Quinazoline clubbed thiazole and 1,3,4-oxadiazole heterocycles: synthesis, characterization, antibacterial evaluation, and molecular docking studies

Article abstract of DOI:10.1080/10426507.2021.1871732

In search of potent antibacterial agents, a series of novel quinazolines, bearing thiazole and 1,3,4-oxadiazole heterocycles 6a–j (3-(4-methyl-5-(4-((arylamino)methyl)-5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-ones)

Full text of DOI:10.1080/10426507.2021.1871732

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Quinazoline clubbed thiazole and 1,3,4-oxadiazole
heterocycles: synthesis, characterization,
antibacterial evaluation, and molecular docking
studies
Nisheeth Desai, Niraj Shihory, Ashvinkumar Khasiya, Unnat Pandit & Vijay
Khedkar
To cite this article: Nisheeth Desai, Niraj Shihory, Ashvinkumar Khasiya, Unnat Pandit & Vijay
Khedkar (2021): Quinazoline clubbed thiazole and 1,3,4-oxadiazole heterocycles: synthesis,
characterization, antibacterial evaluation, and molecular docking studies, Phosphorus, Sulfur, and
Silicon and the Related Elements, DOI: 10.1080/10426507.2021.1871732
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
https://doi.org/10.1080/10426507.2021.1871732
Quinazoline clubbed thiazole and 1,3,4-oxadiazole heterocycles: synthesis,
characterization, antibacterial evaluation, and molecular docking studies
Nisheeth Desaia , Niraj Shihorya, Ashvinkumar Khasiyaa, Unnat Panditb, and Vijay Khedkarc
aDivision of Medicinal Chemistry, Department of Chemistry, (DST-FIST Sponsored and UGC NON-SAP), Mahatma Gandhi Campus, Maharaja
b
Krishnakumarsinhji Bhavnagar University, Bhavnagar, Gujarat, India; Intellectual Property Management Cell, Jawaharlal Nehru University,
c
New Delhi, India; Department of Pharmaceutical Chemistry, School of Pharmacy, Vishwakarma University, Pune, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received 21 October 2020
Accepted 1 January 2021
In search of potent antibacterial agents, a series of novel quinazolines, bearing thiazole and 1,3,4-
oxadiazole heterocycles 6a–j (3-(4-methyl-5-(4-((arylamino)methyl)-5-thioxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-ones) were synthesized and the structures of the
compounds were elucidated by standard spectroscopic techniques. In order to evaluate their anti-
bacterial potential, the antibacterial assay of synthesized compounds 6a–j was performed against
MTCC strains, wherein compounds 6d (3-(4-methyl-5-(4-(((4-nitrophenyl)amino)methyl)-5-thioxo-
4,5-dihydro-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-one) (Escherichia coli, MIC ¼
100mg mLꢀ1) and 6e (3-(5-(4-(((2-chlorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-oxadiazol-
2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-4(3H)-one) (E. coli, MIC ¼ 62.5 mg mLꢀ1) were most
active against Gram-negative bacteria while compound 6f (3-(5-(4-(((4-chlorophenyl)amino)-
methyl)-5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-4(3H)-
one) (Staphylococcus aureus, MIC ¼ 50 mg mLꢀ1) was most active against Gram-positive bacteria.
Furthermore, molecular docking simulation was performed to determine the probable binding
mode and affinity of the synthesized compounds toward bacterial DNA gyrase. The preliminary
results pave the way for further designing the thiazole based 1,3,4-oxadiazoles heterocycles for
enhancing their potency as antibacterial agents.
KEYWORDS
1,3,4-oxadiazole; antibacter-
ial activity; molecular
docking; quinazo-
line; thiazole
GRAPHICAL ABSTRACT
Introduction
designed to kill microorganisms is an additional challenge for
those working in this synthetic chemistry field. There is a press-
ing need for the discovery of new and potent antimicrobial
drugs.[3] The deterioration of the human population due to the
high prevalence of infectious diseases is becoming a worldwide
problem.[4] Thiazole, quinazoline, and 1,3,4-oxadiazole scaffolds
and their compounds display a wide range of biological activities
Recently, the study of common scaffolds through a strategic
design of their heterocyclic components has gained major atten-
tion in medicinal chemistry. Heterocycles containing several het-
eroatoms such as oxygen, nitrogen, and sulfur have a critical
importance for medicinal chemists.[1] Infectious diseases caused
by bacteria and viruses are life-threatening and are increasing in
many countries.[2] Overcoming resistance to existing drugs such as antimicrobial,[5–7] antifungal,[8,9] anticancer,[10]
CONTACT Nisheeth Desai
dnisheeth@rediffmail.com
Division of Medicinal Chemistry, Department of Chemistry, (DST-FIST Sponsored and UGC NON-SAP),
Mahatma Gandhi Campus, Maharaja Krishnakumarsinhji Bhavnagar University, Bhavnagar, Gujarat, India.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2021.1871732.
ß 2021 Taylor & Francis Group, LLC

2
N. DESAI ET AL.
Figure 1. Concept of design based on clinical drugs containing the quinazoline, thiazole or 1,3,4-oxadiazole moieties.
antitubercular,[11–14] antimalarial,[15] analgesic,[16] anticonvul- manuscript which is as depicted in Figure 1. DNA gyrase
sant,[17] hypoglycemic,[18] antioxidant,[19] and other biological
subunit b is a target to be inhibited by multiple scaffolds
properties such as genotoxic potential and lipid peroxidation
inhibition.[20,21] On further conjugating, 1,3,4-oxadiazole and
thiazole are proven to demonstrate antimicrobial properties and
to restrain bacteria by blocking their biosynthesis through certain
bacterial lipids by additional mechanisms.[22] In the present
study, we report the scientific rationale in designing hybrid het-
erocycles by conjugating 1,3,4-oxadiazoles with different thiazole
nuclei to form novel heterocyclic compounds exhibiting better
potency toward established microbes. The synthesized com-
pounds are equally promising for medicinal chemists when com-
pared with commercially available drugs containing quinazoline,
thiazole, and 1,3,4-oxadiazole scaffolds. The structural similarities
of these compounds are shown in Figure 1. The most prominent
examples of established agents containing quinazoline, thiazole
and 1,3,4-oxadiazoles nuclei include the Diproqualone,
Avantrombopag, and Lusutrombopag.[23–25]
These research findings motivated us to explore thiazole
based 1,3,4-oxadiazole heterocycles as potential antibacterial
agents. The objective of our study was to explore the com-
bination of three heterocycles which may exhibit synergistic
effect while improving their antibacterial activity. The pre-
sent study reports, (1) novel hybrid heterocyclic molecules
consisting of quinazoline based thiazole, 1,3,4-oxadiazoles;
(2) evaluation of their antibacterial potency; (3) and investi-
gation of their active inhibitor’s interaction with bacterial
DNA gyrase by docking study. In order to strategically
develop and establish novel promising antimicrobial agents,
and also being a target situated in the bacterial cell. It is the
most vulnerable target for the molecules approaching the
bacteria. This motivated us to evaluate the binding affinity
of the title class of molecules against this crucial bacter-
ial enzyme.
