groups like −NO2 and −Cl,
but the antitubercular activity against M. bovis BCG was
affected by electron-donating groups like −CH3 and −OCH3.
The antitubercular activity of titled compounds 4a−t was
determined using a Nitrate reductase assay and an XTT
Reduction Menadione assay, respectively, against M. tuber-
culosis H37Ra and M. bovis BCG. The primary screening was
done at doses of 30, 10, and 3 μg/mL at first. For the current
study, we chose drugs that showed 90% bacilli inhibition at or
below 30 μg/mL for the dose−response curve. We chose the
drugs rifampicin and isoniazid as a reference, both of which are
commercially accessible for clinical use.29 Tables 2 and 3
summarize the findings.
Structure−Activity Relationship. We created some novel
pyrazole−oxadiazole hybrids as possible antitubercular agents
in this study. The current study’s findings revealed some
encouraging results in terms of the structure−activity relation-
ship. To investigate the impact of functional groups on
antitubercular assessment, we used a variety of electron-
withdrawing and electron-donating functional groups. Func-
tional groups have played a key role in improving
antitubercular activity in both primary and secondary screen-
ing. In primary and secondary screening, the electron-
withdrawing −NO 2 group at the fourth position in
benzohydrazide derivatives exhibited significant antitubercular
action. In initial screening, it displayed 95.09% inhibition
against the M. tb. strain, with MIC values of 0.92 and 1.26 μg/
mL in active and dormant states, respectively. In primary and
secondary screening, the electron-donating −OCH3 group,
which was placed at the fourth position, showed significant
28276
Article
action against the M. tb. strain. It inhibited the M. tb. strain by
95.44% in the primary screening, with MIC values of 19.42 and
1.12 μg/mL in active and dormant states, respectively.
The antitubercular activity of both the screening, the
electron-donating −CH3 group at the third and fourth
positions had showed excellent activity against the M. bovis
strain. In primary screening, a 3-CH3 derivative of the
benzohydrazide motif showed 99.24% inhibition and a MIC
of 2.71 μg/mL in the active state and 2.47 μg/mL in the
dormant state against the M. bovis strain. In the active and
dormant states, the 4-CH3 derivative of the benzohydrazide
scaffold inhibited M. bovis with a MIC of 2.19 and 2.12 μg/mL,
respectively. In both screenings, the SAR study of benzohy-
drazide derivatives revealed that electron-donating tendencies
were more prevalent than electron-withdrawing tendencies.
The functional groups like −CH3 and −OCH3 at various
positions showed increased effectiveness against M. tb. and M.
bovis strains. Electron-withdrawing functional groups in
acetohydrazide derivatives exhibited good efficacy against the
M. tb. strain. In primary screening, the −NO2 group at the
second position showed 95.19% inhibition against the M. tb.
strain, with MIC values of 2.56 μg/mL in the active state and
2.32 μg/mL in the dormant state. The electron-withdrawing
−Cl group in the second position showed 93.68% inhibition in
primary and secondary screening against the M. tb. strain,
having MIC values of 24.43 and 1.03 μg/mL in active and
dormant states, respectively. The electron-withdrawing −NO2
and −Cl groups at the second position are more prominent
than electron-donating groups at various positions, according
to an evaluation of acetohydrazide derivatives. The cumulative
impacts of active motifs of pyrazole−oxadiazole hybrids (4a−
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t) on the structure−activity relationship are demonstrated in

Ser94 (2.41),
H-bonding
Figure 3.

(2.57),

(2.77)

(1.98)

(2.30)

(2.14)

(1.99)
Ala22

Ser20

Thr196
Lys165

Lys165

Lys165
Molecular Docking Study. Molecular docking is now a
well-established computational technique for predicting the
predominant binding mode(s) of a ligand within a protein

(2.135)

(2.362)

(2.644)
stacking
(biological target) of a given three-dimensional structure, and

Phe149

Phe149
π−π

Phe97
it has become a vital aspect of drug development research. It
gives researchers information on binding affinities, binding

(−1.122), Thr196 (−1.626),

(−1.711), Lys165 (−2.343),

(−1.199), Lys165 (−2.278),

(−1.879), Ser209 (−1.298),

mechanisms, and types of interactions that guide protein−

(−1.008), Ser20 (−1.905)

(−2.797), Ser20 (−1.246)

Lys165 (−2.62), Met147

electrostatic (kcal/mol)
ligand complexation, allowing them to develop and examine

Ile219 (−1.587), Lys165

Ile210 (−1.968), Ser209

Ile219 (−1.134), Ser209

Ile219 (−1.949), Ile210

115 (−1.104), Gly96
261 (−0.972), Met199
115 (−1.527), Ala22
the potential of existing lead compounds and their equivalents.

169 (−1.101), 148

In the absence of resources to perform enzymatic assays, in
silico computational chemistry techniques such as molecular

(−1.019)

(−1.514)

(−0.907)
docking have become critical for identifying the targets for
various molecules and their associated thermodynamic
interactions with the target enzyme that govern pathogen
inhibition. Mycobacterial enoyl reductase is said to be

(−1.928), Tyr158 (−1.92), Phe149 (−2.145), Met147 (−1.768), Met103 (−2.843), 99 (−1.067), Met98 (−1.018), Met97 (−1.186), Gly96
(−1.343), Ala191 (−1.968), Lys165 (−1.685), Met161 (−2.058), Tyr158 (−7.209), Ala157 (−1.567), Met155 (−1.093), Phe149 (−4.211),
Met147 (−2.55), Met103 (−4.69), Met98 (−1.443), Met97 (−1.903), Gly96 (−1.844), Ile95 (−0. 956), Ser94 (−2.361), Ile21 (−2.832),

Ala198 (−2.206), 197 (−1.785), Thr196 (−2.607), Lys165 (−1.098), Met161 (−2.168), Phe149 (−0.964), 148 (−1.325), Met147 (−2.952),

Ile215 (−2.153), Ile202 (−2.073), Met199 (−2.55), Ala198 (−2.256), Thr196 (−3.008), Ile194 (−2.197), Pro193 (−1.352), 192 (−0.964),
122 (−1.526), Met103 (−1.463), 100 (−1.971), 99 (−1.184), Met98 (−1.394), Met97 (−1.587), Gly96 (−2.034), Ile95 (−2.61), Ser94
inhibited by the oxadiazole scaffold (InhA).30−32 As a result,

Ala191 (−1.812), Met161 (−3.095), Tyr158 (−4.064), Phe149 (−4.414), 148 (−1.567), Met147 (−3.112), Met103 (−3.963), Met98
(−1.636), Tyr158 (−2.63), Ala157 (−0.931), Phe149 (−3.592), 148 (−1.487), Met147 (−2.197), Met103 (−3.31), Met98 (−1.465),
Ile215 (−2.438), Leu207 (−1.711), Ile202 (−1.788), Met199 (−2.915), Ala198 (−2.376), Thr196 (−3.184), Ile194 (−2.484), Pro193

