1,3-Oxazole-isoniazid hybrids: Synthesis, antitubercular activity, and their docking studies

Article abstract of DOI:10.1002/jhet.3893

A series of novel N′-([2-aryl-5-methyl-1,3-oxazole-4-yl]methylene)isonicotino/nicotino hydrazides 10a-l were prepared by the condensation reaction of 2-aryl-5-methyl-1,3-oxazole-4-carbaldehydes 8a-f with the corresponding isonicotino/nicotino hydrazides 9

Full text of DOI:10.1002/jhet.3893

Received: 24 November 2019
DOI: 10.1002/jhet.3893
Revised: 12 December 2019
Accepted: 24 December 2019
A R T I C L E
1,3-Oxazole-isoniazid hybrids: Synthesis, antitubercular
activity, and their docking studies
Shailesh R. Shah | Kanubhai D. Katariya
Department of Chemistry, Faculty of
Abstract
Science, The Maharaja Sayajirao
University of Baroda, Vadodara, India
A series of novel N0-([2-aryl-5-methyl-1,3-oxazole-4-yl]methylene)isonicotino/
nicotino hydrazides 10a-l were prepared by the condensation reaction of
2-aryl-5-methyl-1,3-oxazole-4-carbaldehydes 8a-f with the corresponding
isonicotino/nicotino hydrazides 9a/9b. The structures of the new compounds
were elucidated by various spectroanalytical techniques, including IR, 1H
NMR, 13C NMR, elemental (C,H,N), and mass analysis. All the newly prepared
INH-1,3-oxazole hybrids were evaluated for their in vitro antitubercular activ-
ity against Mycobacterium tuberculosis H37Rv. Among all the synthesized
hybrids, compounds 10c and 10i derivatives displayed highest antitubercular
activity with minimal inhibitory concentration 1.56 μg/mL. Further, molecular
docking studies against the InhA enzyme were carried out to understand the
interactions between potent hybrids and the target enzyme. Thus, these kind
hybrids have the potentiality for the discovery of new antitubercular agents for
deployment in the control and eradication of tuberculosis.
Correspondence
Kanubhai D. Katariya, Department of
Chemistry, Faculty of Science, The
Maharaja Sayajirao University of Baroda,
Vadodara 390002, India.
Email: kanukatariya-chemphd@
msubaroda.ac.in
Funding information
University Grants Commission
1 | INTRODUCTION
Nitrogen-containing heterocycles constitute a major part
of natural products[6] and possess a wide range of applica-
Tuberculosis (TB) is one of the deadly diseases and remains
a foremost global health problem as it is still a leading
killer in the world.[1,2] Approximately 100 million people
are affected with TB every year. TB accounts for nearly
3 million deaths worldwide annually.[3] The development
of drug-resistant TB, multidrug-resistant TB, and total drug
resistance increases the challenges in the elimination of TB
worldwide.[2] It has been reported that a few bacterial
strains have developed drug resistance to as many as nine
drugs.[4] Natural products are extremely useful templates
for the development of a number of the new drug mole-
cules[5] and they have received immense attention as
potential anti-TB agents.[6,7] Various natural products have
been reported to show resistant against strains of Mycobac-
terium tuberculosis.[8–10] No new anti-TB drugs have been
developed in the TB therapy in the course of the past few
years, creating an urgent need of design and developing of
new drugs and strategies for an effective TB treatment.
tions in medicinal chemistry.[11,12] Isoniazid (INH) is iso-
nicotinic acid hydrazide, which is a widely employed first-
line drug used for the treatment of TB[13,14] for more than
60 years and it still rests one of the furthermost effective anti-
TB drug agents. INH and its derivatives, the N-containing
heterocyclic hydrazide and derivatives, have added impor-
tance in medicinal chemistry due to their variety of biological
activities such as antimycobacterial,[15] antibacterial,[16]
antivirus,[17] antifungal,[18] antitumor,[19] and analgesic[20]
activities. Among the numerous activities, the anti-TB activ-
ity is significant and due to that, it is currently used in the
treatment of TB. Within the last few years, syntheses of sev-
eral derivatives of INH have been reported and some of them
display excellent in vitro antimycobacterial activity.[21,22] On
the other hand, compounds possessing oxazoles have also
displayed promising anti-TB activity.[23]
Hydrazones showed diverse biological activities not
only because of hydrazone linkage but also due to various
J Heterocyclic Chem. 2020;1–10.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
SHAH AND KATARIYA
heterocyclic moieties brought together either from
hydrazine, hydrazide or from a carbonyl compound.
Hydrazones have been studied widely for a variety of
biological activities including antimycobacterial,[24]
antimalarial,[25] antibacterial,[26] antidepressant,[27]
anticonvulsant,[28] anti-inflammatory,[29] analgesic,[25]
and antitumor[30] activities. Due to broad biological
activities of hydrazones, various types of hydrazides and
hydrazones have attracted continuous interest in the
medicinal field; among them, INH hydrazone deriva-
tives exhibit excellent anti-TB activity[15,26] (Figure 1).
In recent times, the amalgamation of biologically active
molecules has been one of the most modern topics in the
field of medicinal chemistry. It is assumed that the combi-
nation of two or more bioactive heterocycles in a single
molecule may not only synergize their biological potency
but may also improve their ability to act upon more than
one biological target. As per the reports, a large number of
scaffolds with the incorporation of two molecular entities
on a single frame, with varied biological profiles, display
unusual enhanced biological properties.[31]
Keeping this in mind, we have designed and synthe-
sized target molecules (10a-l) based on the concept of
molecular hybridization, which makes it possible to bring
together biologically potent entities, that is, INH-oxazole,
into a single molecular framework Figure 2. All new
INH-oxazole hybrids were characterized using various
spectroanalytical techniques and were evaluated for their
in vitro antitubercular activity against M. tuberculosis
H37Rv. Further, molecular docking study was carried out
to understand the interactions between synthesized mole-
cules and InhA enzyme.
