Affiliation:
1. Department of Chemistry, (DST-FIST Sponsored) Mahatma Gandhi Campus, Division of Medicinal Chemistry, Maharaja
Krishnakumarsinhji Bhavnagar University, Bhavnagar 364 002, India
2. Department of Pharmaceutical Chemistry,
Division of Computer-Aided Drug Design, R.C. Patel Institute of Pharmaceutical Education and Research, Shirpur
(Dhule)-425405, Maharashtra, India
3. School of Science, Indrashil University, Rajpur, Kadi 382740, India
Abstract
Aim:
This study aims to synthesize antimicrobial agents and their molecular docking,
and DFT studies of benzothiazole-imidazolone scaffolds.
Background:
Benzothiazole and imidazolone analogues are of interest due to their potential
activity against microbial infections. In search of suitable antimicrobial compounds, we report
here the synthesis, characterization, and biological activities of benzothiazole and imidazolone
analogues (4a-l).
Objective:
The benzothiazole clubbed imidazolone motifs were synthesized, characterized, and
screened for their antimicrobial activity. Molecular docking was carried out for the development
of antimicrobial agents based on the results of biological activity obtained.
Methods:
We have synthesized a new series of benzothiazole-clubbed imidazolone hybrids by
using multi-step reactions in the search for antimicrobial agents (4a-l). The structures were
determined by 1H NMR, 13C NMR, IR, and mass spectroscopy techniques. Moreover, synthesized
compounds were evaluated for their antimicrobial activity by using a Serial Broth Dilution
method. In addition, molecular electrostatic potential, geometric optimization, and molecular
reactivity analyses (HOMO-LUMO) of 4c, which is one of the compounds with the highest
antibacterial activity, were performed.
Results:
The in vitro antimicrobial activity was evaluated against pathogenic strains. Among
them, compounds 4c showed the most potent biological activity against Gram-negative bacteria,
E. coli with MIC values of 50 μg/mL, and compound 4c active against A. clavatus with MIC
values of 100 μg/mL. Active compound 4c HUMO-LUMO energies, molecular electrostatic potential
analysis, and geometric optimization parameters were calculated with a 6-31G ** base set
using DFT/B3LYP theory, and the results were displayed. Molecular docking studies were
performed on E. coli DNA Gyrase B to understand the binding interaction of compound 4c, and it
was observed that compound 4c interacted with Arg76 amino acid of the active site through
hydrophobic interaction.
Conclusion:
Benzothiazole-clubbed imidazolone hybrids (4a-l) indicated promising antimicrobial
activity. Among them, compounds 4b (MIC=50 μg/mL C. albicans), 4c (MIC=50 μg/mL, E. coli),
4e (MIC= 100 μg/mL, A. niger), and 4g (MIC= 50 μg/mL, S. pyogenes) with electronwithdrawing
bromo, chloro, and fluoro group at the para position of the phenyl ring
on benzothiazole-imidazolone hybrids indicated remarkable potency compared to the standard
drug. The geometric optimization, molecular reactivity, and MESP analyses of 4c were calculated
with the B3LYP/6-31G ** base set and ΔE = ELUMO-EHOMO, which was found to be -
0.12096 eV. In addition, the binding affinity scores correlated well with the in vitro antimicrobial
activity (4c), while their binding modes proposed the involvement of steric, electrostatic, and hydrogen-
bonding interactions with the active site.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Molecular Medicine,General Medicine