Ile215 (−1.36), Leu207 (−1.033), Ile202 (−2.438), Met199 (−2.054), Ala198 (−2.077), Thr196 (−1.48), Lys165 (−1.782), Met161
the 3D structure of M. tuberculosis mycobacterial enoyl

Ile215 (−1.248), Leu207 (−1.001), Ile202 (−1.748), Met199 (−1.831), Ala198 (−2.032), 197 (−0.967), Thr196 (−1.522), Met161
reductase (InhA) complexed with its inhibitor was chosen as
the target protein for the molecular docking study for the

Table 4. Results of the Per-Residue Interaction Analysis for the Pyrazole Clubbed Oxadiazole Hybrid Heterocycles
active compounds (4e, 4f, 4g, 4p, and 4s) in the series to

per-residue interaction energy analysis

Met97 (−1.211), Gly96 (−2.566), Ile95 (−1.145), Ser94 (−1.875), Ile21 (−1.679), Ser20 (−1.193), Ile16 (−0.987)
rationalize the promising antitubercular results and investigate
the possible interactions of the studied compounds. The enoyl-
ACP (CoA) reductase (FabI/ENR/InhA) is a key enzyme in

(−2.111), 41 (−2.473), Ile21 (−2.046), Ser20 (−1.798), Ser19 (−1.078), Thr17 (−1.89), Ile16 (−2.208)
the type II fatty acid biosynthesis pathway in mycobacteria,
and its inhibition stunts the growth of a fast-growing model
organism. Mycobacterium smegmatis has been demonstrated to
block mycolic acid formation and promote cell lysis,33 making

(−1.447), Met97 (−1.818), Gly96 (−2.095), Ile21 (−2.087), Ser20 (−1.446), Ile16 (−1.076)
(−2.182), Ile95 (−1.439), Ser94 (−1.943), Ile21 (−1.881), Ser20 (−1.187), Ile16 (−1.326)
it a suitable target for medication development against
tuberculosis.
The outcome of the molecular docking study revealed that
van der Waals (kcal/mol)

all the studied compounds (4e, 4f, 4g, 4p, and 4s) were
successfully docked, making a snug fit into the active site of
InhA at coordinates very close to that of the native ligand in
the crystal structure with varying degrees of affinities. Their
complexes with protein structure were stabilized by several
bonded and nonbonded interactions with the amino acids
surrounding the active site. The findings of the molecular
docking investigation are described in Table 4, which shows
that there is a substantial association between docking scores
and biological activity, with active molecules producing higher
scores and those with low activity producing lower docking
scores. Their binding energies were likewise found to be
negative (−66.459 to −55.157 kcal/mol), indicating that they
Ser20 (−1.992), Gly14 (−1.127)

could be used to rationally design compounds that target InhA.

Furthermore, the thermodynamic elements influencing the
binding of these compounds to InhA were investigated in-
depth by analyzing per-residue interactions between the
enzyme and these ligands. However, for the sake of brevity,
we have discussed these details for compound 4e, which is the
most active, while we summarized for other molecules in Table
4.
The best docked configuration of the most active oxadiazole
derivative 4e into the active site of mycobacterial enoyl
−66.459

−55.157

−58.133

−62.547

−64.465
binding
energy

reductase (InhA) (Figure 4) revealed that the inhibitor snugly

fits the active site, making multiple intimate contacts through
bonded and nonbonded interactions. This molecule has the
highest affinity in the series (docking score of −10.366 and
−10.366

−8.037

−8.159

−8.909

−9.972
docking
score

binding energy of −66.459 kcal/mol), which can be explained

in terms of unique bonded and nonbonded per-residue
interactions with the active site residues. The visual inspection
entry

