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, Viresh Mohanlall

Journal Name: Current Topics in Medicinal Chemistry

Volume 21 , Issue 4 , 2021


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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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Article Details

VOLUME: 21
ISSUE: 4
Year: 2021
Published on: 02 November, 2020
Page: [295 - 306]
Pages: 12
DOI: 10.2174/1568026620666201102121606
Price: $65

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