2 | RESULTS AND DISCUSSION
2.1 | Chemistry
The synthesis of the final 1,3-oxazole-INH hybrids is
as depicted in Scheme 1. The synthesis was started with
the preparation of six 2-aryl-5-methyl-1,3-oxazole-
4-carbaldehydes 23a-e. Consequently, 4-substituted benz-
aldehydes 5a-f were reacted with diaceyl monoxime in
glacial acetic acid to give 2-aryl-4,5-dimethyl-1,3-oxazole-
3-oxides 6a-f,[32] which were further converted to 2-aryl-
4-(chloromethyl)-5-methyl-1,3-oxazoles 7a-f on heating
with POCl3 in dichloroethane.[32] The 2-aryl-5-methyl-1,
3-oxazole-4-carbaldehydes 8a-f were obtained by reacting
2-aryl-4-(chloromethyl)-5-methyl-1,3-oxazoles 7 with bis-
TBAC (Bis-Tetrabutylammonium dichromate) in chloro-
form[33] (Scheme 1). Some oxazolyl carbaldehydes 8a-f are
reported using some other synthetic route with no physical
or spectral data available.[34,35] Further employing these
oxazolyl carbaldehydes, N0-([2-Aryl-5-methyl-1,3-oxazolyl]
methylene) isonicotino/nicotino-hydrazides 10a-l were
FIGURE 1 Isoniazid-based hydrazone derivatives as anti-
tuberculosis agents
FIGURE 2 Design strategy for the
synthesis of hydrazone linked isoniazid-
1,3-oxazole hybrids via molecular
hybridization approach

SHAH AND KATARIYA
3
O
SCHEME 1 Synthesis of
1,3-oxazole-isoniazid hybrids
CHO
O
Cl
N
N
N
i
iii
ii
H
O
O
O
R
R
R
R
5
6
8
7
8a, R = H; 8b, R = CH3; 8c, R = OCH3; 8d, R = Cl, 8e, R = Br, 8f, R = F
H
O
N
Ar
+
R
H2N
Ar =
N
O
N
N
O
9a
9b
9
8
iv
O
O
R
N
N
N
Ar
H
10
10a/10g; R = H
10c/10i; R = OCH3 10d/10j; R = Cl
10e/10k; R = Br 10f/10l; R = F
10b/10h; R = CH3
Reagents and conditions: i) Diacetyl monoxime, AcOH, HCl (g), 3h ii) POCl3,
1,2-dichloroethane, 6h iii) Bis-TBAC, CHCl3, 2h, iv) EtOH, AcOH, 80 oC, 3-4 h.
synthesized by condensation[36] of 2-aryl-5-methyl-1,-
3-oxazole-4-carbaldehydes 8a-f with the corresponding
isonicotino/nicotino hydrazides 9a/9b in ethanol using
acetic acid as a catalyst to afford the final new INH-1,-
3-oxazole hybrids 10a-l. All the synthesized aryl
oxazolyl carbaldehydes 8(a-f) and 1,3-oxazole-INH
hybrids 10(a-l) were characterized by various spectro-
analytical techniques.
signals were similar to the structures of the corresponding
hybrid compounds and are found in between δ 124 and
159 ppm. All the synthesized aryl oxazolyl carbaldehydes 8
(a-f) and hybrids 10(a-l) were analyzed with the help of
Shimadzu, GC-MS QP-2010 Plus mass spectrometer. The
molecular ion peaks of all the compounds were observed
as (M + H)+ and were found to be in accordance with the
expected mass values.
The IR spectra of 1,3-oxazole-INH hybrids 10(a-l)
showed the typical N─H stretching bands in between 3295
and 3200 cm−1. A strong band of C═O stretching was
observed at ~1695 cm−1. The 1,3-oxazole-INH hybrids 10
2.2 | Antitubercular activity study
1
(a-f) showed characteristic H NMR signals with distinct
All the new 1,3-oxazole-INH hybrid compounds 10(a-l)
were evaluated for their antitubercular activity against
M. tuberculosis H37Rv strain. The minimal inhibitory
concentration (MIC) was evaluated for all compounds,
which were measured as the minimum concentration of
tested compound required to inhibit the bacterial growth
completely. The MIC values (μg/mL) of all the newly syn-
thesized compounds 10a-l and three antitubercular drugs
(INH, Rifampicin, Ethambutol) as a standard were deter-
mined in triplicate and are as presented in Table 1.
chemical shifts for different kinds of protons. The methyl
protons were observed at δ 2.6 ppm for all the 12 com-
pounds. The methylene proton on the imine linkage
(─N═CH─) was observed as singlet between δ 7.4 and
7.5 ppm, and N─H proton of the hydrazine group was
observed most downfield between δ 12.0 and 14.0 ppm as a
singlet. The aromatic proton of pyridine ring was observed
as a doublet between δ 8.8 and 7.9 ppm with coupling con-
stant J = 6.0 Hz while the other aromatic protons were
observed as a doublet at δ 7.5 and 8.0 ppm, respectively,
with coupling constant J = 8.0 Hz. The 13C NMR spectra of
hybrids 10(a-f) showed methyl carbon on oxazole ring sig-
nal at δ 11.4 ppm and the signal at δ 162 ppm is observed
for the carbonyl carbon (─C═O). The imine carbon
(─C═N) is observed at δ 150.7 ppm for hybrid compounds.
For the compounds, 10(g-l) pyridine ring carbon was
observed at δ 148 ppm. The rest of the aromatic carbon
All
newly
synthesized
compounds
showed
antitubercular activity against MTB with MICs ranged
between 1.56 and 25 μg/mL. Among all the tested com-
pounds, 10c and 10i displayed a potent antitubercular
activity with MIC value of 1.56 μg/mL, two compounds
10b and 10h inhibited MTB with MIC value of 6.25 μg/
mL, and compound 10a showed MIC value of 12.5 μg/
mL. Two compounds 10g and 10a inhibited MTB at MIC

4
SHAH AND KATARIYA
TABLE 1 Lipscomb's parameters, binding affinity, and antitubercular activity (% inhibition) of INH-1,3-oxazole hybrids
ID
─R
Log P
−2.602
−1.921
−1.603
−1.518
−0.699
−1.432
−2.813
−2.811
−1.852
−1.627
−2.047
−0.681
—
Molar refractivity
58.605
61.907
64.737
64.815
71.313
61.404
59.656
64.434
66.766
64.970
70.118
63.095
—
H-bond donor
H-bond acceptors
MIC (μg/mL)
10a
─H
0
2
12.5
6.25
1.56
25
10b
─CH3
─OCH3
─Cl
─Br
─F
0
2
10c
0
3
10d
0
2
10e
0
3
>25
>25
25
10f
0
2
10g
─H
0
2
10h
─CH3
─OCH3
─Cl
─Br
─F
0
2
6.25
1.56
>25
25
10i
0
3
10j
0
2
10k
0
2
10l
0
2
>25
0.1
INH
Rifampicin
Ethambutol
—
—
—
—
—
—
—
—
—
—
0.2
—
—
—
3.13
Abbreviations: INH, isoniazid; MIC, minimal inhibitory concentration.
Bold values in Table 1 corresponding to the compounds showed the highest activity among all synthesized compounds.
value of 25 μg/mL and other four compounds 10e, 10f,
10j, 10l inhibited MTB with MIC at >25 μg/mL. When
compared with the first-line antitubercular drug, Etham-
butol (MIC 3.13 μg/mL) two compounds 10c and 10i
were found to show potent activity (MIC 1.56 μg/mL) as
compared to the standard drug Ethambutol. All the other
compounds showed moderate activity when compared
with other anti-TB drugs, INH (MIC 0.1 μg/mL) and
rifampicin (MIC 0.2 μg/mL).