4p
4g
4e

4s
4f

of the bound pose of 4e revealed that the compound is

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Figure 4. Binding mode of compound 4e into the active site of mycobacterial enoyl reductase (InhA) (on the right side: the π−π stacking
interaction is represented using green lines, while pink lines represent the hydrogen bonding interactions).
stabilized within the active site through an extensive network of
favorable van der Waals contacts with Ile215 (−2.438 kcal/
mol), Ile202 (−1.788 kcal/mol), Met199 (−2.915 kcal/mol),
Ala198 (−2.376 kcal/mol), Thr196 (−3.184 kcal/mol), Ile194
(−2.484 kcal/mol), Pro193 (−1.343 kcal/mol), Ala191
(−1.968 kcal/mol), Tyr158 (−7.209 kcal/mol), Ala157
(−1.567 kcal/mol), and Phe149 (−4.211 kcal/mol) through
the N′-(1-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene)-4-nitrobenzo-
hydrazidebenzohydrazide component of 4e got engaged in a
similar network of van der Waals interactions with Leu207
(−1.711 kcal/mol), Lys165 (−1.685 kcal/mol), Met161
(−2.058 kcal/mol), Met155 (−1.093 kcal/mol), Met147
(−2.55 kcal/mol), Met103 (−4.69 kcal/mol), Met98
(−1.443 kcal/mol), Met97 (−1.903 kcal/mol), Gly96
(−1.844 kcal/mol), Ile95 (−0.956 kcal/mol), Ser94 (−2.361
kcal/mol), Ile21 (−2.832 kcal/mol), Ser20 (−1.992 kcal/mol),
and Gly14 (−1.127 kcal/mol) residues lining the active site of
InhA. Significant electrostatic interactions with Ile210 (−1.968
kcal/mol), Ser209 (−1.711 kcal/mol), Lys165 (−2.343 kcal/
mol), 115 (−1.527 kcal/mol), Ala22 (−1.008 kcal/mol), and
Ser20 (−1.905 kcal/mol) residues in the active site are also
responsible for 4e’s increased binding affinity. Furthermore, at
bonding distances of 2.41, 2.25, and 2.77, respectively, a strong
hydrogen bonding interaction was detected between the nitro
group and the Ser94, Ala22, and Ser20 residues. A significant
π−π stacking was also observed between the Phe149 (2.135)
and the p-chlorophenyl ring of 4e. Such hydrogen bonding
interactions and the pi−pi stacking serve as an ″anchor″
guiding the 3D space position of the ligand in the active site
and facilitate the steric and electrostatic interactions adding to
the stability of the enzyme-inhibitor complex. The other
oxadiazole analogues (4f, 4g, 4p, and 4s) were also seen to
possess an optimum binding affinity for the enzyme engaging
in a similar network of interactions with the active side residues
but quantitatively decreasing gradually with their observed
antitubercular activity. Overall, the per-residue interaction
analysis revealed that the primary driving forces for mechanical
interlocking of these ligands are the steric complementarity
between these ligands and the active site of InhA that is
reflected in the relatively higher number of favorable van der
Waals interactions compared to other components contribu-
ting to the overall binding affinity.
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■ CONCLUSIONS
The findings of the investigation suggested that the titled
compounds will be important in the development of
antitubercular drugs in the future. Microwave-assisted syn-
thesis and the hybrid molecule idea were used to produce and
develop the active chemicals. Our findings showed that the
chemical transformation took place in a relatively short period,
the purity of the compounds was higher, and the yields were
higher than the traditional approach. As a result, the
pharmaceutical industry will rely heavily on this technique.
Our previously published work was used to describe the
compounds (Figure 2). The fact that the molecule with the
nitro group at the para position has outstanding activity and a
high docking score motivated us to develop new hybrids based
on the oxadiazole core structure and explore their
antitubercular activity. The study found that compounds
with electron-withdrawing functional groups had excellent
MICs against M. tuberculosis H37Ra, whereas compounds with
electron-donating functional groups have antitubercular action
against M. bovis BCG but no activity against M. tuberculosis
H37Ra. The pyrazole−oxadiazole hybrids 4e, 4h, 4p, and 4s
were found to be most effective against M. tuberculosis H37Ra,
while 4f and 4g have substantial activity against M. bovis BCG.
Molecular docking studies were used to gain an insight into the
mechanism of action, which suggested that these molecules
possess significant binding affinity toward the critical target
mycobacterium InhA. These findings revealed important
information about possible binding interactions, implying
that this class of compounds can be further selected to build
InhA specific inhibitors. Iterative synthesis and computer
modeling are being used to make a variety of structural
changes, and the results will be shared as soon as possible.
■
EXPERIMENTAL SECTION
Materials and Methods. Melting points were determined
on an electrothermal melting point apparatus and are reported
uncorrected. The completion of the reaction and purity of all
compounds were checked on aluminum-coated TLC plates 60
F254 (E. Merck) using chloroform/methanol (9.5:0.5 v/v) as
the mobile phase and visualized under ultraviolet (UV) light or
iodine vapor. Elemental analysis (% C, H, N) was carried out
by a Perkin-Elmer 2400 CHN analyzer. IR spectra of all
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compounds were taken on a Perkin-Elmer FT-IR spectropho-
tometer in KBr. 1H NMR and 13C NMR spectra were recorded
on Bruker (400 MHz) and (100 MHz) spectrometers,
respectively, using DMSO-d6 as a solvent and TMS as an
internal standard. Chemical shifts are reported in parts per
million (ppm). A mass spectrum was scanned on a Shimadzu
LC−MS 2010 spectrophotometer. Anhydrous reactions were
carried out in oven-dried glassware in a nitrogen atmosphere.
Microwave-assisted synthesis was carried out using Synthos
