Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

Venugopala, K. N. and Sandeep, C. and Pran Kishore Deb and Tratrat, Christophe and Pillay, Melendhran and Chopra, Deepak and Nizar A. Al-Shar'i and Wafa Hourani and Dahabiyeh, Lina A. and Borah, Pobitra and Rahul, D. N. and Nayak, Susanta K. and Padmashali, B. and Morsy, Mohamed A. and Aldhubiab, Bandar E. and Mahesh, A. and Nair, Anroop B. and Sreeharsha, N. and Haroun, Michelyne and Sheena, S. and Viresh, M. and Raghuprasad, M. (2021) Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme. Journal of Enzyme Inhibition and Medicinal Chemistry, 36 (1). pp. 1471-1486.

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Abstract

A series of 1,2,3-trisubstituted indolizines (2a-2f, 3a-3d, and 4a-4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b-2d, 3a-3d, and 4a-4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a-4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16-64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

Item Type:	Article
Uncontrolled Keywords:	Indolizine; mycobacterium tuberculosis; InhA; docking; X-ray crystal structure
Subjects:	C Chemical Science > Organic Chemistry
Divisions:	Department of > Organic Chemistry
Depositing User:	Mr Umendra uom
Date Deposited:	28 Feb 2022 05:27
Last Modified:	21 Jun 2022 11:01
URI:	http://eprints.uni-mysore.ac.in/id/eprint/17277

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