According to the results obtained in in vitro screen-
ing, the structural correlations of all newly prepared com-
pounds with respect to their antitubercular potency
revealed that compounds bearing methoxy (10c and 10i)
and methyl (10b and 10h) groups on phenyl ring
FIGURE 3 Percentage cell viability of 1,3-oxazole-isoniazid
attached to the oxazole scaffold displayed better activity
compared to other compounds. Compounds with no sub-
stitution on phenyl ring (10a and 10g) showed lesser
activity than compounds 10c and 10i but higher than
those compounds substituted with electron withdrawing
groups (10d, 10e, 10f, 10j, 10k, 10l). Finally, we have con-
cluded that the presence of methyl and methoxy groups
on phenyl ring attached to the oxazole moiety appeared
to be important for observed activity.
hybrids on HEK-293T cells
showed that the potent hybrid analogs 10c and 10i did not
display noteworthy changes in cytotoxicity as compared to
vehicle (DMSO) treatment and can be studied further for
mechanistic evaluation.
The safety profile of antitubercular active 1,3-oxazole-
INH hybrids with MIC ≤12.5 μg/mL were evaluated by
testing in vitro cytotoxicity for Human Embryonic Kid-
ney (HEK-293T) cells employing 3-(4,5-dimethyl thiazol-
2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
Percentage cell viability of five hybrid analogs at 50 μg/mL
concentration are as presented in Figure 3. The results
2.3 | Molecular docking study
Molecular docking studies were performed on all new
1,3-oxazole-INH hybrids 10a-l of the series with the
enzyme, InhA. Docking simulation was done with the
aid of Schrödinger Maestro-11.5. The protein structures
obtained from the protein data bank (PDB code: 1P44)

SHAH AND KATARIYA
5
were initially subjected to various processes such as
removal of water molecules and removal of heteroatoms,
using the Protein Preparation Wizard of Schrödinger
2015. All the compounds (ligands) were filtered by speci-
fying options for screening like remove molecules that
have a molecular weight of greater than 650 remove mol-
ecules with too many H-bond acceptor and donor atoms
acceptor groups >3, Donor groups >3, Energy minimiza-
tion was done by choosing a Ligprep (OPLS) module of
Schrodinger. The extent of the interactions of the docking
study was observed based on the docking score, hydrogen
bonding, π-H and π-π interactions of the ligands with the
protein. The docking score of the compounds is in the
range −7.73 to −9.37 (Table 2). Along with other types of
interactions, one or more hydrogen bonding were
observed by the interactions of the compounds with the
amino acid residues of InhA.
From the results of the docking, the highest docking
score was observed for the compound 10c (−9.37). The
docking score of the two active TB compounds of the series
namely 10i and 10h was found to be −8.96 and −8.57 with
H-bond interaction between Tyr 158 and oxygen atom of
the carbonyl group. Compound 10d also showed π-π inter-
actions with amino acid residue Tyr 158. It is interesting to
note that all five (10a, 10b, 10c, 10h, 10i) and the reference
ligand showed similar interactions in to the active site of
target enzyme. The greater inhibitory activity of compound
10c and 10i with methoxy substitutions and compounds
10b and 10h with methyl substitutions on the phenyl ring
compared with other analogs could be justified based on
the docking results as compounds showed higher docking
score than that of other hybrid compounds. Docking pose
of the two compounds 10a and 10b in the active pocket of
InhA is as shown in Figure 4.
3 | EXPERIMENTAL SECTION
3.1 | General Chemistry
TABLE 2 Docking results of the active 1,3-oxazole-INH
hybrids on InhA
Docking
score
Glide
energy
Amino acids interacted
with ligands
ID
The chemicals were used as received without further
purification. Organic solvents were purified by distilla-
tion prior to use. Column chromatography was carried
out using silica gel (60-120 mesh). Thin-layer chromatog-
raphy was performed on the precoated silica gel 60 F254
aluminium sheets. Melting points are determined in open
capillary and are uncorrected. FT-IR spectra were
recorded on Bruker Alpha FTIR spectrometer between
4000 and 400 cm−1 in solid state as KBr discs. The NMR
INH −13.10
−53.78
−49.30
−50.42
−45.88
−50.52
−42.27
Tyr 158, Met 199, Gly 96
Tyr 158
10c
10i
−9.37
−8.96
−8.58
−8.27
−7.73
Tyr 158
10h
10b
10a
Tyr 158,Gly 96
Tyr 158, Met 199
Tyr 158
Abbreviation: INH, isoniazid.
FIGURE 4 Docking pose of the compounds 10a and 10b in the active pocket of InhA. Yellow dotted line shows hydrogen binding and
blue dotted line represents the hydrophobic interactions

6
SHAH AND KATARIYA
spectra were recorded on 400 MHz Bruker Avance-III
instrument and chemical shifts are given in parts per mil-
lion. In the NMR data for 19F decoupled 1H NMR experi-
ments, the data for the affected signals only are included.
3.2.2 | 5-Methyl-2-(4-methylphenyl)-
1,3-oxazole-4-carbaldehyde, 8b
Yield = 48%; white solid; M.P. = 106ꢀC; IR (KBr)
cm−1: 2918, 2861, 2740, 1689, 1596, 1112, 1052, 769;
1H NMR (400 MHz, CDCl3, δ ppm): 2.41 (s, 3H,
─CH3), 2.73 (s, 3H, ─CH3), 7.28 (d, 2H, J = 8.0 Hz, Ar-
H), 7.94 (d, 2H, J = 8.0 Hz, Ar-H), 10.01 (1s, 1H,
─CHO); 13C NMR (100 MHz, CDCl3, δ ppm): 11.7
(─CH3), 21.5, 123.6, 126.5, 129.6, 135.8, 141.4, 156.3,
160.7, 185.4 (─C═O). ESI-MS: (m/z) 202.0 (M + H)+
for M = C12H11NO2.
1
19F chemical shift values are of H decoupled 19F signals.
Thermo Fischer elemental analyzer was used for elemen-
tal analysis. Mass spectra were recorded on Shimadzu,
GC-MS QP-2010 Plus mass spectrometer.
3.2 | General Procedure For The
Synthesis of 2-aryl-5-methyl-1,3-oxazole-
4-carbaldehydes, 8a-f
2-Aryl-5-methyl-1,3-oxazole-4-carbaldehydes 8a-f were pre-
pared from 4-substituted aldehydes and diacetyl monoxime.