3000.34
General Procedure for the Preparation of N′-(1-(2-(3-
(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-
1,3,4-oxadiazol-3(2H)-yl)ethylidene) Substituted Hydra-
zides (4a-t) by the Conventional Method. Preparation of
N′-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene) Benzohydrazide (2). 3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazole-4-carbaldehyde (1, 0.01 mol) and benzohy-
drazide (0.01 mol) were dissolved in 1,4-dioxane (20 mL) and
refluxed for 4 h. The crystals developed as soon as the product
was cooled, and the product was crystallized from methanol to
obtain compound 2. Yield 63%, mp 187−189 °C.
Preparation of 1-(2-(3-(4-Chlorophenyl)-1-phenyl-1H-pyr-
azol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethanone (3).
Acetic anhydride (0.03 mol) was added to compound N′-
((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)methylene)-
benzohydrazide (2, 0.01 mol) and refluxed at 140 °C for 5 h.
The resulting mixture was transferred to crushed ice once the
reaction mixture reached the room temperature. The
precipitates were filtered and crystallized with methanol after
being oven-dried, yielding compound 3. Yield 73%, mp 180−
182 °C. Anal. calcd for C25H19ClN4O2: C-67.79, H-4.32, N-
12.62; found: C-67.86, H-4.4, N-12.6%.
Preparation of N′-(1-(2-(3-(4-Chlorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene)
Substituted Hydrazides (4a-t). An equimolar mixture of
intermediate compound 1-(2-(3-(4-chlorophenyl)-1-phenyl-
1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethanone
(3, 0.01 mol) and appropriate benzohydrazides (0.01 mol) was
dissolved in ethanol (95%) (20 mL), and a pinch of anhydrous
ZnCl2 was added to the mixture. The reaction mixture was
then refluxed for 7−9 h at 80 °C. The crystals formed after
cooling the reaction mixture were filtered and recrystallized
from methanol to give compound 4a−t.
General Procedure for the Preparation of N′-(1-(2-(3-
(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-
1,3,4-oxadiazol-3(2H)-yl)ethylidene) Substituted Hydra-
zides (4a−t) by Microwave-Assisted Synthesis. Prepara-
tion of N′-((3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene) Benzohydrazide (2). Compounds 3-(4-chloro-
phenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (1, 0.01 mol),
benzohydrazide (0.01 mol), and 1,4-dioxane (5 mL) were
swirled together and microwave irradiated for 30 s. This
reaction mixture was heated for a further 5 min. When the
reaction was finished, the contents were placed in crushed ice
with water and recrystallized in methanol to form compound 2,
resulting in an 82% yield.
Preparation of 1-(2-(3-(4-Chlorophenyl)-1-phenyl-1H-pyr-
azol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethanone (3).
This silica gel (1 g) was added to a combination of compound
N′-((3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-
methylene)benzohydrazide (2, 0.01 mol) and acetic anhydride
(3 mL) at room temperature. Under microwave irradiation, the
absorbed material was air-dried and magnetically agitated for 5
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min at a maximum power of 250 W at 30 s intervals. The
product was extracted from methanol when the reaction
mixture was cooled. A crude product was obtained by diluting
methanolic extract with ice-cold water, which was then filtered,
washed, and recrystallized from methanol to yield compound
3, resulting in an 88% yield.
Preparation of N′-(1-(2-(3-(4-Chlorophenyl)-1-phenyl-1H-
pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)ethylidene)
Substituted Hydrazides (4a−t). 1-(2-(3-(4-Chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethanone (3, 0.01 mol) and appropriate benzohydrazides (0.01
mol) were dissolved in pure alcohol (99.9%), and a pinch of
anhydrous ZnCl2 was added. Under microwave irradiation, the
reaction mixture was magnetically agitated for 8−10 min with a
maximum power of 300 W intermittently at 30 s intervals. The
reaction mixture was then quenched, and the resulting
precipitates were filtered, washed, and recrystallized from
methanol to yield compounds 4a−t.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)benzohydrazide (4a). Yield 77%, mp 229−232
°C; IR (KBr) λmax: 3365 (N−H stretching, secondary amide),
3066, 3024 (C−H stretching, aromatic ring), 1691 (CO
stretching), 1548, 1488 (CC, CN stretching, aromatic
ring), 1232 (C−O−C stretching, oxadiazole ring), 747 (C−Cl
stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.16 (s,
3H, −CH3), 5.65 (s, 1H, C2−H, oxadiazole ring), 6.88−8.04
(m, 20H, Ar−H and C5−H pyrazole), 12.36 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.5, 78.2,
117.6, 119.4 (2), 123.4, 125.3 (2), 126.1, 127.3 (2), 128.7 (4),
128.8 (2), 129.3 (4), 131.2, 131.7, 132.1, 132.5, 132.6, 134.8,
139.4, 147.3, 149.2, 157.6, 163.8; LCMS: m/z = 561.2 (M+);
anal. calcd for C32H25ClN6O2: C, 68.51; H, 4.49; N, 14.98;
found: C, 68.62; H, 4.55; N, 15.00%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-hydroxybenzohydrazide (4b). Yield 65%, mp
227−230 °C; IR (KBr) λmax: 3465 (O−H stretching, Ar−OH),
3370 (N−H stretching, secondary amide), 3068, 3028 (C−H
stretching, aromatic ring), 1696 (CO stretching), 1550,
1492 (CC, CN stretching, aromatic ring), 1200 (C−O−
C stretching, oxadiazole ring), 740 (C−Cl stretching) cm−1;
1
H NMR (DMSO-d6, 400 MHz): 2.19 (s, 3H, −CH3), 5.35 (s,
1H, −OH), 5.69 (s, 1H, C2−H oxadiazole ring), 6.92−8.09
(m, 19H, Ar−H and C5−H pyrazole), 12.35 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.8, 78.6,
117.2, 117.3 (2), 119.3 (2), 119.4, 121.5, 123.4, 126.4 (2),
128.6, 128.9 (2), 129.1, 129.4 (4), 129.5, 129.7, 131.0, 131.2,
133.6, 134.8, 139.2, 147.2, 149.3, 150.2, 159.3, 163.7; LCMS:
m/z = 577.6 (M+); anal. calcd for C32H25ClN6O3: C, 66.61; H,