Results and discussion
Chemistry
The reaction conditions employed in the synthesis of stra-
tegically designed compounds 6a–j are explained in Scheme
1. The nucleophilic attack of compound
3
with
NH2NH2ꢁH2O afforded compound 4 in EtOH at reflux tem-
perature. Compound 4 was further characterized by the
presence of three strong IR bands showing functional pres-
ence at 3131 (>NH), 3311, and 3255 cmꢀ1 (-NH2) in the IR
spectrum. In compound 4, presence of -NH-NH2 functional
1
group was recorded in the H NMR spectrum at 4.2 (-NH2)
and 8.94 (>NH) ppm. Further, the mass fragmentation and
elemental analysis results were also consistent with the
assigned structure. The condensation of compound 4, with
KOH, CS2 using EtOH at reflux temperature for 12 h,
yielded the corresponding oxadiazole 5. The final com-
pounds 6a–j were derived by coupling reaction of com-
pound 5, with various substituted aniline and HCHO under
reflux using EtOH for 3 h. The structural characterization of
the concept of design thinking was applied in this newly synthesized compounds 6a–j was done by spectral

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
3
Scheme 1. Synthetic pathway of the reported compounds 6a–j.
analysis. The IR spectrum of compound 6a, as an example, modeling was also performed showing the potency of these
exhibited the characteristic absorption band of the carbonyl
group exhibited at 1713 cmꢀ1. The vibrations appeared at
3109, 2940 cmꢀ1 corresponding to C-H stretching, aromatic
ring, -CH3 stretching, and –CH2 stretching, respectively.
Characteristic absorption observed at 1227 cmꢀ1 was due to
C-O-C stretching vibration of 1,3,4-oxadiazole ring. A
strong absorption band observed at 3233 cmꢀ1 is the dis-
scaffolds in the heterocyclic research for scouting novel anti-
bacterial agent. Among the synthesized compounds, (3-(5-
(4-(((4-chlorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-
4(3H)-one) (Compound 6f) possessed excellent activity at
MIC of 50 mg mLꢀ1 and good activity at MIC of
150 mg mLꢀ1 against S. aureus and E. coli respectively [See
Figure S28 (Supporting Information)]. (3-(5-(4-(((2-chloro-
phenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-
yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-4(3H)-one)
(Compound 6e) exhibited very good activity at MIC of
62.5 mg mLꢀ1 and good activity at MIC of 150 mg mLꢀ1
against E. coli and P. aeruginosa respectively. This may be
attributed to the presence of lipophilic H-bond acceptor
type of group like 2-chloro and 4-chloro present on benzene
ring of oxadiazole functionality. (3-(4-methyl-5-(4-(((4-
nitrophenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-oxa-
diazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-one)
(Compound 6d) shown a good activity with MIC of
100 mg mLꢀ1 against E. coli.
1
tinctive peak of (-NH). In H NMR spectra, the emergence
of singlet peaks at d ¼ 2.49 and 5.82 ppm were due to three
protons of methyl groups and proton of –NH respectively.
In the 13C NMR spectrum, synthetic product 6a displayed a
signal at d ¼ 177.5 ppm arising from the C ¼ O group, and
the signal obtained in the region of d ¼ 17.4 ppm confirmed
the presence of carbon of methyl group. The molecular ion
peak is observed at m/z ¼ 542.10 which is in confirmative
evidence of the suggested molecular weight and elemental
analysis. [For detailed information see Supporting
Information].
Antibacterial assay
The in vitro antibacterial activity of newly synthesized tar-
geted compounds 6a–j was screened against pathogenic bac-
terial strains for two Gram-positive bacterial strains like
Experimental
Materials and methods
Staphylococcus
aureus
(MTCC-96),
and
Melting points were determined via in open capillary
method. The reactions were monitored using thin-layer
Streptococcus pyogenes (MTCC-442) while two Gram-nega-
tive bacterial strains like Escherichia coli (MTCC-443) and
Pseudomonas aeruginosa (MTCC-1688) were also used in
the biological screening. The antibacterial potency of the
strategically designed compounds was investigated by min-
imum inhibitory concentration (MIC) applying conventional
broth microdilution method using gentamycin as a reference
drug.[26] The results of antibacterial activity are tabulated in
[Table S1 (Supporting Information)]. Based on the results
presented in this research article and to further design and
chromatography (TLC) on silica gel plates (Merck, 60, F254
)
was used to check purity and reaction monitoring and com-
pletion. Percentage of carbon, hydrogen, and nitrogen were
checked via Perkin-Elmer 2400 CHN analyzer. IR spectra of
the synthesized compounds were recorded on Shimadzu IR
Prestige-21 (CE) Fourier transform infrared spectrophotom-
1
eter using KBr; the frequencies were reported in cmꢀ1. H
NMR spectra were recorded on Varian Gemini at 400 MHz
synthesize active molecules for the future, the molecular and 13C NMR spectra on a Varian Mercury at 100 MHz

4
N. DESAI ET AL.
using dimethyl sulfoxide (DMSO)-d6 as a solvent and tetra- The excess EtOH and unreacted NH2NH2ꢁH2O were dis-
methylsilane as an internal standard. 1H NMR data were tilled out. The reaction mass was poured into a beaker con-
given in multiplicity (s, singlet; d, doublet; t, triplet; m, mul- taining water (100 mL). The solid was crystallized using
tiple) and chemical shifts were in d ppm unit. Mass spectra ethanol to obtain a pure white crystalline product. Yield:
were scanned on a Shimadzu LCMS 2010 spectrometer. The 65%; m.p. 130–132 ꢂC; IR (KBr, cmꢀ1): 3311, 3255 (N-H,
reactions were carried out in oven-dried glass wares under a primary amine), 3131 (N-H, primary amine),3031, 2827 (C-
nitrogen atmosphere and Bu€chi rotavapor was used for the H, -CH ¼ CH-), 2759 (C-H), 1733 (>C ¼ O), 1694,
1
distillation.[27] The progress of the reaction and the purity 1619(C ¼ C, C ¼ N), 1234 (C-O-C), 1147 (C ¼ S), H NMR
of the synthesized compound was checked on TLC (400 MHz, DMSO-d6): d ¼ 8.9 (m, 1H, -NH-NH2), 8.2 ꢀ 7.3
[Aluminium sheet silica gel 60 F254 (E. Merck)] using n-hex- (m, 9H, Ar-H), 4.2 (m, 2H, -NH-NH2), 2.4 (m, 3H, Het-
ane: ethyl acetate (7:3) as an irrigator and the plates were CH3), 13C NMR (100 MHz, DMSO-d6): d ¼ 166.7 (C2 of
developed in an iodine chamber or observed under UV thiazole ring), 160.3(2) (C4 of quinazoline ring and C-
1
light. The Supporting Information contains sample IR, H, C ¼ O-N), 156.8 (C4 of thiazole ring), 155.1 (C2 of quinazo-
and 13C NMR spectra of the products 6 (Supporting line ring), 147.6 (C10 quinazoline ring), 133.8 (C8 of quina-
Information Figures S10–S27).
zoline ring), 132.6 (C5 of thiazole ring), 130.3 (C4 of phenyl
ring), 128.9(2) (C3 and C5 of phenyl ring), 128.4 (C1 of phe-
nyl ring), 128.3(2) (C2 and C6 of phenyl ring), 127.5 (C7 of
quinazoline ring), 126.5 (C6 of quinazoline ring), 126.1 (C9
of quinazoline ring), 120.6 (C5 of quinazoline ring), 16.5
(CH3), MS (m/z): 377.09 (Mþ); Anal. Calcd. for:
C19H15N5O2S: C, 60.41%; H, 4.08%; N, 18.50% Found: C,
60.46%; H, 4.01%; N, 18.56%.