To an ice-cold mixture of 4-substituted aldehydes 5 (1 eq)
and diacetyl monoxime (1 eq) in acetic acid (3-fold), dry HCl
gas was passed for 3 hours at 0ꢀC. The reaction mixture was
then diluted with diethyl ether (6-fold). Separated solid was
filtered, washed with diethyl ether, and dried under vacuum
to obtain 2-aryl-4,5-dimethyloxazole 3-oxide 6 as white
solids. To an ice-cold suspension of 2-aryl-4,5-dimethyl-
1,3-oxazole-3-oxides 6 (1 eq) in dichloro ethane (DCE)
(5-fold) was added POCl3 (1.1 eq) dropwise over a period of
2 hours at 10ꢀC. The reaction mixture was slowly heated to
60ꢀC and stirred at that temperature for 3 hours. The reac-
tion mixture was cooled to room temperature, poured into
ice cold water, and extracted with DCE. The combined
organic extracts were washed with water, dried over CaCl2,
and concentrated under vacuum to furnish 2-aryl-
4-(chloromethyl)-5-methyl-1,3-oxazoles 7 in excellent yields.
A homogeneous solution of the 2-aryl-4-(chloromethyl)-
5-methyl-1,3-oxazoles 7 (1 eq) and bis-tetrabutyl ammonium
dichromate (0.6 eq) in chloroform (7.5 mL) was heated
under reflux for 2 hours. The crude product was filtered
through silica gel to eliminate the chromium salt. The silica
was than washed with diethyl ether (100 mL). Evaporation
of the combined organic layers afforded pure 2-aryl-
5-methyl-1,3-oxazole-4-carbaldehydes 8a-f.
3.2.3 | 2-(4-Methoxyphenyl)-5-methyl-
1,3-oxazole-4-carbaldehyde, 8c
Yield = 51%; light yellow solid; M.P. = 114ꢀC; IR (KBr)
cm−1: 2920, 2839, 1691, 1597, 1441, 1128, 1046, 829; H
1
NMR (400 MHz, CDCl3, δ ppm): 2.73 (s, 3H, ─CH3),
3.71 (s, 3H, ─OCH3), 7.31 (d, 2H, J = 8.0 Hz, Ar-H),
7.86 (d, 2H, J = 8.0 Hz, Ar-H), 10.02 (s, 1H, ─CHO); 13C
NMR (100 MHz, CDCl3, δ ppm): 11.7 (─CH3), 55.8
(─OCH3), 124.6, 126.5, 128.6, 136.8, 140.4, 155.3, 162.7,
185.6 (─C═O). ESI-MS: (m/z) 218.0 (M + H)+ for
M = C12H11NO3.
3.2.4 | 2-(4-Chlorophenyl)-5-methyl-
1,3-oxazole-4-carbaldehyde, 8d
Yield = 59%; white solid; M.P. = 109ꢀC; IR (KBr) cm−1
:
1
3071, 2956, 2853, 2746, 1687, 1596, 1066, 1004, 829; H
NMR (400 MHz, CDCl3, δ ppm): 2.73 (s, 3H, ─CH3), 7.46
(d, 2H, J = 6.8 Hz, Ar-H), 7.90 (d, 2H, J = 6.8 Hz, Ar-H),
10.02 (s, 1H, ─CHO); 13C NMR (100 MHz, CDCl3, δ
ppm): 11.8 (─CH3), 124.8, 127.3, 127.8, 129.0, 129.2,
135.9, 137.4, 156.7, 159.5, 185.3 (─C═O). ESI-MS: (m/z)
221.95 (M + H)+ for M = C11H8ClNO2.
3.2.5 | 2-(4-Bromophenyl)-5-methyl-
1,3-oxazole-4-carbaldehyde, 8e
3.2.1 | 5-Methyl-2-phenyl-1,3-oxazole-
4-carbaldehyde, 8a
Yield = 54%; light yellow solid; M.P. = 128ꢀC; IR (KBr) cm−1:
2956, 2818, 2742, 1687, 1599, 1354, 1064, 1000, 827; 1H NMR
(400 MHz, CDCl3, δ ppm): 2.73 (s, 3H, ─CH3), 7.64 (d, 2H,
J = 8.4 Hz, Ar-H), 7.93 (d, 2H, J = 8.4 Hz, Ar-H), 10.02 (s, 1H,
─CHO); 13C NMR (100 MHz, CDCl3, δ ppm): 11.8 (─CH3),
125.2, 125.6, 127.7, 127.9, 132.0, 132.2, 136.0, 156.7, 159.6,
185.3 (─C═O). ESI-MS: (m/z) 265.90 (M + H)+ for
M = C11H8BrNO2.
Yield = 49%; white solid; M.P. = 88ꢀC; IR (KBr) cm−1
:
1
3064, 2921, 2840, 2741, 1691, 1597, 1129, 1074, 830; H
NMR (400 MHz, CDCl3, δ ppm): 2.73 (s, 3H, ─CH3), 7.49
(m, 3H, Ar-H), 8.07 (m, 2H, Ar-H), 10.04 (s, 1H, ─CHO);
13C NMR (100 MHz, CDCl3, δ ppm): 11.8 (─CH3), 126.3,
126.5, 128.9, 131.0, 135.9, 156.4, 160.4, 185.5 (─C═O).
ESI-MS: (m/z) 188.0 (M + H)+ for M = C11H9NO2.

SHAH AND KATARIYA
7
3.2.6 | 2-(4-Fluorophenyl)-5-methyl-
1,3-oxazole-4-carbaldehyde, 8f
NMR (400 MHz, CDCl3, δ ppm): 2.47 (3H, s, ─CH3), 2.63
(s, 3H, ─CH3), 7.35 (d, 2H, J = 8.0 Hz, Ar-H), 7.49 (s, 1H,
─N═CH─), 7.90 (d, 2H, J = 8.4 Hz, Ar-H), 7.94 (d, 2H,
J = 6.0 Hz, Py-H), 8.86 (d, 2H, J = 6.0 Hz, Py-H), 13.92 (s,
1H, ─NH); 13C NMR (100 MHz, CDCl3, δ ppm): 10.9
(─CH3), 21.6 (─CH3), 121.4, 123.0, 126.3, 129.9, 131.1,
133.0, 140.8, 142.2, 150.6, 151.6, 161.9 (C═O); ESI-MS:
(m/z) 321.14 (M + H)+. Anal. Calc. for C18H16N4O2; C,
64.23; H, 3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
Yield = 50%; light yellow solid; M.P. = 121ꢀC; IR (KBr)
cm−1: 3080, 2841, 2740, 1680, 1604, 1506, 1155, 1048, 850;
1H NMR (400 MHz, CDCl3, δ ppm): 2.73 (s, 3H, ─CH3),
7.18 (m, 2H, Ar-H), 8.15 (m, 2H, Ar-H), 10.02 (s, 1H,
─CHO); 19F NMR (376 MHz, CDCl3, δ ppm): −107.9; 13
C
NMR (100 MHz, CDCl3, δ ppm): 11.8 (─CH3), 116.2,
116.4, 122.4, 129.20, 129.29, 141.8, 144.4, 162.2, 165.9,
185.9 (─C═O). ESI-MS: (m/z) 206.0 (M + H)+ for
M = C11H8FNO2.