4.37; N, 14.56; found: C, 66.63; H, 4.50; N, 14.70%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-3-hydroxybenzohydrazide (4c). Yield 69%, mp
209−211 °C; IR (KBr) λmax: 3447 (O−H stretching, Ar−OH),
3367 (N−H stretching, secondary amide), 3066, 3024 (C−H
stretching, aromatic ring), 1691 (CO stretching), 1548,
1488 (CC, CN stretching, aromatic ring), 1232 (C−O−
C stretching, oxadiazole ring), 747 (C−Cl stretching) cm−1;
1
H NMR (DMSO-d6, 400 MHz): 2.17 (s, 3H, −CH3), 5.30 (s,
1H, −OH), 5.69 (s, 1H, C2−H oxadiazole ring), 6.90−8.05
(m, 19H, Ar−H and C5−H pyrazole), 12.30 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.9, 78.4,
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115.3, 117.9, 119.4, 119.6 (2), 120.4, 123.1, 125.4 (2), 126.3,
128.4 (2), 128.8 (2), 129.3 (4), 130.5, 131.5, 131.9, 134.1,
135.9, 139.2, 147.3, 149.4, 157.6, 158.2, 158.3, 163.7; LCMS:
m/z = 577.1 (M+); anal. calcd for C32H25ClN6O3: C, 66.61; H,
4.37; N, 14.56; found: C, 66.70; H, 4.50; N, 14.65%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-4-hydroxybenzohydrazide (4d). Yield 65%, mp
241−244 °C; IR (KBr) λmax: 3434 (O−H stretching, Ar−OH),
3380 (N−H stretching, secondary amide), 3070, 3012 (C−H
stretching, aromatic ring), 1612 (CO stretching), 1509,
1412 (CC, CN stretching, aromatic ring), 1232 (C−O−
C stretching, oxadiazole ring), 730 (C−Cl stretching) cm−1;
1
H NMR (DMSO-d6, 400 MHz): 2.15 (s, 3H, −CH3), 5.32 (s,
1H, −OH), 5.66 (s, 1H, C2−H oxadiazole ring), 6.90−8.09
(m, 19H, Ar−H and C5−H pyrazole), 12.36 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.3, 78.1,
116.3 (2), 117.6, 119.4 (2), 123.7, 125.1, 125.6 (2), 126.4,
128.0, 128.1 (2), 128.4 (2), 128.6, 129.3 (4), 131.0, 131.7,
132.4, 134.8, 139.4, 147.1, 149.4, 157.4, 161.7, 163.7; LCMS:
m/z = 577.2 (M+); anal. calcd for C32H25ClN6O3: C, 66.61; H,
4.37; N, 14.56; found: C, 66.62; H, 4.39; N, 14.60%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-4-nitrobenzohydrazide (4e). Yield 58%, mp 271−
273 °C; IR (KBr) λmax: 3388 (N−H stretching, secondary
amide), 3077, 3013 (C−H stretching, aromatic ring), 1530,
1610 (CO stretching), 1530 (NO stretching, Ar−NO2),
1500, 1429 (CC, CN stretching, aromatic ring), 1200
(C−O−C stretching, oxadiazole ring), 700 (C−Cl stretching)
cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.12 (s, 3H, −CH3),
5.60 (s, 1H, C2−H oxadiazole ring), 6.85−8.04 (m, 19H, Ar−
H and C5−H pyrazole), 12.32 (s, 1H, −CONH); 13C NMR
(DMSO-d6, 100 MHz): 12.0, 78.7, 117.4, 119.7 (2), 123.5,
124.4 (2), 125.3 (2), 126.7, 128.3 (2), 128.4 (2), 129.3 (4),
129.4 (2), 131.4, 134.4, 138.3, 138.4, 139.4, 147.2, 149.5,
150.7, 151.0, 157.5, 163.7; LCMS: m/z = 605.2 (M+); anal.
calcd for C32H24ClN7O4: C, 63.42; H, 3.99; N, 16.18; found:
C, 63.55; H, 4.10; N, 16.20%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-3-methylbenzohydrazide (4f). Yield 73%, mp
245−247 °C; IR (KBr) λmax: 3344 (N−H stretching,
secondary amide), 3066, 3002 (C−H stretching, aromatic
ring), 2930 (C−H stretching, −CH3 group), 1619 (CO
stretching), 1503, 1412 (CC, CN stretching, aromatic
ring), 1214 (C−O−C stretching, oxadiazole ring), 705 (C−Cl
stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.11 (s,
3H, −CH3), 2.34 (s, 3H, −CH3), 5.61 (s, 1H, C2−H
oxadiazole ring), 6.82−8.02 (m, 19H, Ar−H and C5−H
pyrazole), 12.31 (s, 1H, −CONH); 13C NMR (DMSO-d6, 100
MHz): 12.1, 21.7, 78.1, 117.5, 119.5 (2), 123.7, 124.7, 125.0,
125.1 (2), 126.7, 128.1 (2), 128.4 (2), 129.4 (4), 131.5, 131.8,
131.9, 132.2, 132.4, 134.4, 134.7, 138.3, 139.2, 147.3, 149.4,
157.9, 163.5; LCMS: m/z = 575.7 (M+); anal. calcd for
C33H27ClN6O2: C, 68.92; H, 4.73; N, 14.61; found: C, 68.96;
H, 4.80; N, 14.69%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-4-methylbenzohydrazide (4g). Yield 71%, mp
233−236 °C; IR (KBr) λmax: 3312 (N−H stretching,
secondary amide), 3016, 3020 (C−H stretching, aromatic
ring), 2924 (C−H stretching, −CH3 group), 1600 (CO
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stretching), 1546, 1440 (CC, CN stretching, aromatic
ring), 1240 (C−O−C stretching, oxadiazole ring), 701 (C−Cl
stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.08 (s,
3H, −CH3), 2.34 (s, 3H, −CH3), 5.68 (s, 1H, C2−H
oxadiazole ring), 6.80−7.99 (m, 19H, Ar−H and C5−H
pyrazole), 12.35 (s, 1H, −CONH); 13C NMR (DMSO-d6, 100
MHz): 12.4, 21.8, 78.1, 117.3, 119.3 (2), 123.7, 125.3 (2),
126.8, 127.4 (2), 128.6 (2), 128.9 (2), 129.3 (4), 129.4 (2),
129.8, 131.5, 131.8, 132.8, 134.8, 139.4, 147.2, 149.7, 151.1,
157.3, 163.7. LCMS: m/z = 575.3 (M+); anal. calcd for
C33H27ClN6O2: C, 68.92; H, 4.73; N, 14.61; found: C, 68.96;
H, 4.63; N, 14.70%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-4-methoxybenzohydrazide (4h). Yield 62%, mp
248−251 °C; IR (KBr) λmax: 3320 (N−H stretching,
secondary amide), 3014, 3020 (C−H stretching, aromatic
ring), 2850 (C−H stretching, −OCH3),2824, 1605(CO
stretching), 1554, 1428 (CC, CN stretching, aromatic
ring), 1212 (C−O−C stretching, oxadiazole ring), 758 (C−Cl
stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.05 (s,
3H, −CH3), 3.80 (s, 3H, −OCH3), 5.72 (s, 1H, C2−H
oxadiazole ring), 6.80−7.80 (m, 19H, Ar−H and C5−H
pyrazole), 12.33 (s, 1H, −CONH); 13C NMR (DMSO-d6, 100
MHz): 12.8, 55.6, 78.4, 114.7 (2), 117.7, 119.4 (2), 123.0,
125.4 (2), 126.7, 128.1, 128.4 (2), 128.7 (2), 128.8 (2), 129.4
(4), 131.2, 131.7, 132.0, 134.7, 139.4, 147.4, 149.4, 157.1,
163.7, 164.0; LCMS: m/z = 591.2 (M+); anal. calcd for
C33H27ClN6O3: C, 67.06; H, 4.60; N, 14.22; found: C, 67.09;
H, 4.70; N, 14.26%.
Characterization of 3-Chloro-N′-(1-(2-(3-(4-chlorophen-
yl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-
3(2H)-yl)ethylidene)benzohydrazide (4i). Yield 68%, mp
183−185 °C; IR (KBr) λmax: 3338 (N−H stretching,
secondary amide), 3023, 3020 (C−H stretching, aromatic