Synthesis of ethyl 4-methyl-2-(4-oxo-2-phenyl (3-
hydroquinazolin-3-yl))-1,3-thiazole-5-carboxylate
(compound 3)
In a round bottom flask, a mixture of ethyl-2-amino-4-
methyl-1,3-thiazole-5-carboxylate
(Compound
1)
(0.012 mol) and 2-phenyl-4H-benzo[d][1,3]oxazin-4-one
(0.01 mol) (Compound 2) (prepared as per the reported lit-
erature method[28]) were added in pyridine (50 mL) and the
reaction mixture was refluxed for 8–9 h. The progress of the
reaction was monitored periodically and on completion of
Synthesis and characterization of 3-(4-methyl-5-(5-
thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-
phenylquinazolin-4(3H)-one (compound 5)
the reaction, the reaction mixture was poured over ice-cold A mixture of compound 4 (0.01 mol), KOH (0.01 mol), CS2
water. The reaction mixture was acidified using dilute (0.02 mol), and EtOH (95%, 100 mL) was refluxed for 12 h.
hydrochloric acid (10% v/v) to remove unreacted compound The excess solvent was removed by vacuum evaporation and
1. The obtained solid was filtered and washed using cold the residue was dissolved in water and acidified with
water. The resulting solid was crystallized using ethanol. CH3COOH (40% v/v) to get a solid product. It was filtered,
Yield: 77%; m.p. 173–175 ꢂC; IR (KBr, cmꢀ1): 3031, 2827 dried, and crystallized using H2O:EtOH (60:40). Yield: 63%;
(C-H, -CH ¼ CH-), 2759 (C-H), 1733 (>C ¼ O), 1694, 1663, m.p. 178–181 ꢂC; IR (KBr, cmꢀ1): 3037, 2835 (C-H,
1619 (C ¼ C, -COO-, C ¼ N), 1147 (C ¼ S), 1H NMR -CH ¼ CH-), 2761 (C-H), 1737 (>C ¼ O), 1686, 1630
(400 MHz, DMSO-d6): d ¼ 8.21 ꢀ 7.48 (m, 9H, Ar-H), 4.2 (C ¼ C, C ¼ N), 1239 (C-O-C), 1152 (C ¼ S), 1H NMR
(m, 2H, -O-CH2), 2.3 (m, 3H, Het-CH3), 1.3 (m, 3H, -CH3), (400 MHz, DMSO-d6): d ¼ 13.2 (s, 1H, N-NH), 8.2–7.3 (m,
13C NMR (100 MHz, DMSO-d6): d ¼ 167.9 (C2 of thiazole 9H, Ar-H), 2.2 (m, 3H, Het-CH3), 13C NMR (100 MHz,
ring), 163.8 (-C ¼ O), 162.5 (C4 of quinazoline ring), 155.3 DMSO-d6): d ¼ 189.7 (C5 of oxadiazole ring), 166.4 (C2 of
(C4 of thiazole ring), 154.8 (C2 of quinazoline ring), 148.7 thiazole ring), 160.4 (C4 of quinazoline ring), 157.8 (C2 of
(C9 of quinazoline ring),135.3 (C7 of quinazoline ring),130.3 oxadiazole ring), 156.6 (C4 of thiazole ring), 156.1 (C2 of
(C4 of phenyl ring), 128.8(2) (C3 and C5 of phenyl ring), quinazoline ring), 148.6 (C10 of quinazoline ring), 133.7 (C8
128.7 (C1 of phenyl ring), 128.4(2) (C2 and C6 of phenyl of quinazoline ring), 132.1(C5 of thiazole ring), 130.5 (C4 of
ring), 127.9 (C8 of quinazoline ring), 126.3 (C6 of quinazo- phenyl ring), 128.9 (C1 of phenyl ring), 128.6(2) (C3 and C5
line ring), 120.1 (C10 of quinazoline ring), 117.1 (C5 of qui- of phenyl ring), 128.5(2) (C2 and C6 of phenyl ring), 127.3
nazoline ring), 115.2 (C5 of thiazole ring), 62.5 (O-CH2), (C7 of quinazoline ring), 126.8 (C9 of quinazoline ring),
16.1 (CH3), 15.2 (CH3), MS (m/z): 391.10 (Mþ); Anal. 126.3 (C6 of quinazoline ring), 120.1 (C5 of quinazoline
Calcd. for:C21H17N3O3S: C, 64.44%; H, 4.38%; N, 10.73%. ring), 17.5 (CH3), MS (m/z): 419.05 (Mþ); Anal. Calcd. for:
Found: C, 64.47%; H, 4.41%; N, 10.80%.
C20H13N5O2S2:C, 57.21%; H, 3.18%; N, 16.75%. Found: C,
57.26%; H, 3.12%; N, 16.70%.
Synthesis and characterization of N-amino[4-methyl-2-
(4-oxo-2-phenyl(3-hydroquinazolin-3-yl))(1,3-thiazol-5-
yl)]carboxamide (compound 4)
General preparation of 3-(4-methyl-5-(4-
((phenylamino)methyl)-5-thioxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-
ones, (compounds 6a–j)
Compound 3 (0.01 mol) and NH2NH2ꢁH2O (99%, 0.015 mol)
were taken in a round bottom flask and the reaction mixture
was refluxed for 10 min. EtOH (95%) was added till both Compound 5 was mixed with aromatic amines and the mix-
the layers were miscible and refluxing was continued for 5 h. ture was applied heat under controlled conditions using

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
5
ethanol (95%, 50 mL) with formaldehyde (36%, 0.02 mol) for (>C ¼ O), 1694, 1614 (C ¼ C, C ¼ N), 1557 (C-NO2), 1227
3 h. The resulting solid was poured into water (100 mL) and (C-O-C), 1153 (C ¼ S), 1H NMR (400 MHz, DMSO-d6):
crystallized using methanol.
d ¼ 8.35–6.88 (m, 13H, Ar-H), 6.19 (s, 2H, Het –CH2-NH-),
4.93 (s, 2H, -CH2), 2.48 (s, 3H, -CH3), 13C NMR (100 MHz,
DMSO-d6): d ¼ 178.1 (C5 of oxadiazole ring), 166.9 (C2 of
thiazole ring), 160.6 (C4 of quinazoline ring), 156.8 (C2 of
oxadiazole ring), 156.2 (C4 of thiazole ring), 148.5 (C2
of quinazoline ring), 146.8 (C3 of phenyl ring), 133.2 (C1 of
phenyl ring), 132.8 (C5 of thiazole ring), 131.3 (Ar-C), 130.8
(Ar-C), 128.8(2) (Ar-C), 128.5 (Ar-C), 128.1(2) (Ar-C),
127.6 (Ar-C), 126.4 (Ar-C), 126.8 (Ar-C), 125.5 (Ar-C),
120.2 (C5 of quinazoline ring), 118.1 (Ar-C), 117.4 (Ar-C),