3.3.3 | N0-((2-(4-methoxyphenyl)-
5-methyl-1,3-oxazol-4-yl)methylene)
isonicotino-hydrazide,10c
3.3 | General Procedure For The
Synthesis of N0-([2-aryl-5-methyl-1,3-oxazol-
4-yl]methylene)isonicotino/nicotino
hydrazides, 10a-l
Yield = 0.12 g, 79%; light yellow solid; M.P. = 178ꢀC; IR
1
(KBr) cm−1: 3246, 1690, 1525, 1230, 835, 731; H NMR
(400 MHz, CDCl3, δ ppm): 2.47 (s, 3H, ─CH3), 3.71 (s,
3H, ─OCH3), 7.34 (d, 2H, J = 8.0 Hz, Ar-H), 7.51 (s, 1H,
─N═CH─), 7.92 (d, 2H, J = 8.0 Hz, Ar-H), 7.92 (d, 2H,
J = 6.0 Hz, Py-H), 8.86 (d, 2H, J = 6.0 Hz, Py-H), 13.92 (s,
1H, ─NH); 13C NMR (100 MHz, CDCl3, δ ppm): 10.9
(─CH3), 58.1(─OCH3), 121.5, 124.0, 125.3, 129.7, 130.1,
132.4, 141.7, 141.3, 151.7, 150.8, 161.8 (C═O); ESI-MS:
(m/z) 336.01 (M + H)+; Anal. Calc. for C18H16N4O3; C,
64.23; H, 3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
To a magnetically stirred solution of 2-aryl-5-methyl-1,
3-oxazole-4-carbaldehydes 8a-f (0.54 mmol, 1 eq) in etha-
nol, was added an equimolar amount INH 9a/9b
(0.54 mmol, 1 eq) and a few drops of acetic acid as a cata-
lyst. The reaction mixture was refluxed for 3 to 4 hours
until the completion of the reaction is observed on TLC.
After completion of the reaction, the reaction mixture
was poured on crushed ice. The solids precipitated were
filtered, washed with ethanol, and recrystallized from
ethanol to afford the desired compounds.
3.3.4 | N0-((2-(4-chlorophenyl)-5-methyl-
1,3-oxazol-4-yl)-methylene)-isonicotino-
hydrazide,10d
3.3.1 | N0-([5-methyl-2-phenyl-1,3-oxazol-
4-yl]-methylene)-isonicotinohydrazide, 10a
Yield = 0.10 g, 71%; light yellow solid; M.P. = 178ꢀC; IR
1
(KBr) cm−1: 3261, 1695, 1536, 1290, 866, 736; H NMR
Yield = 0.12 g, 74%; light yellow solid; M.P. = 174ꢀC; IR
(400 MHz, CDCl3, δ ppm): 2.65 (s, 3H, ─CH3), 7.49 (s,
1H, ─N═CH─), 7.53 (d, 3H, J = 8.8 Hz, Ar-H), 7.91 (d,
2H, J = 4.4 Hz, Py-H), 7.94 (d, 2H, J = 8.8 Hz, Ar-H), 7.95
(s, 1H, ─N═CH─), 8.86 (d, 2H, J = 4.4 Hz, Py-H), 13.73
(s, 1H, ─NH); 13C NMR (100 MHz, CDCl3, δ ppm): 10.9
(─CH3), 121.3, 124.5, 126.3, 127.7, 131.3, 132.5, 132.6,
1140.7, 150.7, 152.4, 158.8, 162.0 (C═O); ESI-MS: (m/z)
341.08 (M + H)+; Anal. Calc. for C17H13ClN4O2; C,
64.23; H, 3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
1
(KBr) cm−1: 3248, 1690, 1554, 1287, 1218, 846, 687; H
NMR (400 MHz, CDCl3, δ ppm): 2.65 (s, 3H, ─CH3), 7.51
(s, 1H, ─N═CH─), 7.56 (m, 3H, Ar-H), 7.94 (d, 2H,
J = 6.0 Hz, Py-H), 8.02 (d, 2H, J = 7.6 Hz, Ar-H), 8.87 (d,
2H, J = 6.0 Hz, Py-H), 13.88 (s, 1H, ─NH); 13C NMR
(100 MHz, CDCl3, δ ppm): 10.9 (─CH3), 121.3, 124.5,
126.3, 127.7, 131.3, 132.5, 132.6, 1140.7, 150.7, 152.4,
158.8, 162.0 (C═O); ESI-MS: (m/z) 307.11 (M + H)+;
Anal. Calc. for C17H14N4O2; C, 64.23; H, 3.97; N, 3.94;
found: C, 63.98; H, 3.75; N, 3.69.
3.3.5 | N0-((2-(4-bromophenyl)-5-methyl-
1,3-oxazol-4-yl)-methylene)isonicotino-
hydrazide, 10e
3.3.2 | N0-((5-methyl-2-(4-methylphenyl)-
1,3-oxazol-4-yl)-methylene)isonicotino-
hydrazide, 10b
Yield = 0.11 g, 78%; light yellow solid; M.P. = 184ꢀC; IR
1
(KBr) cm−1: 3264, 1695, 1535, 1283, 866, 731; H NMR
Yield = 0.12 g, 79%; light yellow solid; M.P. = 194ꢀC; IR
(400 MHz, CDCl3, δ ppm): 2.65 (s, 3H, ─CH3), 7.49 (s,
1H, ─N═CH─), 7.69 (d, 2H, J = 8.4 Hz, Ar-H), 7.86 (d,
1
(KBr) cm−1: 3246, 1692, 1500, 1288, 122, 839, 731; H

8
SHAH AND KATARIYA
2H, J = 8.4 Hz, Ar-H), 7.91 (d, 2H, J = 6.0 Hz, Py-H), 8.86
(d, 2H, J = 6.0 Hz, Py-H), 13.72 (s, 1H, ─NH); 13C NMR
(100 MHz, CDCl3, δ ppm): 10.9 (─CH3), 121.3, 124.5,
126.3, 127.7, 131.3, 132.5, 132.6, 1140.7, 150.7, 152.4,
158.8, 162.0 (C═O); ESI-MS: (m/z) 358.03 (M + H)+;
Anal. Calc. for C17H13BrN4O2; C, 64.23; H, 3.97; N, 3.94;
found: C, 63.98; H, 3.75; N, 3.69.
7.70 (d, 2H, J = 8.4 Hz, Ar-H), 7.89 (d, 2H, J = 8.4 Hz,
Ar-H), 8.41 (d, 1H, J = 8.0 Hz, Py-H), 8.83 (d, 1H,
J = 4.4 Hz, Py-H), 9.29 (s, 1H, Py-H), 13.70 (s, 1H, ─NH
proton); 13C NMR (100 MHz, CDCl3, δ ppm): 11.5
(─CH3), 21.5 (─CH3), 124.1, 124.2, 126.3, 129.6, 130.2,
132.0, 135.8, 141.1, 141.3, 148.9, 150.4, 152.8, 159.9, 161.9
(─C═O); ESI-MS: (m/z) 321.14 (M + H)+; Anal. Calc. for
C18H16N4O2; C, 64.23; H, 3.97; N, 3.94; found: C,
63.98; H, 3.75; N, 3.69.
