Exploration of green catalytic Hantzsch process for synthesis of polyhydroquinoline derivatives and their in silico & in vitro evaluation as anti-tubercular agents

Abstract

Polyhydroquinolines (PHQ) were long known for various pharmacological activities and numerous methods were reported for their synthesis by using different reaction conditions and catalysts. An attempt has been made to synthesize PHQs by following the environmental friendly green chemical approaches by using reusable and recyclable catalyst and solvent materials. Twelve compounds (2A-2L) were synthesized with varied substitutions on the aromatic ring by following the Hantzsch one-pot approach with bleaching earth clay and polyethylene glycol. Use of novel reaction conditions has improved the yield and drastically reduced the time required for the completion of the reaction. The DFT analysis revealed the structural features and the stability of the compound, and later the compounds were subjected to molecular docking against two key proteins of the M. tuberculosis H37 Ra InhA and DprE1. It was found that few of the compounds showed excellent binding interactions compared to the co-crystalized ligand. Later, all the synthesized compounds were subjected to the in vitro antimycobacterial activity using the Kirby-Bauer disk diffusion method, MICs were calculated by REMA assay and the hemolytic assay was performed to check cytotoxicity. Compounds 2K and 2E were found to show better inhibitory activity than the standard rifampin. The antimycobacterial activity of the PHQ compounds might be due to the interaction of the InhA and DprE1, which can be correlated positively and supported by the structural features and the in silico interaction data. Parallelly, molecular dynamic simulation studies were carried out with ligand 2K for the time frame of 100 ns against both targets InhA and DprE1 revealing the formation of stable complexes which further validate the ligand 2K as a potential lead molecule for further studies. The compounds can be further subjected to lead optimization for improved activity.