116.7 (Ar-C), 115.8 (Ar-C), 70.9 (-CH2-NH), 17.8 (C6 of
thiazole ring), MS (m/z): 569.0 (Mþ); Anal. Calcd. for:
C27H19N7O4S2: C, 56.93; H, 3.36; N, 17.21; Found: C, 56.92;
H, 3.34; N, 17.27%
Physical constant and characterization of 3-(5-(4-(((2-
fluorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (compound 6a)
Gray (Yield 62%) m.p. 212–214 ꢂC; IR (KBr, cmꢀ1): 3233
(N-H), 3109, 2940 (C-H, -CH ¼ CH-), 1713 (>C ¼ O), 1651
1
(C ¼ C, C ¼ N), 1228 (C-O-C), 1018 (C ¼ S), 779 (C-F), H
NMR (400 MHz, DMSO-d6): d ¼ 8.28–6.49 (m, 13H, Ar-H),
5.82 (s, 1H, Het –CH2-NH-), 4.93 (s, 2H, CH2), 2.49 (s,
3H,-CH3), 13C NMR (100 MHz, DMSO-d6): d ¼ 177.5 (C5 of
oxadiazole ring), 166.3 (C2 of thiazole ring), 160.9 (C4
of quinazoline ring), 157.4 (C2 of oxadiazole ring), 155.8 (C4
of thiazole ring), 155.6 (C2 of quinazoline ring), 154.2 (C2 of
phenyl ring), 148.7 (C10 of quinazoline ring), 133.4 (C1 of
phenyl ring), 132.4 (C5 of thiazole ring), 130.5 (Ar-C), 130.2
(Ar-C), 128.8(2) (Ar-C), 128.4 (Ar-C), 128.1(2), 127.6 (Ar-
C), 126.8 (Ar-C), 126.4 (Ar-C), 125.7 (Ar-C), 124.7 (Ar-C),
121.5 (C5 of quinazoline ring), 116.3 (Ar-C), 112.8 (Ar-C),
70.7 (-CH2-NH), 17.4 (C6 of thiazole ring), MS (m/z): 542.6
(Mþ); Anal. Calcd. for: C27H19FN6O2S2: C, 59.77; H, 3.53;
N, 15.49; Found: C, 59.56; H, 3.90; N, 15.41%
Physical constant and characterization of 3-(4-methyl-5-
(4-(((4-nitrophenyl)amino)methyl)-5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (6d)
Dark yellow (Yield 64%) m.p. 210–212 ꢂC; IR (KBr, cmꢀ1):
3217 (N-H), 3025, 2839 (C-H, -CH ¼ CH-), 2761 (C-H),
1735 (>C ¼ O), 1692, 1611 (C ¼ C, C ¼ N), 1559 (C-NO2),
1224 (C-O-C), 1155 (C ¼ S), 1H NMR (400 MHz, DMSO-
d6): d ¼ 8.33–6.92 (m, 13H, Ar-H), 6.29 (s, 1H, Het –CH2-
NH-), 4.93 (s, 2H, CH2), 2.52 (s, 3H, -CH3), 13C NMR
(100 MHz, DMSO-d6): d ¼ 178.6 (C5 of oxadiazole ring),
167.9 (C2 of thiazole ring), 160.3 (C4 of quinazoline
ring), 156.6 (C2 of oxadiazole ring), 156.5 (C4 of thiazole
ring), 148.7 (C2 of quinazoline ring), 146.4 (C4 of phenyl
ring), 135.6 (C1 of phenyl ring), 134.1 (C5 of thiazole ring),
131.7 (Ar-C), 129.2 (Ar-C), 128.9(2) (Ar-C), 128.8 (Ar-C),
128.5(2) (Ar-C), 127.2 (Ar-C), 126.3 (Ar-C), 126.1 (Ar-C),
125.5 (Ar-C), 119.8 (C5 of quinazoline ring), 118.7 (Ar-C),
117.4 (Ar-C), 116.9 (Ar-C), 115.5 (Ar-C), 70.7 (-CH2-NH),
17.9 (C6ofthiazole ring), MS (m/z): 569.0 (Mþ); Anal. Calcd.
for: C27H19N7O4S2: C, 62.44; H, 4.12; N, 15.60; Found: C,
62.45; H, 4.14; N, 15.62%
Physical constant and characterization of 3-(4-methyl-5-
(4-(((2-nitrophenyl)amino)methyl)-5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (6b)
Pale yellow (Yield 59%) m.p. 215–218 ꢂC; IR (KBr, cmꢀ1):
3518 (N-H), 3078, 2932 (C-H, -CH ¼ CH-), 1690 (>C ¼ O),
1589, 1512 (C ¼ C, C ¼ N), 1342 (-NO2), 1258 (C-O-C),
1
1057 (C ¼ S), H NMR (400 MHz, DMSO-d6): d ¼ 8.32–6.91
(m, 13H, Ar-H), 5.84 (s, 1H, Het –CH2-NH-), 4.91 (s, 2H,
-CH2), 2.47 (s, 3H, -CH3), 13C NMR (100 MHz, DMSO-d6):
d ¼ 178.2 (C5 of oxadiazole ring), 167.5 (C2 of thiazole ring),
160.5 (C4 of quinazoline ring), 156.9 (C2 of oxadiazole
ring), 156.2 (C4 of thiazole ring), 148.4 (C2 of quinazoline
ring), 146.2 (C10 of quinazoline ring), 135.5 (C2 of phenyl
ring), 132.6 (C1of phenyl ring), 131.8 (C5 of thiazole ring),
130.1 (Ar-C), 128.5(2) (Ar-C), 128.4 (Ar-C), 128.3(2) (Ar-
C), 127.4 (Ar-C), 126.8 (Ar-C), 126.6 (Ar-C), 125.7 (Ar-C),
118.6 (Ar-C), 117.7 (C5 of quinazoline ring), 116.4 (Ar-C),
115.6 (Ar-C), 114.2 (Ar-C), 69.4 (-CH2-NH), 17.7 (C6 of
thiazole ring), MS (m/z): 569.6 (Mþ); Anal. Calcd. for:
C27H19N7O4S2: C, 56.93; H, 3.36; N, 17.21; Found: C, 56.91;
H, 3.37; N, 17.24%
Physical constant and characterization of 3-(5-(4-(((2-
chlorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (6e)
White (Yield 61%) m.p. 216–218 ꢂC; IR (KBr, cmꢀ1): 3311
(N-H), 2975, 2833 (C-H, -CH ¼ CH-), 2753 (C-H), 1725
(>C ¼ O), 1689, 1619 (C ¼ C, C ¼ N), 1227 (C-O-C), 1156
(C ¼ S), 755 (C-Cl), 1H NMR (400 MHz, DMSO-d6):
d ¼ 8.27–6.89 (m, 13H, Ar-H), 6.29 (s, 1H, Het –CH2-NH-),
4.91 (s, 2H,-CH2), 2.47 (s, 3H, -CH3), 13C NMR (100 MHz,
DMSO-d6): d ¼ 177.2 (C5 of oxadiazole ring), 167.9 (C2 of
thiazole ring), 160.5 (C4 of quinazoline ring), 156.2 (C2 of
oxadiazole ring), 156.1 (C4 of thiazole ring), 148.3 (C2 of
quinazoline ring), 146.4 (C2of phenyl ring), 135.4 (C1 of
Physical constant and characterization of 3-(4-methyl-5-
(4-(((3-nitrophenyl)amino)methyl)-5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (6c)
Gray (Yield 60%) m.p. 206–209 ꢂC; IR (KBr, cmꢀ1): 3317 phenyl ring), 134.8 (C5 of thiazole ring), 133.1 (Ar-C), 129.4
(N-H), 3037, 2834 (C-H, -CH ¼ CH-), 2756 (C-H), 1727 (Ar-C), 128.7(2) (Ar-C), 128.6 (Ar-C), 128.4(2) (Ar-C),