3.3.6 | N0-((2-(4-fluorophenyl)-5-methyl-
1,3-oxazol-4-yl)-methylene)
isonicotinohydrazide, 10f
3.3.9 | N0-((2-(4-methoxyphenyl)-
5-methyl-1,3-oxazol-4-yl)methylene)
nicotinohydrazide, 10i
Yield = 0.11 g, 74%; light yellow solid; M.P. = 188ꢀC; IR
1
(KBr) cm−1: 3255, 1694, 1498, 1290, 871, 739; H NMR
(400 MHz, CDCl3, δ ppm): 2.65 (s, 3H, ─CH3), 7.24 (d,
2H, J = 8.8 Hz, Ar-H), 7.49 (s, 1H, ─N═CH─), 7.91 (d,
1H, J = 6.0 Hz, Py-H), 8.02 (m, 2H, Ar-H), 8.87 (d, 2H,
J = 6.0 Hz, Py-H), 13.76 (s, 1H, ─NH); 19F NMR
(376 MHz, CDCl3, δ ppm): −106.6; 13C NMR (100 MHz,
CDCl3, δ ppm): 10.9 (─CH3), 116.6 (2JCF = 23 Hz), 121.3,
128.5 (2JCF = 8 Hz), 131.2 (3JCF = 3 Hz), 132.8, 140.8,
150.7, 162.0 (─C═O); ESI-MS: (m/z) 325.11 (M + H)+;
Anal. Calc. for C17H13FN4O2; C, 64.23; H, 3.97; N, 3.94;
found: C, 63.98; H, 3.75; N, 3.69.
Yield = 0.12 g, 78%; light yellow solid; M.P. = 182ꢀC; IR
(KBr) cm−1: 3221, 1544, 1275, 836, 721; 1H NMR
(400 MHz, CDCl3, δ ppm): 2.47 (s, 3H, ─CH3 protons),
3.75 (s, 3H, ─OCH3 protons), 7.24 (d, 2H, J = 8.4 Hz, Ar-
H), 7.48 (s, 1H, ─N═CH─), 7.50 (d, 1H, J = 8.4 Hz, Py-
H), 8.04 (d, 2H, J = 8.4 Hz, Ar-H), 8.42 (d, 1H,
J = 8.0 Hz, Py-H), 8.84 (d, 1H, J = 3.2 Hz, Py-H), 9.30 (s,
1H, Py-H), 13.72 (s, 1H, ─NH proton); 13C NMR
(100 MHz, CDCl3, δ ppm): 11.5 (─CH3), 55.8 (─OCH3),
123.1, 124.8, 125.3, 128.7, 131.1, 133.5, 134.8, 140.1, 142.3,
147.5, 151.1, 153.8, 158.6, 161.7 (─C═O); ESI-MS: (m/z)
321.14 (M + H)+; Anal. Calc. for C18H16N4O3; C,
64.23; H, 3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
3.3.7 | N0-([5-methyl-2-phenyl-1,3-oxazol-
4-yl]methylene)nicotinohydrazide, 10g
Yield = 0.12 g, 76%; light yellow solid; M.P. = 196ꢀC; IR
3.3.10 | N0-((2-(4-chlorophenyl)-5-methyl-
1,3-oxazol-4-yl)-methylene)-
1
(KBr) cm−1: 3223, 1655, 1561, 1288, 1194, 874; H NMR
(400 MHz, DMSO-d6, δ ppm): 2.61 (s, 3H, ─CH3 protons),
7.54 (s, 1H, ─N═CH─), 7.58 (m, 4H, Ar-H), 7.98 (d, 2H,
J = 4.8 Hz, Py-H), 8.25 (d, 1H, J = 8.0 Hz, Ar-H), 8.76 (d,
1H, J = 4.8 Hz, Py-H), 9.04 (d, 1H, J = 2.0 Hz, Py-H),
12.06 (s, 1H, ─NH proton); 13C NMR (100 MHz, DMSO-
d6, δ ppm): 11.4 (─CH3), 124.2, 126.3, 126.7, 129.4, 129.7,
131.3, 132.1, 135.9, 141.1, 148.8, 151.0, 152.8, 159.8, 162.1
(─C═O); ESI-MS: (m/z) 307.12 (M + H)+; Anal. Calc. for
C17H14N4O2; C, 64.23; H, 3.97; N, 3.94; found: C,
63.98; H, 3.75; N, 3.69.
nicotinohydrazide, 10j
Yield = 0.10 g 70%; light yellow solid; M.P. = 194ꢀC; IR
(KBr) cm−1: 3295, 1690, 1541, 1289, 845, 734; H NMR
1
(400 MHz, CDCl3, δ ppm): 2.65 (s, 3H, ─CH3 protons),
7.52 (s, 1H, ─N═CH─), 7.52 (m, 3H, Ar-H), 7.97 (d, 2H,
J = 8.4 Hz, Ar-H), 8.42 (d, 1H, J = 4.0 Hz, Py-H), 8.84 (d,
1H, J = 4.0 Hz, Py-H), 9.30 (s, 1H, Py-H), 13.71 (s, 1H,
─NH proton); 13C NMR (100 MHz, CDCl3, δ ppm): 11.6
(─CH3), 124.1, 125.6, 128.1, 129.8, 132.3, 135.9, 141.1,
148.9, 150.9, 15.8, 158.8 (─C═O); ESI-MS: (m/z) 341.08
(M + H)+; Anal. Calc. for C17H13ClN4O2; C, 64.23; H,
3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
3.3.8 | N0-((5-methyl-2-(4-methylphenyl)-
1,3-oxazol-4-yl)-methylene)-
nicotinohydrazide, 10h
3.3.11 | N0-((2-(4-bromophenyl)-
5-methyl-1,3-oxazol-4-yl)-methylene)-
nicotinohydrazide, 10k
Yield = 0.12 g, 78%; light yellow solid; M.P. = 178ꢀC; IR
(KBr) cm−1: 3218, 1560, 1290, 744, 710; 1H NMR
(400 MHz, CDCl3, δ ppm): 2.47 (s, 3H, ─CH3 protons),
2.63 (s, 3H, ─CH3 protons), 7.48 (s, 1H, ─N═CH─), 7.50
(d, 1H, J = 8.0 Hz, Py-H), 7.53 (s, 1H, ─CH─ proton),
Yield = 0.11 g, 76%; light yellow solid; M.P. = 202ꢀC; IR
1
(KBr) cm−1: 3218, 1650, 1561, 1220, 846, 709; H NMR

SHAH AND KATARIYA
9
(400 MHz, CDCl3, δ ppm): 2.64 (s, 3H, ─CH3), 7.48 (s,
1H, ─N═CH─), 7.50 (d, 1H, J = 8.0 Hz, Py-H), 7.53 (s,
1H, ─CH─ proton), 7.70 (d, 2H, J = 8.4 Hz, Ar-H), 7.89
(d, 2H, J = 8.4 Hz, Ar-H), 8.41 (d, 1H, J = 8.0 Hz, Py-H),
8.83 (d, 1H, J = 4.4 Hz, Py-H), 9.29 (s, 1H, Py-H), 13.70
(s, 1H, ─NH proton); 13C NMR (100 MHz, CDCl3, δ
ppm): 10.9 (─CH3), 123.7, 124.5, 126.2, 127.8, 129.4,
131.3, 132.2, 132.6, 135.9, 148.1, 152.0, 158.8, 162.1
(─C═O); ESI-MS: (m/z) 385.03 (M + H)+; Anal. Calc. for
C17H13BrN4O2; C, 64.23; H, 3.97; N, 3.94; found: C,
63.98; H, 3.75; N, 3.69.
