Design, synthesis, characterization, and anti-tubercular activity of novel ethyl-3-benzoyl-6, 8-difluoroindolizine-1-carboxylate analogues: Molecular target identification and molecular docking studies

Abstract

A series of novel Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r) were synthesized by reacting 3,5-difluoropyridine, with phenacyl bromide to get quaternary pyridinium N-ylide in the presence of acetone and potassium iodide as a catalyst, further these pyridinium N-ylide intermediate reacts with various electron-deficient acetylenes, to get Ethyl-3-benzoyl-6,8-difluoroindolizine-1-carboxylate analogues (4a-r). All newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR, 13C NMR, IR, and HRMS. All the synthesized intermediates and final compounds were evaluated for their anti-tubercular activities against M. tuberculosis H37Rv (ATCC 27294). All the compounds exhibited anti-tuberculosis activity in the range of 6.25–50 µM against H37Rv. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for these compounds. The molecular target identification for these compounds was also carried out using a computational method approach. Docking studies were performed to investigate the binding affinities as well as the interaction of these compounds with target proteins. In this study, 4h, 4b, and 4o emerged as the promising anti-TB agents against M. tuberculosis H37Rv, with MIC99 values of 2.61 µg/mL, 4.67 µg/mL, and 5.02 µg/mL respectively.