6
N. DESAI ET AL.
127.5 (Ar-C), 126.8 (Ar-C), 126.2 (Ar-C), 125.9 (Ar-C), Physical constant and characterization of 3-(4-methyl-5-
(5-thioxo-4-((m-tolylamino)methyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-
one (6h)
119.4(C5 of quinazoline ring), 118.1 (Ar-C), 117.5 (Ar-C),
116.7 (Ar-C), 115.6 (Ar-C), 72.4 (-CH2-NH), 17.3 (C6 of
thiazole ring), MS (m/z): 559.0 (Mþ); Anal. Calcd. for:
C27H19ClN6O2S2: C, 58.01; H, 3.43; N, 15.03; Found: C,
57.82; H, 3.79; N, 14.97%
Brown, (Yield 58%) m.p. 220–223 ꢂC; IR (KBr, cmꢀ1): 3313
(N-H), 3032, 2837 (C-H, -CH ¼ CH-), 2756 (C-H), 1724
(>C ¼ O), 1692, 1614 (C ¼ C, C ¼ N), 1226 (C-O-C), 1152
1
(C ¼ S), H NMR (400 MHz, DMSO-d6): d ¼ 8.27–6.58 (m,
13H, Ar-H), 6.35 (s, 1H, Het –CH2-NH-), 4.9 (s, 2H, CH2),
2.48 (s, 3H, -CH3), 2.34 (s, 3H, Het-CH3) , 13C NMR
(100 MHz, DMSO-d6): d ¼ 177.1 (C5 of oxadiazole ring),
166.6 (C2 of thiazole ring), 160.3 (C4 of quinazoline
ring), 157.7 (C2 of oxadiazole ring), 156.9 (C4 of thiazole
Physical constant and characterization of 3-(5-(4-(((4-
chlorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-1,3,4-
oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-phenylquinazolin-
4(3H)-one (6f)
Off-white (Yield 60%) m.p. 212–215 ꢂC; IR (KBr, cmꢀ1): ring), 156.5 (C2 of quinazoline ring), 148.7 (C3 of phenyl
ring), 144.3 (C1 of phenyl ring), 133.6 (C5 of thiazole ring),
132.3 (Ar-C), 130.6 (Ar-C), 129.8(2) (Ar-C), 129.4 (Ar-C),
128.9(2) (Ar-C), 128.7 (Ar-C), 128.3(2) (Ar-C), 127.3 (Ar-
C), 126.6 (Ar-C), 126.7 (Ar-C), 120.2 (C5 of quinazoline
3313 (N-H), 3033, 2830 (C-H, -CH ¼ CH-), 2755 (C-H),
1727 (>C ¼ O), 1691, 1617 (C ¼ C, C ¼ N), 1229 (C-O-C),
1
1155 (C ¼ S), 759 (C-Cl), H NMR (400 MHz, DMSO-d6):
d ¼ 8.32–6.92 (m, 13H, Ar-H), 6.37 (s, 1H, Het –CH2-NH-),
4.91 (s, 2H, CH2-NH-Ar), 2.46 (s, 3H, -CH3), 13C NMR
ring), 117.1 (Ar-C), 114.4(2) (Ar-C), 70.2 (-CH2-NH), 21.4
(C7 in phenyl ring), 17.6 (C6 of thiazole ring), MS (m/z):
(100 MHz, DMSO-d6): d ¼ 178.2 (C5 of oxadiazole ring),
538.6 (Mþ); Anal. Calcd. for: C28H22N6O2S2: C, 62.44; H,
167.7 (C2 of thiazole ring), 160.9 (C4 of quinazoline
4.12; N, 15.60; Found: C, 62.48; H, 4.15; N, 15.63%
ring), 156.5 (C2 of oxadiazole ring), 156.2 (C4 of thiazole
ring), 148.5 (C2 of quinazoline ring), 146.7 (C4 of phenyl
ring), 133.8 (C1 of phenyl ring), 132.3 (C5 of thiazole ring),
131.7 (Ar-C), 130.7 (Ar-C), 128.8(2) (Ar-C), 128.5 (Ar-C),
128.2(2) (Ar-C), 127.9 (Ar-C), 126.6 (Ar-C), 126.2 (Ar-C),
125.6 (Ar-C), 120.7 (C5 of quinazoline ring), 117.1 (Ar-C),
116.4 (Ar-C), 115.9 (Ar-C), 114.1 (Ar-C), 72.7 (-CH2-NH),
17.9 (C6 of thiazole ring), MS (m/z): 559.0(Mþ); Anal.
Calcd. for: C27H19ClN6O2S2: C, 58.01; H, 3.43; N, 15.03;
Found: C, 58.02 H, 3.45; N, 15.01%
Physical constant and characterization of 3-(4-methyl-5-
(5-thioxo-4-((p-tolylamino)methyl)-4,5-dihydro-1,3,4-
oxadiazol-2-yl)thiazol-2-yl)-2-phenylquinazolin-4(3H)-
one (6i)
White (Yield 62%) m.p. 207–209 ꢂC; IR (KBr, cmꢀ1): 3320
(N-H), 3029, 2829 (C-H, -CH ¼ CH-), 2757 (C-H), 1721
(>C ¼ O), 1690, 1617 (C ¼ C, C ¼ N), 1222 (C-O-C), 1157
1
(C ¼ S), H NMR (400 MHz, DMSO-d6): d ¼ 8.34–6.44 (m,
13H, Ar-H),6.31 (s, 1H, Het –CH2-NH-), 4.92 (s, 2H, CH2),
2.48 (s, 3H Het -CH3), 2.33 (s, 3H, -CH3), 13C NMR
(100 MHz, DMSO-d6): d ¼ 177.6 (C5 of oxadiazole ring),
166.9 (C2 of thiazole ring), 160.7 (C4 of quinazoline ring),
157.6 (C2 of oxadiazole ring), 156.4 (C4 of thiazole ring),
156.1 (C2 of quinazoline ring), 148.1 (C4 of phenyl ring),
144.4, (C1 of phenyl ring), 135.8 (C5 of thiazole ring), 133.7
(Ar-C), 130.7 (Ar-C), 129.2 (2) (Ar-C), 129.1 (Ar-C),
128.6(2) (Ar-C),128.5 (Ar-C), 128.1(2) (Ar-C),127.7 (Ar-C),
126.8 (Ar-C), 124.4 (Ar-C), 118.6 (C5 of quinazoline ring),
114.4(2) (Ar-C), 70.7 (-CH2-NH), 21.9 (C7 in phenyl ring),
17.9 (C6 of thiazole ring), MS (m/z): 538.6 (Mþ); Anal.
Calcd. for: C28H22N6O2S2: C, 62.44; H, 4.12; N, 15.60;
Found: C, 62.45; H, 4.18; N, 15.65%
Physical constant and characterization of 3-(5-(4-(((3,4-
dichlorophenyl)amino)methyl)-5-thioxo-4,5-dihydro-
1,3,4-oxadiazol-2-yl)-4-methylthiazol-2-yl)-2-
phenylquinazolin-4(3H)-one (6g)
White (Yield 63%) m.p. 219–222 ꢂC; IR (KBr, cmꢀ1): 3315
(N-H), 3029, 2833 (C-H, -CH ¼ CH-), 2755 (C-H), 1724
(>C ¼ O), 1692, 1619 (C ¼ C, C ¼ N), 1228 (C-O-C), 1158
1
(C ¼ S), H NMR (400 MHz, DMSO-d6): d ¼ 7.82–6.33 (m,
12H, Ar-H), 6.3 (s, 1H, Het –CH2-NH-), 4.92 (s, 2H, CH2),
2.48 (s, 3H, -CH3), 13C NMR (100 MHz, DMSO-d6):
d ¼ 177.7 (C5 of oxadiazole ring), 166.9 (C2 of thiazole ring),
160.1 (C4 of quinazoline ring), 157.5 (C2 of oxadiazole ring),
156.5 (C4 of thiazole ring), 156.3 (C2 of quinazoline ring),
148.9 (C3 of in phenyl ring), 147.7 (C4 of phenyl ring),
133.5 (C1 of phenyl ring), 132.7 (C5 of thiazole ring), 131.1
(Ar-C), 130.4 (Ar-C),129.5 (Ar-C), 128.5(2) (Ar-C), 128.4
(Ar-C), 128.1(2) (Ar-C), 127.5 (Ar-C), 126.9 (Ar-C), 126.4
(Ar-C), 121.6 (Ar-C), 120.4 (C5 of quinazoline ring), 115.9
(Ar-C), 113.4 (Ar-C), 70.7 (-CH2-NH), 17.3 (C6 of thiazole
ring), MS (m/z): 593.5 (Mþ); Anal. Calcd. for:
C27H18Cl2N6O2S2: C, 54.64; H, 3.06; N, 14.16; Found: C,
54.61; H, 3.04; N, 14.20%
Physical constant and characterization of 3-(4-methyl-5-
(4-(((2-methyl-4-nitrophenyl)amino)methyl)-5-thioxo-4,5-
dihydro-1,3,4-oxadiazol-2-yl)thiazol-2-yl)-2-
phenylquinazolin-4(3H)-one (6j)
White (Yield 63%) m.p. 211–214 ꢂC; IR (KBr, cmꢀ1): 3329
(N-H), 3028, 2825 (C-H, -CH ¼ CH-), 2752 (C-H), 1724
(>C ¼ O), 1692, 1616 (C ¼ C, C ¼ N), 1552 (C-NO2), 1225
(C-O-C), 1152 (C ¼ S), 1H NMR (400 MHz, DMSO-d6):
d ¼ 8.27–6.93 (m, 12H, Ar-H), 5.83 (s, 1H, Het –CH2-NH-),

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
7
Figure 2. Binding mode of 6e into the active site of DNA gyrase subunit.