positive control tube and an inoculated tube (negative
control). Bright fluorescence detected by the
corresponding MGIT tube was noticed in the form of
bright orange color in the bottom of the tube and also an
orange reflection on the meniscus. The primary screening
was conducted at concentration of 6.25 μg/mL against
M. tuberculosis H37Rv in BACTEC MGIT system. If any
compound is demonstrating 99% inhibition in the pri-
mary screen, it is described as the most potent com-
pound. All the other compounds were re-examined for
their actual MIC by using Lowenstein-Jensen MIC
method. The highest dilution showing at least 99% inhibi-
tion is taken as MIC.
The secondary antimycobacterial screening for test
compounds was obtained for M. tuberculosis H37Rv, by
using L.J. (Lowenstein and Jensen) MIC method. 2-fold
serial dilutions (50.0, 25.0, 12.5, 6.25, 3.13, 1.56, and
0.78 μg/mL) of each test compound in DMSO (dimethyl
sulfoxide) were added in the liquid L.J. Medium and then
media were sterilized by inspissation method. A culture of
M. tuberculosis H37Rv growing on L.J. medium was
harvested in 0.85% saline in bijou bottles. These tubes were
then incubated at 37ꢀC for 24 hours followed by streaking
of M. tuberculosis H37Rv (5 × 104 bacilli per tube). These
tubes were then incubated at 37ꢀC 1ꢀC. Growth of bacilli
was seen after 12 days, 22 days, and finally 28 days of incu-
bation. Tubes having the compounds were compared with
control tubes where medium alone was incubated with
M. tuberculosis H37Rv. The concentration at which no
development of colonies occurred or <20 colonies was
taken as MIC concentration of test compound. INH was
used as a reference control against M. tuberculosis H37Rv
being a standard drug in use.
3.3.12 | N0-((2-(4-fluorophenyl)-5-methyl-
1,3-oxazol-4-yl)-methylene)-
nicotinohydrazide, 10l
Yield = 0.12 g, 76%; light yellow solid; M.P. = 212ꢀC; IR (KBr)
1
cm−1: 3249, 1692, 1557, 1290, 848, 708; H NMR (400 MHz,
CDCl3, δ ppm): 2.64 (s, 3H, ─CH3), 7.24 (d, 2H, J = 8.4 Hz, Ar-
H), 7.48 (s, 1H, ─N═CH─), 7.50 (d, 1H, J = 8.4 Hz, Py-H), 8.04
(d, 2H, J = 8.4 Hz, Ar-H), 8.42 (d, 1H, J = 8.0 Hz, Py-H), 8.83
(d, 1H, J = 3.2 Hz, Py-H), 9.30 (s, 1H, Py-H),13.72 (s, 1H, ─NH
proton); 19F NMR (376 MHz, CDCl3, δ ppm): −106.9; 13C
NMR (100 MHz, CDCl3, δ ppm): 11.6 (─CH3), 116.8
(2JCF = 22 Hz), 124.1, 128.8, 128.9 (2JCF = 9 Hz), 129.5, 132.2,
135.9, 141.2, 148.9, 152.8, 161.9 (─C═O); ESI-MS: (m/z)
325.12 (M + H)+; Anal. Calc. for C17H13FN4O2; C, 64.23; H,
3.97; N, 3.94; found: C, 63.98; H, 3.75; N, 3.69.
3.4 | Experimental Procedure For
Antitubercular Activity
The preliminary antimycobacterial assessment for the
final synthesized compounds was carried out using
BACTEC mycobacterial growth indicator tube (MGIT)
method. The MGITs containing 4 mL of modified Middle
brook 7H9 Broth Base were numbered as per the title
compounds to be tasted for antimycobacterial efficacy at
various concentrations prepared. The suspension was
allowed to sit for 20 minutes and the tubes were cen-
trifuged at 3000 rpm for 15 minutes. After that, prepared
suspension of 104 to 107 CFU/mL of M. tuberculosis
H37Rv was added in the medium to be incubated and
0.1 mL of egg-based medium (L.J.) was also added. The
MGIT tubes were then tightly recapped, mixed well, and
incubated into BACTEC MGIT instrument at (37 1)ꢀC
until positivity is observed. The readings were measured
daily starting from the second day of incubation. Positive
cultures were usually detected within 10 days. For read-
ing the actual results, the MGIT tubes were removed
from incubator and placed on the UV light next to a
3.5 | Cytotoxicity Evaluation
Anti-tubercular active compounds with MIC ≤12.5 μg/
mL were further examined for cytotoxicity in a HEK-
293T cell line at the concentration 50 μg/mL. After
24 hours of exposure, cell viability of HEK-293T cells was
evaluated based on cellular conversion of MTT into a
formazan product.
4 | CONCLUSION
In this study, we reported the synthesis of N0-([2-aryl-
5-methyl-1,3-oxazole-4-yl]methylene)isonicotino/nicotino
hydrazides 10a-l by the condensation reaction of 2-aryl-
5-methyl-1,3-oxazole-4-carbaldehydes 8a-f with the corr-
esponding isonicotino/nicotino hydrazides 9a/9b. in vitro
antitubercular evaluations and docking studies showed that

10
SHAH AND KATARIYA
[14] J. Palomino, A. Martin, Antibiotics 2014, 3, 317.
[15] Y. Hu, S. Zhang, F. Zhao, C. Gao, L. Feng, Eur J Med Chem
2017, 133, 255.
[16] J. P. Raval, T. N. Akhaja, D. M. Jaspara, K. N. Myangar,
N. H. Patel, J Saudi Chem Soc 2014, 18, 101.
[17] R. Narang, B. Narasimhan, S. Sharma, D. Sriram,
P. Yogeeswari, E. De Clercq, Med Chem Res 2012, 21, 1557.
[18] M. Malhotra, S. Sharma, A. Deep, Med Chem Res 2012, 21,
1237.
