Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme.
Katharigatta Narayanaswamy VenugopalaSandeep ChandrashekharappaPran Kishore DebChristophe TratratMelendhran PillayDeepak ChopraNizar A Al-Shar'iWafa HouraniLina A DahabiyehPobitra BorahRahul D NagdeveSusanta K NayakBasavaraj PadmashaliMohamed A MorsyBandar E Al-DhubiabMahesh AttimaradAnroop Balachandran NairNagaraja SreeharshaMichelyne HarounSheena ShashikanthViresh MohanlallRaghu Prasad MailavaramPublished in: Journal of enzyme inhibition and medicinal chemistry (2021)
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.
Keyphrases
- mycobacterium tuberculosis
- multidrug resistant
- drug resistant
- molecular docking
- pulmonary tuberculosis
- acinetobacter baumannii
- gram negative
- molecular dynamics simulations
- escherichia coli
- klebsiella pneumoniae
- single cell
- cancer therapy
- emergency department
- oxidative stress
- drug delivery
- ionic liquid
- pseudomonas aeruginosa