4.81 (s, 2H, CH2), 2.51 (s, 3H, Het-CH3), 2.15 (s, 3H, CH3), docking scores (–7.970 to –6.749) [See Table S1 (Supporting
13C NMR (100 MHz, DMSO-d6): d ¼ 177.5 (C5 of oxadiazole
Information)]. Their docking scores and glide binding ener-
gies corroborated well with the observed antimicro-
bial activities.
ring), 166.7 (C2 of thiazole ring), 160.9 (C4 of quinazoline
ring), 157.5 (C2 of oxadiazole ring), 156.9 (C4 of thiazole
ring), 156.8 (C2 of quinazoline ring), 152.6, (C2 of phenyl
ring), 148.9 (C4 of phenyl ring), 136.7 (C1 of phenyl ring),
133.5 (C5 of thiazole ring), 132.8 (Ar-C), 130.4 (Ar-C),
128.9(2) (Ar-C), 128.6 (Ar-C), 128.4(2) (Ar-C), 127.7 (Ar-
C), 127.4 (Ar-C), 126.9 (Ar-C), 126.6 (Ar-C), 126.2 (Ar-C),
121.7 (C5 of quinazoline ring), 120.6 (Ar-C), 114.4 (Ar-C),
71.7 (-CH2-NH), 17.7 (C7 phenyl ring), 16.6 (C6 of thiazole
ring), MS (m/z): 583.6 (Mþ); Anal. Calcd. for:
C28H21N7O4S2: C, 57.62; H, 3.63; N, 16.80; Found: C, 57.67;
H, 3.64; N, 16.85%
The binding affinity exhibited by these molecules is
attributed to significant bonded and non-bonded interactions
with residues lining the active site of the enzyme. The per-
residue interaction analysis for one of the most active analog
6e (Figure 2) showed that the molecule is embedded into
the active site through a series of significant van der Waals
interactions observed with Val:A167(–1.400 kcal molꢀ1),
Thr:A165(–3.547 kcal molꢀ1), Ser:A121(–1.104 kcal molꢀ1),
Val:A120(–2.628 kcal molꢀ1), Gly:A119(–2.116 kcal molꢀ1),
Gly:A117(–2.503 kcal molꢀ1), Ile:A78(–5.592 kcal molꢀ1),
Gly:A77(–1.753 kcal molꢀ1), Arg:A76(–2.479 kcal molꢀ1),
Asp:A73(–1.155 kcal molꢀ1), Val:A71(–1.639 kcal molꢀ1),
Glu:A50(–4.227 kcal molꢀ1), Asp:A49(–1.605 kcal molꢀ1),
Ala:A47(–2.047 kcal molꢀ1), Asn:A46(–4.635 kcal molꢀ1),
Asp:A45(–1.014 kcal molꢀ1), Val:A43(–1.135 kcal molꢀ1), and
Glu:A42(–1.514 kcal molꢀ1) through the 4-methylthiazol-2-
yl-2-phenylquinazolin-4(3H)-one portion of the molecule
while the 3-(5-(4-(((2-chlorophenyl)amino)methyl)-5-thioxo-
4,5-dihydro-1,3,4-oxadiazol-2-yl) component interacted siꢀm1i-
larly with Val:A118(–1.515 kcal molꢀ1), Ala:A96(–3.08 kcal mol ),
His:A95(–2.537 kcal molꢀ1), Met:A91(–1.113 kcal molꢀ1),
Molecular docking
DNA gyrase is a well-studied drug target present in almost
all bacteria and is known to play essential roles in bacterial
DNA replication.[29] It is a heterotetrameric protein consist-
ing of two GyrA subunits and two GyrB subunits (A2B2)
encoded by the gyrA and gyrB genes, respectively. While the
GyrA subunit mediates the enzyme-catalyzed DNA break-
age-reunion reaction, the GyrB subunit contains an ATPase
activity which facilitates the DNA strand-passing reaction of
DNA gyrase. The low structural homology exhibited by
these enzymes with human topoisomerases and being critical
for the survival of the microorganism make them attractive
drug targets for antibacterial therapy. The B-subunit of
DNA gyrase (GyrB) consist of ATP binding pocket and
small molecules inhibition of this pocket is plausible which
has resulted in several lead compounds.[30,31]
To gain better understanding on the potency of the
studied compounds, to elucidate the plausible mechanism by
which they can induce antimicrobial activity and guide fur-
ther SAR studies, we proceeded to examine the interaction
of these thiazole based 1,3,4-oxadiazoles heterocycles with
DNA gyrase subunit b (PDB ID:1KZN). These calculations
were performed using the standard protocol implemented in
the GLIDE (Grid-Based Ligand Docking with Energetics)
Ile:A90(–4.986 kcal
molꢀ1),
Val:A89(–1.954 kcal
molꢀ1),
Ala:A86(–3.164 kcal molꢀ1), and Pro:A79(–2.685 kcal molꢀ1) resi-
dues of the active site. The enhanced binding of 6e is also contrib-
uted by several significant electrostatic interactions through
Arg:A136(–2.776),
Arg:A76(–2.878),
Ala:A96(–1.724),
Asp:A74(–1.112),
His:A95(–1.085),
Asp:A73(–1.769),
Asp:A49(–2.776), Asn:A46(–1.157), Glu:A42(–1.709) residues
lining the active site of DNA gyrase. A very similar network of
balanced steric, as well as electrostatic interactions, contrib-
uted to the binding affinity of all the synthesized molecules in
the series (Supporting Information Figures S1–S9).
Furthermore, these thiazole-based 1,3,4-oxadiazoles hetero-
cycles were found to be engaged in a significant hydrogen
bonding interaction with Asn46 residue which serves as an
“anchor” that guides the orientation of these molecules into
the 3D space of the active site and facilitate the non-bonded
(steric and electrostatic) interactions. Overall, these results of
the molecular docking study showed that these thiazole-based
1,3,4-oxadiazoles heterocycles could interact significantly with
the DNA gyrase. In the absence of available resources to per-
€
module of the Small Drug Discovery Suite (Schrodinger,
LLC, New York, NY).[32–34] It was observed that all the syn-
thesized molecules could dock nicely into the active site of
DNA gyrase with good binding energies ranging from
ꢀ45.222 to ꢀ40.057 kcal molꢀ1with equally significant form enzyme-based experiments, the in silico approach of

8
N. DESAI ET AL.
molecular docking provides a viable option to identify and
optimize the leads targeting crucial antibacterial enzymes. The
results obtained herein suggest that the quinazoline clubbed
thiazole and 1,3,4-oxadiazoles could serve as promising leads
for structure-based lead optimization to identify more potent
analogs through iterative design, synthesis, and biological
evaluation. The docking score of co-crystallized ligand-
Chlorobiocin, an aminocoumarin antibacterial that inhibits
the enzyme DNA gyrase, was found to be ꢀ9.902 Glide energy
Funding
One of the authors Prof. Nisheeth C. Desai is thankful to the
University Grant Commission, New Delhi for awarding BSR Faculty-
Fellowship 2019 (No. F 18-1/2011 (BSR)) and financial assistance.