ring), 1609 (CO stretching), 1562, 1430 (CC, CN
stretching, aromatic ring), 1219 (C−O−C stretching,
oxadiazole ring), 775, 758 (C−Cl stretching) cm−1; 1H
NMR (DMSO-d6, 400 MHz): 2.06 (s, 3H, −CH3), 5.71 (s,
1H, C2−H oxadiazole ring), 6.82−7.99 (m, 19H, Ar−H and
C5−H pyrazole), 12.34 (s, 1H, −CONH); 13C NMR (DMSO-
d6, 100 MHz): 12.4, 78.1, 117.4, 119.7 (2), 120.1, 123.1, 125.4
(2), 125.7, 126.7, 127.4, 128.1 (2), 128.4 (2), 129.1 (4), 130.7,
131.5, 132.4, 132.7, 134.7, 134.8, 135.7, 139.4, 147.1, 149.2,
157.5, 163.4; LCMS: m/z = 594.1 (M+); anal. calcd for
C32H24Cl2N6O2: C, 64.54; H, 4.06; N, 14.11; found: C, 64.70;
H, 4.10; N, 14.20%.
Characterization of 4-Chloro-N′-(1-(2-(3-(4-chlorophen-
yl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-
3(2H)-yl)ethylidene)benzohydrazide (4j). Yield 74%, mp
191−193 °C; IR (KBr) λmax: 3336 (N−H stretching,
secondary amide), 3014, 3001 (C−H stretching, aromatic
ring), 1606 (CO stretching), 1534, 1429 (CC, CN
stretching, aromatic ring), 1212 (C−O−C stretching,
oxadiazole ring), 770, 754 (C−Cl stretching) cm−1; 1H
NMR (DMSO-d6, 400 MHz): 2.06 (s, 3H, −CH3), 5.73 (s,
1H, C2−H oxadiazole ring), 6.82−7.96 (m, 19H, Ar−H and
C5−H pyrazole), 12.33 (s, 1H, −CONH); 13C NMR (DMSO-
d6, 100 MHz): 12.0, 78.3, 117.3, 119.2 (2), 120.3, 123.7, 125.4
(2), 126.1, 128.0 (2), 128.1 (4), 129.6 (4), 130.3 (2), 130.8,
131.7, 132.7, 134.4, 137.1, 139.2, 147.1, 149.3, 157.3, 163.9;
LCMS: m/z = 595.2 (M+); anal. calcd for C32H24Cl2N6O2: C,
64.54; H, 4.06; N, 14.11; found: C, 64.60; H, 4.10; N, 14.15%.
https://doi.org/10.1021/acsomega.1c04411
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Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-phenylacetohydrazide (4k). Yield 57%, mp
244−246 °C; IR (KBr) λmax: 3333 (N−H stretching,
secondary amide), 3014, 3020 (C−H stretching, aromatic
ring), 2855 (C−H stretching, −CH2−), 1595 (CO
stretching), 1554, 1428 (CC, CN stretching, aromatic
ring), 1218 (C−O−C stretching, oxadiazole ring), 758 (C−Cl
stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz): 2.00 (s,
3H, −CH3), 3.81 (s, 2H, −CH2), 5.70 (s, 1H, C2−H
oxadiazole ring), 7.26−7.62 (m, 20H, Ar−H and C5−H
pyrazole), 12.36 (s, 1H, −CONH); 13C NMR (DMSO-d6, 100
MHz): 12.9, 16.5, 42.7, 79.2, 117.3, 119.7 (2), 123.8, 125.7
(2), 126.7, 127.4, 128.2 (2), 128.4 (2), 129.1 (2), 129.3 (4),
129.6 (2), 130.7, 131.7, 134.7, 135.7, 139.8, 147.0, 149.4,
150.4, 171.9; LCMS: m/z = 575.1 (M+); anal. calcd for
C33H27ClN6O2: C, 68.52; H, 4.73; N, 14.61; found: C, 68.60;
H, 4.75; N, 14.70%.
Characterization of N-(2-(2-(1-(2-(3-(4-Chlorophenyl)-1-
phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)hydrazinyl)-2-oxoethyl)benzamide (4l). Yield
60%, mp 275−278 °C; IR (KBr) λmax: 3012, 3020, 3030
(C−H stretching, aromatic ring), 2867 (C−H stretching,
−CH2−), 1700, 1632 (CO stretching), 1550, 1430 (CC,
CN stretching, aromatic ring), 1210 (C−O−C stretching,
oxadiazole ring), 715 (C−Cl stretching) cm−1; 1H NMR
(DMSO-d6, 400 MHz): 2.02 (s, 3H, −CH3), 2.23 (s, 2H,
−CH2), 5.69 (s, 1H, C2−H oxadiazole ring), 6.99−7.99 (m,
19H, Ar−H and C5−H pyrazole), 7.51 (s, 1H, −NHCH2),
7.56 (s, 1H, NH), 12.33 (s, 1H, −CONH); 13C NMR
(DMSO-d6, 100 MHz): 12.4, 45.7, 78.1, 117.5, 119.2 (2),
123.7, 125.7 (2), 126.3, 127.4 (2), 128.5 (4), 128.7 (2), 129.4
(4), 131.5, 131.7, 132.4, 132.7, 134.7, 134.8, 139.4, 147.4,
149.1, 157.4, 167.2, 171.2; LCMS: m/z = 618.2 (M+); anal.
calcd for C34H28ClN7O3: C, 66.07; H, 4.57; N, 15.86; found:
C, 66.10; H, 4.75; N, 15.96%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(o-tolyloxy)acetohydrazide (4m). Yield 64%,
mp 226−228 °C; IR (KBr) λmax: 3009, 3035, 3025 (C−H
stretching, aromatic ring), 2930 (C−H stretching, −CH3
group), 2860 (C−H stretching, −CH2−), 1735, 1635 (C
O stretching), 1555, 1435 (CC, CN stretching, aromatic
ring), 1325, 1200 (C−O−C stretching, oxadiazole ring), 720
(C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz):
2.01 (s, 3H, −CH3), 2.16 (s, 3H, CH3), 4.66 (s, 2H, −OCH2),
5.69 (s, 1H, C2−H oxadiazole ring), 6.84−7.99 (m, 19H, Ar−
H and C5−H pyrazole), 12.33 (s, 1H, −CONH); 13C NMR
(DMSO-d6, 100 MHz): 12.0, 15.2, 69.4, 78.1, 112.4, 117.3,
119.4 (2), 120.7, 123.1, 125.1 (2), 126.2, 126.4, 126.6, 128.3
(2), 128.4 (2), 129.3 (4), 131.4, 131.6, 131.7, 132.4, 134.0,
139.1, 147.2, 149.5, 157.1, 158.4, 171.3; LCMS: m/z = 605.3
(M+); anal. calcd for C34H29ClN6O3: C, 67.49; H, 4.57; N,
15.86; found: C, 67.56; H, 4.63; N, 15.90%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(m-tolyloxy)acetohydrazide (4n). Yield 63%,
mp 212−215 °C; IR (KBr) λmax: 3012, 3040, 3030 (C−H
stretching, aromatic ring), 2925 (C−H stretching, −CH3
group), 2800 (C−H stretching, −CH2−), 1695, 1640 (C
O stretching), 1528, 1418 (CC, CN stretching, aromatic
ring), 1302, 1215 (C−O−C stretching, oxadiazole ring), 730
(C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz):
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2.03 (s, 3H, −CH3), 2.19 (s, 3H, CH3), 4.73 (s, 2H, −OCH2),
5.71 (s, 1H, C2−H oxadiazole ring), 6.78−7.93 (m, 19H, Ar−
H and C5−H pyrazole), 12.39 (s, 1H, −CONH); 13C NMR
(DMSO-d6, 100 MHz): 12.1, 21.1, 69.3, 78.2, 111.6 (2), 113.4,
117.3, 119.4 (2), 121.6, 123.5, 125.2 (2), 126.8, 128.3 (2),
128.7 (2), 129.2, 129.4 (4), 131.5, 132.2, 134.7, 139.4, 139.5,
147.2, 149.3, 157.2, 160.1, 171.1; LCMS: m/z = 605.4 (M+);
anal. calcd for C34H29ClN6O3: C, 67.49; H, 4.57; N, 15.86;
found: C, 67.58; H, 4.63; N, 15.96%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(p-tolyloxy)acetohydrazide (4o). Yield 70%,
mp 239−241 °C; IR (KBr) λmax: 3014, 3045, 3035 (C−H
stretching, aromatic ring), 2920 (C−H stretching, −CH3
group), 2813 (C−H stretching, −CH2−), 1697, 1647 (C
O stretching), 1530, 1416 (CC, CN stretching, aromatic
ring), 1336, 1216 (C−O−C stretching, oxadiazole ring), 763