[19] P. Dandawate, E. Khan, S. Padhye, H. Gaba, S. Sinha,
J. Deshpande, Bioorg Med Chem Lett 2012, 22, 3104.
[20] G. Nigade, P. Chavan, M. Deodhar, Med Chem Res 2012,
21, 27.
the derivative compounds (10a-l) exhibited important activity
against M. tuberculosis H37Rv. Two hybrid compounds 10c
and 10i displayed the highest inhibition with MIC value of
1.56 μg/mL. Furthermore, the current study showed that the
presence of methyl and methoxy groups significantly affected
the behavior of INH-1,3-oxazole hybrids as antitubercular
agents. Further structural modifications to these derivatives
could be used to prepare a library of antitubercular analogs
with enhanced activity and selectivity.
ACKNOWLEDGMENTS
The authors are thankful to The Department of Chemis-
try, The M S University of Baroda for necessary facilities
to carry this work. Financial assistance from the Univer-
sity Grants Commission (UGC) New Delhi in form of the
Major Research Project MRP 39-897/2010 SR to KDK is
acknowledged. NIRT (National Institute for Research in
TB), Chennai is gratefully acknowledged. NMR facility
from DST-FIST programme is gratefully acknowledged.
[21] N. Nayak, J. Ramprasad, U. Dalimba, Bioorg Med Chem Lett
2015, 25, 5540.
[22] M. O. Rodrigues, J. B. Cantos, C. R. M. D'Oca, K. L. Soares,
T. S. Coelho, L. A. Piovesan, Bioorg Med Chem 2013, 21, 6910.
[23] Y. K. Abhale, A. V. Sasane, A. P. Chavan, S. Husen,
K. K. Deshmukh, S. Bhansali, Eur J Med Chem 2017, 132, 333.
[24] D. Sriram, P. Yogeeswari, K. Madhu, Bioorg Med Chem Lett
2005, 15, 4502.
[25] M. Alam, G. Verma, M. Shaquiquzzaman, A. Marella,
M. Akhtar, M. A. Ali, J Pharm Bioallied Sci 2014, 6, 69.
[26] Ł. Popiołek, Med Chem Res 2017, 26, 287.
[27] K. N. De Oliveira, P. Costa, J. R. Santin, L. Mazzambani,
C. Bürger, C. Mora, Bioorg Med Chem 2011, 19, 4295.
[28] V. Angelova, V. Karabeliov, P. A. Andreeva-Gateva,
J. Tchekalarova, Drug Dev Res 2016, 77, 1.
[29] M. A. Abdelgawad, M. B. Labib, M. Abdel-Latif, Bioorg Chem
2017, 74, 212.
[30] M. C. Mandewale, U. C. Patil, S. V. Shedge, U. R. Dappadwad,
R. S. Yamgar, Beni-Suef Univ J Basic Appl Sci 2017, 6, 354.
[31] S. Mishra, P. Singh, Eur J Med Chem 2016, 124, 500.
[32] D. A. Brooks, G. J. Etgen, C. J. Rito, A. J. Shuker,
S. J. Dominianni, A. M. Warshawsky, J Med Chem 2001, 44,
2061.
[33] P. Rajakumar, M. G. Swaroop, Tetrahedron Lett 2004, 45, 6165.
[34] Cheng, P. T.; Devasthale, P.; Jeon, Y.; Chen, S.; Zhang, H.
United States Patent. US 6,414,002 B1, 2002.
[35] Seiji, S.; Satoshi, M.; Chiharu, M.; Motohiro, I.; Toshio, S.;
Shigekazu, F. World Intellectual Property Organization. WO
2015/008872 A1, 2015.
[36] A. M. Vijesh, A. M. Isloor, S. Prashant, S. Sundershan, H. Kun
Fun, Eur J Med Chem 2013, 62, 410.
ORCID
Kanubhai D. Katariya https://orcid.org/0000-0003-
3860-4355
REFERENCES
[1] J. C. Garcia-Monco, Tuberculosis. in Neurologic Aspects of Sys-
temic Disease Part III, Vol. 121 (Eds: J. Biller, J. M. Ferro), Edin-
burgh, London: Elsevier, 2014, p. 1485.
[2] J. Heyckendorf, C. Lange, J. Martensen, Multidrug-Resistant Tuber-
culosis. in Emerging Infectious Diseases (Eds: Ö. Ergönül, F. Can,
L. Madoff, M. Akova), Academic Press, Amsterdam 2014, p. 420.
[3] M. Basanagouda, V. B. Jambagi, N. N. Barigidad,
S. S. Laxmeshwar, V. Devaru, Narayanachar Eur J Med Chem
2014, 74, 225.
[4] K. A. El Sayed, P. Bartyzel, X. Shen, T. L. Perry,
J. K. Zjawiony, M. T. Hamann, Tetrahedron 2000, 56, 949.
[5] D. J. Newman, G. M. Cragg, J Nat Prod 2016, 79, 629.
[6] J. A. Joule, Chapter four—natural products containing nitro-
gen heterocycles—some highlights 1990–2015. in Heterocyclic
Chemistry in the 21st CenturyA Tribute to Alan Katritzky, Vol.
119 (Eds: E. F. V. Scriven, C. A. Ramsden), Edinburgh,
London: Academic Press, 2016, p. 81.
[7] J. M. Nguta, R. Appiah-Opong, A. K. Nyarko, D. Yeboah-
Manu, P. G. A. Addo, Int J Mycobacteriol 2015, 4, 165.
[8] D. Quan, G. Nagalingam, R. Payne, J. A. Triccas, Int J Infect
Dis 2017, 56, 212.
[9] C. E. Salomon, L. E. Schmidt, Curr Top Med Chem 2012, 12, 735.
[10] A. García, V. Bocanegra-García, J. P. Palma-Nicolás, G. Rivera,
Eur J Med Chem 2012, 49, 1.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Shah SR, Katariya KD.
1,3-Oxazole-isoniazid hybrids: Synthesis,
antitubercular activity, and their docking studies.
J Heterocyclic Chem. 2020;1–10. https://doi.org/10.
1002/jhet.3893
[11] S. J. Tantry, S. D. Markad, V. Shinde, J. Bhat, G. Balakrishnan,
K. Amit, J Med Chem 2017, 60, 1379.
[12] Z. Li, X. Bai, Q. Deng, G. Zhang, L. Zhou, Y. Liu, Bioorg Med
Chem 2017, 25, 213.
[13] Z. Ma, A. M. Ginsberg, M. Spigelman, A. Agents, in Compre-
hensive Medicinal Chemistry II (Eds: J. B. Taylor, D. J. Triggle),
Elsevier, Oxford 2007, p. 699.