Authors are grateful to the UGC, New Delhi and Department of
Science and Technology, New Delhi [grant no. DST-FIST-SR/FST/CSI-
212/2010] for financial support under the NON-SAP and DST-FIST
programs, respectively.
of ꢀ50.733 kcal molꢀ1 [35]
.
ORCID
Nisheeth Desai
http://orcid.org/0000-0001-6864-8661
Structure-activity relationship study
References
The result of antibacterial screening of compounds 6a–j
showed that the presence of electron- withdrawing group in
screened compounds is responsible for the antibacterial
activity. Among various functional groups with –I effect, the
presence of ꢀ4-Cl showed excellent activity against bacterial
strains. However, other electron-withdrawing group-2-Cl
and electron-donating group ꢀ3-CH3 showed moderate
activity against S. aureus, E. coli, and P. aeruginosa species.
These findings were found to be in harmony with the
observed binding affinity data were the compound 6e (-2Cl)
showed the highest binding score (Glide score: ꢀ7.970,
Glide energy: ꢀ45.222 kcal molꢀ1) as compared to the com-
pound of formulae 6f (–4Cl) and 6 h (-3-CH3).
[1] Majumdar, P.; Pati, A.; Patra, M.; Behera, R.; Behera, A. K.
Acid Hydrazides, Potent Reagents for Synthesis of Oxygen-,
Nitrogen-, and/or Sulfur-Containing Heterocyclic Rings. Chem.
Rev. 2014, 114, 2942–2977. DOI: 10.1021/cr300122t.
[2] Jansen, K. U.; Knirsch, C.; Anderson, A. S. The Role of
Vaccines in Preventing Bacterial Antimicrobial Resistance. Nat.
Med. 2018, 24, 10–19. DOI: 10.1038/nm.4465.
[3] Li, X.; Ma, S. Advances in the Discovery of Novel
Antimicrobials Targeting the Assembly of Bacterial Cell
Division Protein FtsZ. Eur. J. Med. Chem. 2015, 95, 1–15. DOI:
10.1016/j.ejmech.2015.03.026.
[4] Neeraja, P.; Srinivas, S.; Mukkanti, K.; Dubey, P. K.; Pal, S. 1H-
1,2,3-Triazolyl-Substituted
1,3,4-Oxadiazole
Derivatives
Containing Structural Features of Ibuprofen/Naproxen: Their
Synthesis and Antibacterial Evaluation. Bioorg. Med. Chem.
Lett. 2016, 26, 5212–5217. DOI: 10.1016/j.bmcl.2016.09.059.
[5] Singla, N.; Singh, G.; Bhatia, R.; Kumar, A.; Kaur, R.; Kaur, S.
Design, Synthesis and Antimicrobial Evaluation of 1,3,4-
Conclusion
Oxadiazole/1,2,4-Triazole-Substituted
Thiophenes.
In the present research work, the authors have synthesized
quinazoline clubbed thiazole and 1,3,4-oxadiazoles hetero-
cycles and performed molecular docking studies. The
molecular docking study could provide an insight into the
binding affinity of these molecules toward DNA gyrase. The
key structural elements and their interactions with the active
site are now considered for further optimization of this scaf-
fold to redesign them for increasing their potency as anti-
microbial agents. Results of biological activities revealed that
compound 6f, furnished excellent antibacterial activity
against S. aureus, whereas compounds of formulae 6e, and
6d furnished very good to prominent antibacterial activity
against E. coli. Data reveals that electron-withdrawing
groups were much effective for enhancing the antibacterial
activity on different strains.
ChemistrySelect 2020, 5, 3835–3842. DOI: 10.1002/slct.
202000191.
[6] Long, Q.; Liu, L.; Zhao, Y.; Wang, P.; Chen, B.; Li, Z.; Yang, S.
Fabrication of Furan-Functionalized Quinazoline Hybrids: Their
Antibacterial Evaluation, Quantitative Proteomics, and Induced
Phytopathogen Morphological Variation Studies. J. Agric. Food
Chem. 2019, 67, 11005–11017. DOI: 10.1021/acs.jafc.9b03419.
[7] Desai, N. C.; Bhatt, N. B.; Joshi, S. B. Synthetic Modifications
in Ethyl 2-Amino-4-Methylthiazole-5-Carboxylate: 3D QSAR
Analysis and Antimicrobial Study. Synth. Commun. 2019, 49,
1055–1066. DOI: 10.1080/00397911.2019.1587777.
[8] Shi, J.; Luo, N.; Ding, M.; Bao, X. Synthesis, In Vitro
Antibacterial and Antifungal Evaluation of Novel 1,3,4-
Oxadiazole
Thioether
Derivatives
Bearing
the
6-
Fluoroquinazolinylpiperidinyl Moiety. Chin. Chem. Lett. 2020,
31, 434–438. DOI: 10.1016/j.cclet.2019.06.037.
[9] Devipriya, D.; Roopan, S. M. UV-Light Intervened Synthesis of
Imidazo Fused Quinazoline and Its Solvatochromism,
Antioxidant, Antifungal and Luminescence Properties. J.
Photochem. Photobiol. B Biol. 2019, 190, 42–49. DOI: 10.1016/j.
jphotobiol.2018.11.003.
[10] Sharma, P. C.; Bansal, K. K.; Sharma, A.; Sharma, D.; Deep, A.
Thiazole-Containing Compounds as Therapeutic Targets for
Cancer Therapy. Eur. J. Med. Chem. 2020, 188, 112016. DOI:
10.1016/j.ejmech.2019.112016.
[11] Misra, A.; Dwivedi, J.; Shukla, S.; Kishore, D.; Sharma, S.
Bacterial Cell Leakage Potential of Newly Synthesized
Quinazoline Derivatives of 1,5-Benzodiazepines Analogue. J.
Heterocycl. Chem. 2020, 57, 1545–1558. DOI: 10.1002/jhet.3879.
[12] Bhati, S.; Kumar, V.; Singh, S.; Singh, J. Synthesis,
Characterization, Antimicrobial, Anti-Tubercular, Antioxidant
Activities and Docking Simulations of Derivatives of 2-
Acknowledgments
The authors thank Schr€odinger Inc. for providing Small-Molecule Drug
Discovery Suite to perform the molecular docking studies. Authors are
also thankful to Priyanka Desai, founder of iScribblers for the linguistic
editing of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the authors.

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
9
(Pyridin-3-yl)-1Hbenzo[d]imidazole
and
1,3,4-Oxadiazole [24] Desai, N. C.; Bhatt, N.; Somani, H.; Trivedi, A. Synthesis,
Analogy. LDDD. 2020, 17, 1047–1059. DOI: 10.2174/
1570180816666191122105313.
[13] Desai, N. C.; Trivedi, A.; Somani, H.; Jadeja, K. A.; Vaja, D.;
Antimicrobial and Cytotoxic Activities of Some Novel Thiazole
Clubbed 1,3,4-Oxadiazoles. Eur. J. Med. Chem. 2013, 67, 54–59.
DOI: 10.1016/j.ejmech.2013.06.029.
Nawale, L.; Khedkar, V. M.; Sarkar, D. Synthesis, Biological [25] Du, H.; Ding, M.; Luo, N.; Shi, J.; Huang, J.; Bao, X. Design,
Evaluation, and Molecular Docking Study of Pyridine Clubbed
1,3,4-Oxadiazoles as Potential Antituberculars. Synth. Commun.
2018, 48, 524–540. DOI: 10.1080/00397911.2017.1410892.