(C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400 MHz):
2.09 (s, 3H, −CH3), 2.20 (s, 3H, CH3), 4.79 (s, 2H, −OCH2),
5.75 (s, 1H, C2−H oxadiazole ring), 6.87−7.95 (m, 19H, Ar−
H and C5−H pyrazole),.42 (s, 1H, −CONH); 13C NMR
(DMSO-d6, 100 MHz): 12.8, 21.7, 69.6, 78.1, 114.3 (2), 117.5,
119.1 (2), 123.8, 125.9 (2), 126.3, 128.6 (2), 128.8 (2), 129.4
(4), 130.5 (2), 130.8, 131.4, 131.8, 132.5, 134.7, 139.4, 147.3,
149.3, 155.3, 157.3, 171.3; LCMS: m/z = 605.4 (M+); anal.
calcd for C34H29ClN6O3: C, 67.49; H, 4.83; N, 13.89; found:
C, 67.53; H, 4.90; N, 13.96%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(2-nitrophenoxy)acetohydrazide (4p). Yield
61%, mp 272−275 °C; IR (KBr) λmax: 3036, 3012, 3060
(C−H stretching, aromatic ring), 2860 (C−H stretching,
−CH2−), 1612, 1623 (CO stretching), 1533 (NO
stretching, Ar−NO2), 1545, 1420 (CC, CN stretching,
aromatic ring), 1220 (C−O−C stretching, oxadiazole ring),
723 (C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400
MHz): 2.12 (s, 3H, −CH3), 4.72 (s, 2H, −OCH2), 5.75 (s,
1H, C2−H oxadiazole ring), 6.94−7.98 (m, 19H, Ar−H and
C5−H pyrazole), 12.42 (s, 1H, −CONH); 13C NMR (DMSO-
d6, 100 MHz): 12.4, 68.1, 78.0, 115.0, 117.6, 119.4 (2), 121.9,
123.4, 125.9 (2), 126.7, 127.1, 128.3 (2), 128.7 (2), 129.4 (4),
131.2, 131.4, 131.9, 132.2, 134.0, 139.5, 140.7, 147.1, 149.3,
152.4, 157.2, 171.6; LCMS: m/z = 636.2 (M+); anal. calcd for
C33H26ClN7O5: C, 62.31; H, 4.12; N, 15.41; found: C, 62.36;
H, 4.05; N, 15.60%.
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(3-nitrophenoxy)acetohydrazide (4q). Yield
55%, mp 183−185 °C; IR (KBr) λmax: 3066, 3085, 3012
(C−H stretching, aromatic ring), 2865 (C−H stretching,
−CH2−), 1620, 1612 (CO stretching), 1520 (NO
stretching, Ar−NO2), 1515, 1425 (CC, CN stretching,
aromatic ring), 1225 (C−O−C stretching, oxadiazole ring),
712 (C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400
MHz): 2.18 (s, 3H, −CH3), 4.65 (s, 2H, −OCH2), 5.70 (s,
1H, C2−H oxadiazole ring), 7.38−7.99 (m, 19H, Ar−H and
C5−H pyrazole), 12.44 (s, 1H, −CONH); 13C NMR (DMSO-
d6, 100 MHz): 12.3, 69.2, 78.1, 111.0, 116.3, 117.1, 119.8 (2),
120.1, 123.8, 125.6 (2), 126.3, 128.3 (2), 128.8 (2), 129.6 (4),
130.7, 131.4, 131.9, 132.4, 134.6, 139.1, 147.1, 149.3, 151.1,
157.9, 161.9, 171.3; LCMS: m/z = 635.6 (M+); anal. calcd for
C33H26ClN7O5: C, 62.31; H, 4.12; N, 15.41; found: C, 62.36;
H, 4.20; N, 15.50%.
https://doi.org/10.1021/acsomega.1c04411
ACS Omega 2021, 6, 28270−28284
ACS Omega http://pubs.acs.org/journal/acsodf
Characterization of N′-(1-(2-(3-(4-Chlorophenyl)-1-phe-
nyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-oxadiazol-3(2H)-yl)-
ethylidene)-2-(4-nitrophenoxy)acetohydrazide (4r). Yield
66%, mp 207−210 °C; IR (KBr) λmax: 3061, 3080, 3014
(C−H stretching, aromatic ring), 2800 (C−H stretching,
−CH2−), 1610, 1623 (CO stretching), 1525 (NO
stretching, Ar−NO2), 1517, 1410 (CC, CN stretching,
aromatic ring), 1220 (C−O−C stretching, oxadiazole ring),
725 (C−Cl stretching) cm−1; 1H NMR (DMSO-d6, 400
MHz): 2.14 (s, 3H, −CH3), 4.63 (s, 2H, −OCH2), 5.72 (s,
1H, C2−H oxadiazole ring), 7.25−8.15 (m, 19H, Ar−H and
C5−H pyrazole), 12.47 (s, 1H, −CONH); 13C NMR (DMSO-
d6, 100 MHz): 12.7, 69.3, 78.4, 115.0 (2), 117.9, 119.3 (2),
123.0, 125.1 (2), 125.6 (2), 126.7, 128.0 (2), 128.6 (2), 129.4
(4), 131.0, 131.5, 132.7, 134.7, 139.5, 140.6, 147.8, 149.7,
157.6, 164.6, 171.9; LCMS: m/z = 636.1 (M+); anal. calcd for
C33H26ClN7O5: C, 62.41; H, 4.12; N, 15.41; found: C, 62.50;
H, 4.23; N, 15.50%.
Characterization of 2-(2-Chlorophenoxy)-N′-(1-(2-(3-(4-
chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-ox-
adiazol-3(2H)-yl)ethylidene)acetohydrazide (4s). Yield 73%,
mp 269−272 °C; IR (KBr) λmax: 3061, 3080, 3014 (C−H
stretching, aromatic ring), 2800 (C−H stretching, −CH2−),
1610, 1623 (CO stretching), 1525, 1410 (CC, CN
stretching, aromatic ring), 1220 (C−O−C stretching,
oxadiazole ring), 740, 725 (C−Cl stretching) cm−1; 1H
NMR (DMSO-d6, 400 MHz): 2.18 (s, 3H, −CH3), 4.69 (s,
2H, −OCH2), 5.71 (s, 1H, C2−H oxadiazole ring), 6.95−7.98
(m, 19H, Ar−H and C5−H pyrazole), 12.52 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.0, 68.9,
78.0, 112.7, 117.3, 119.2 (2), 122.8, 122.9, 123.0, 125.3 (2),
126.7, 127.3, 128.6 (2), 128.8 (2), 129.5 (4), 131.0, 131.8,
132.0, 132.7, 134.9, 139.3, 147.9, 149.4, 154.3, 157.6, 171.6;
LCMS: m/z = 625.3 (M+); anal. calcd for C33H26Cl2N6O3: C,
63.37; H, 4.19; N, 13.44; found: C, 63.40; H, 4.20; N, 13.55%.
Characterization of 2-(4-Chlorophenoxy)-N′-(1-(2-(3-(4-
chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-phenyl-1,3,4-ox-
adiazol-3(2H)-yl)ethylidene)acetohydrazide (4t). Yield 69%,
mp 280−282 °C; IR (KBr) λmax: 3051, 3088, 3012 (C−H
stretching, aromatic ring), 2850 (C−H stretching, −CH2−),
1612, 1623 (CO stretching), 1512, 1413 (CC, CN
stretching, aromatic ring), 1224 (C−O−C stretching,
oxadiazole ring), 750, 725 (C−Cl stretching) cm−1; 1H
NMR (DMSO-d6, 400 MHz): 2.23 (s, 3H, −CH3), 4.72 (s,
2H, −OCH2), 5.70 (s, 1H, C2−H oxadiazole ring), 6.90−7.98
(m, 19H, Ar−H and C5−H pyrazole), 12.58 (s, 1H,
−CONH); 13C NMR (DMSO-d6, 100 MHz): 12.8, 69.5,
78.4, 117.0, 117.6 (2), 119.7 (2), 123.0, 125.8 (2), 126.0,
126.9, 128.7 (2), 128.9 (2), 129.3 (4), 130.7 (2), 131.7, 131.9,
132.7, 134.9, 139.6, 147.8, 149.0, 156.9, 157.6, 171.4; LCMS:
m/z = 625.4 (M+); anal. calcd for C33H26Cl2N6O3: C, 63.37;
H, 4.19; N, 13.44; found: C, 63.50; H, 4.30; N, 13.55%.
Methodology for Molecular Docking. The molecular
docking study was performed with the Glide (Grid-Based
Ligand Docking with Energetics)35−37 module incorporated in
the Schrödinger molecular modeling software (Schrödinger,
Inc., USA, 2016) to gain an insight into the binding modes of
the oxadiazole derivatives (4a−t) into the active site of the
