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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

4-Aryl-1,4-Dihydropyridines as Potential Enoyl-Acyl Carrier Protein Reductase Inhibitors: Antitubercular Activity and Molecular Docking Study

Author(s): Katharigatta N. Venugopala*, Pran Kishore Deb, Melendhran Pillay, Deepak Chopra, Sandeep Chandrashekharappa, Mohamed A. Morsy, Bandar E. Aldhubiab, Mahesh Attimarad, Anroop B. Nair, Nagaraja Sreeharsha, Mahmoud Kandeel, Rashmi Venugopala and Viresh Mohanlall

Volume 21, Issue 4, 2021

Published on: 02 November, 2020

Page: [295 - 306] Pages: 12

DOI: 10.2174/1568026620666201102121606

Price: $65

Abstract

Background: Tuberculosis remains one of the most deadly infectious diseases worldwide due to the emergence of multi-drug resistance (MDR) and extensively drug resistance (XDR) strains of Mycobacterium tuberculosis (MTB).

Aims: Currently, available drugs are getting resistant and toxic. Hence, there is an urgent need for the development of potent molecules to treat tuberculosis.

Materials and Methods: Herein, the screening of a total of eight symmetrical 1,4-dihydropyridine (1,4- DHP) derivatives (4a-4h) was carried out for whole-cell anti-TB activity against the susceptible H37Rv and MDR strains of MTB.

Results and Discussion: Most of the compounds exhibited moderate to excellent activity against the susceptible H37Rv. Moreover, the most promising compound 4f (against H37Rv) having paratrifluoromethyl phenyl group at 4-position and bis para-methoxy benzyl ester group at 3- and 5- positions of 1,4-dihydropyridine pharmacophore, exhibited no toxicity, but demonstrated weak activity against MTB strains resistant to isoniazid and rifampicin. In light of the inhibitory profile of the title compounds, enoyl-acyl carrier protein reductase (InhA) appeared to be the appropriate molecular target. A docking study of these derivatives against InhA receptor revealed favorable binding interactions. Further, in silico predicted ADME properties of these compounds 4a-4h were found to be in the acceptable ranges, including satisfactory Lipinski’s rule of five, thereby indicating their potential as drug-like molecules.

Conclusion: In particular, the 1,4-DHP derivative 4f can be considered an attractive lead molecule for further exploration and development of more potent anti-TB agents as InhA inhibitors.

Keywords: Dihydropyridine, Mycobacterium tuberculosis, Anti-TB activity, Molecular docking, InhA, MTT assay.

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