Synthesis, Crystal Structure and in Vitro Antimicrobial Activity
of Novel 1,2,4-Triazolo[1,5-a]pyrimidine-Containing
Quinazolinone Derivatives. Mol. Divers 2020, 1–12. DOI: 10.
[14] Dutta, A.; Sarma, D. Recent Advances in the Synthesis of
1007/s11030-020-10043-z.
Quinazoline Analogues as Anti-TB Agents. Tuberculosis (Edinb) [26] Desai, N. C.; Karkar, T. J.; Vekariya, R. H.; Joshi, S. B.; Jadeja,
2020, 124, 101986. DOI: 10.1016/j.tube.2020.101986.
[15] Bekhit, A. A.; Saudi, M. N.; Hassan, A. M. M.; Fahmy, S. M.;
Ibrahim, T. M.; Ghareeb, D.; El-Seidy, A. M.; Nasralla, S. N. A.;
Bekhit, A. E. Synthesis, In Silico Experiments and Biological
K. A.; Vaja, D. V. Synthesis, Characterization, Molecular
Docking Studies and Biological Activity of Coumarin Linked 2-
Pyridone Heterocycles. Indian J. Chem. 2020, 59B, 231–237.
DOI: http://nopr.niscair.res.in/handle/123456789/54002.
Evaluation of 1,3,4-Trisubstituted Pyrazole Derivatives as [27] Desai, N. C.; Patel, B. Y.; Dave, B. P. Synthesis and
Antimalarial Agents. Eur. J. Med. Chem. 2019, 163, 353–366.
DOI: 10.1016/j.ejmech.2018.11.067.
[16] Abd-Ellah, H. S.; Abdel-Aziz, M.; Shoman, M. E.; Beshr,
Antimicrobial Activity of Novel Quinoline Derivatives Bearing
Pyrazoline and Pyridine Analogues. Med. Chem. Res. 2017, 26,
109–119. DOI: 10.1007/s00044-016-1732-6.
E. A. M.; Kaoud, T. S.; Ahmed, A. F. F. Novel 1,3,4- [28] Kumar, R. A.; Maheswari, C. U.; Ghantasala, S.; Jyothi, C.;
Oxadiazole/Oxime Hybrids: Synthesis, Docking Studies and
Investigation of Anti-Inflammatory, Ulcerogenic Liability and
Analgesic Activities. Bioorg. Chem. 2016, 69, 48–63. DOI: 10.
1016/j.bioorg.2016.09.005.
Reddy, K. R. Synthesis of 3H-Quinazolin-4-Ones and 4H-3,1-
Benzoxazin-4-Ones via Benzylic Oxidation and Oxidative
Dehydrogenation
Using
Potassium
Iodide-Tert-Butyl
Hydroperoxide. Adv. Synth. Catal. 2011, 353, 401–410. DOI:
[17] Mishchenko, M.; Shtrygol, S.; Kaminskyy, D.; Lesyk, R.
10.1002/adsc.201000580.
Thiazole-Bearing 4-Thiazolidinones as New Anticonvulsant [29] Pommier, Y. Drugging Topoisomerases: Lessons and
Agents. Sci. Pharm. 2020, 88, 16. DOI: 10.3390/
Challenges. ACS Chem. Biol. 2013, 8, 82–95. DOI: 10.1021/
scipharm88010016.
cb300648v.
[18] Maghraby, M. T.-E.; Abou-Ghadir, O. M. F.; Abdel-Moty, S. G.; [30] Ehmann, D. E.; Lahiri, S. D. Novel Compounds Targeting
Ali, A. Y.; Salem, O. I. A. Novel Class of Benzimidazole-
Thiazole Hybrids: The Privileged Scaffolds of Potent anti-
Bacterial DNA Topoisomerase/DNA Gyrase. Curr. Opin.
Pharmacol. 2014, 18, 76–83. DOI: 10.1016/j.coph.2014.09.007.
Inflammatory Activity with Dual Inhibition of Cyclooxygenase [31] Maxwell, A.; Lawson, D. M. The ATP-Binding Site of Type II
and 15-Lipoxygenase Enzymes. Bioorg. Med. Chem. 2020, 28,
115403. DOI: 10.1016/j.bmc.2020.115403.
[19] Asma, Kalluraya, B.; Manju, N.; Sharath, C.; L. Synthesis and
Topoisomerases as a Target for Antibacterial Drugs. Curr. Top.
Med. Chem. 2003, 3, 283–303. DOI: 10.2174/
1568026033452500.
Antioxidant Activity Study of Carbothioamide and Their [32] Friesner, R. A.; Murphy, R. B.; Repasky, M. P.; Frye, L. L.;
Corresponding Thiazole Derivatives. J. Heterocycl. Chem. 2020,
57, 3105–3115. DOI: 10.1002/jhet.4018.
Greenwood, J. R.; Halgren, T. A.; Sanschagrin, P. C.; Mainz,
D. T. Extra Precision Glide: Docking and Scoring Incorporating
[20] Desai, N. C.; Joshi, V. V.; Rajpara, K. M.; Makwana, A. H. A
New Synthetic Approach and In Vitro Antimicrobial Evaluation
of Novel Imidazole Incorporated 4-Thiazolidinone Motifs.
a Model of Hydrophobic Enclosure for Protein-Ligand
Complexes. J. Med. Chem. 2006, 49, 6177–6196. DOI: 10.1021/
jm051256o.
Arab. J. Chem. 2017, 10, S589–S599. DOI: 10.1016/j.arabjc.2012. [33] Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.;
10.020.
Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley,
M.; Perry, J. K.; et al. Glide: A New Approach for Rapid,
Accurate Docking and Scoring. 1. Method and Assessment of
Docking Accuracy. J. Med. Chem. 2004, 47, 1739–1749. DOI:
10.1021/jm0306430.
[21] Chandrakantha, B.; Shetty, P.; Nambiyar, V.; Isloor, N.; Isloor,
A. M. Synthesis, Characterization and Biological Activity of
Some New 1,3,4-Oxadiazole Bearing 2-Flouro-4-Methoxy
Phenyl Moiety. Eur. J. Med. Chem. 2010, 45, 1206–1210. DOI:
10.1016/j.ejmech.2009.11.046.
[22] Zheng, Z.; Liu, Q.; Kim, W.; Tharmalingam, N.; Fuchs, B. B.;
Mylonakis, E. Antimicrobial Activity of 1,3,4-Oxadiazole
Derivatives against Planktonic Cells and Biofilm of
Staphylococcus aureus. Future Med. Chem. 2018, 10, 283–296.
DOI: 10.4155/fmc-2017-0159.
[34] Halgren, T. A.; Murphy, R. B.; Friesner, R. A.; Beard, H. S.;
Frye, L. L.; Pollard, W. T.; Banks, J. L. Glide: A New Approach
for Rapid, Accurate Docking and Scoring. 2. Enrichment
Factors in Database Screening. J. Med. Chem. 2004, 47,
1750–1759. DOI: 10.1021/jm030644s.
[35] Phatak, P. S.; Sathe, B. P.; Dhumal, S. T.; Rehman, N. N. M. A.;
Dixit, P. P.; Khedkar, V. M.; Haval, K. P. Synthesis,
Antimicrobial Evaluation, and Docking Studies of Substituted
[23] Torre, B. G.; Albericio, F. The Pharmaceutical Industry in 2018.
An Analysis of FDA Drug Approvals from the Perspective of
Molecules. Molecules 2019, 24, 809. DOI: 10.3390/
molecules24040809.
Acetylphenoxymethyl-Triazolyl-N-Phenylacetamides.
J.
Heterocycl. Chem. 2019, 56, 1928–1938. DOI: 10.1002/jhet.3568.