mycobacterial enoyl reductase (InhA) enzyme. With this
purpose, the crystal structure of the mycobacterial enoyl
reductase (InhA) complexed with its inhibitor was retrieved
from the protein data bank (PDB) (PDB code: 4TZK).38
Since the protein structure file obtained from the PDB was not
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suitable for use in molecular docking studies, first, the
optimization and minimization of the enzyme-inhibitor
complex were performed using the protein preparation wizard
tool applying the OPLS-2005 force field. This involved
eliminating the crystallographically observed water molecules
(water without H bonds) since no water molecule was found
to be conserved in the ligand−protein interaction, adding
hydrogen atoms corresponding to pH 7.0 considering the
appropriate ionization states for the acidic as well as basic
amino acid residues assigning the correct bond orders.
Following the assignment of charge and protonation state,
finally, energy minimization was performed using the OPLS-
2005 force field until the average root-mean-square deviation
(RMSD) of the nonhydrogen atoms reached 0.3 Å to relieve
the steric clashes among the residues due to the addition of
hydrogen atoms.
On the other hand, the initial 3D structures of the
oxadiazole derivatives were sketched using the build panel in
Maestro and subsequently optimized through the LigPrep
module that performs addition of hydrogen atoms; adjustment
of realistic bond lengths as well as angles; and correction of
chiralities, ionization states, tautomers, stereochemistries, and
ring conformations. Partial atomic charges were ascribed using
the OPLS-2005 force field, and possible ionization states were
generated for each ligand at a pH of 7.0. Finally, the geometries
of these compounds were optimized by energy minimization
until a gradient of 0.01 kcal/mol/Å was reached.
After ensuring that the ligand and protein structures were in
the correct form, the shape and properties of the binding site of
the InhA enzyme were defined and set up for docking using the
receptor grid generation panel. Since the inhibitor’s coordinates
in the complex are known, the active site was defined by a 10 ×
10 × 10 Å box centered on the native ligand in the crystal
complex. The receptor grid generation program uses two cubical
boxes with a common centroid for calculations: a larger
enclosing and a smaller binding box. With the non-covalently
bound cocrystallized ligand, the grid file was created using this
native ligand at the center of the two boxes which were kept
sufficiently large in order to allow the ligands to explore a large
portion of the enzyme structure in search of the best binding
conformation.
These optimized protein and ligand geometries were used as
input for the binding affinity study. Glide is an interactive
molecular graphics program for studying ligand−receptor
interactions and identifying the probable binding site for the
biomolecules. The final scoring and ranking of the docked
poses were carried out using Schrödinger’s proprietary extra
precision (i.e., with GlideXP) scoring function. The scoring
function is equipped with force-field-based parameters that
account for contributions from steric and electrostatic
interaction energies, solvation and repulsive interactions,
hydrophobic interactions, hydrogen bonding, and metal−
ligand interactions, all incorporated in the empirical energy
functions. Maestro’s Pose Viewer utility was used to visualize
and analyze the output file generated in terms of the docking
poses of the ligands for the key elements of interaction with the
enzyme.
■
ASSOCIATED CONTENT
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsomega.1c04411.
https://doi.org/10.1021/acsomega.1c04411
ACS Omega 2021, 6, 28270−28284
ACS Omega http://pubs.acs.org/journal/acsodf
Additional figures illustrating the characterization of
synthetics by 1H NMR and 13C NMR, mass, and IR
spectra (PDF)
■
AUTHOR INFORMATION
Corresponding Author
Nisheeth C. Desai − Division of Medicinal Chemistry,
Department of Chemistry, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University,
Bhavnagar, Gujarat 364002, India; orcid.org/0000-
0001-6864-8661; Email: dnisheeth@rediffmail.com
Authors
Kandarp Bhatt − Division of Medicinal Chemistry,
Department of Chemistry, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University,
Bhavnagar, Gujarat 364002, India
Jahnvi Monapara − Division of Medicinal Chemistry,
Department of Chemistry, Mahatma Gandhi Campus,
Maharaja Krishnakumarsinhji Bhavnagar University,
Bhavnagar, Gujarat 364002, India
Unnat Pandit − Special Centre for Systems Medicine,
Jawaharlal Nehru University, New Delhi 110067, India;
orcid.org/0000-0001-5526-9814
Vijay M. Khedkar − Department of Pharmaceutical
Chemistry, School of Pharmacy, Vishwakarma University,
Pune, Maharashtra 411048, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsomega.1c04411
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Prof. Nisheeth C. Desai is thankful to the University Grant
Commission, New Delhi, for the financial support under BSR
Faculty-Fellowship 2019 (F18-1/2011 (BSR)). Jahnvi D.
Monapara is grateful to the Department of Science and
Technology, INSPIRE PROGRAM, for the award of INSPIRE
Fellowship (IF180817). The authors are thankful to the
National Repository of Small Molecules (NRM) facility, CSIR-
National Chemical Laboratory (CSIR-NCL), Pune, for
performing the antitubercular activity. The authors are also
thankful to Schrödinger Inc. for providing the demo license of
Schrödinger Suite that has tremendously helped in the
computational study. The authors are also thankful to Priyanka
Desai, founder of iScribblers, for the linguistic editing of the
manuscript.
■
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