Discovery of new leads against Mycobacterium tuberculosis using scaffold hopping and shape based similarity

BM212 [1,5-diaryl-2-methyl-3-(4-methylpiperazin-1-yl)-methyl-pyrrole] is a pyrrole derivative with strong inhibitory activity against drug resistant Mycobacterium tuberculosis and mycobacteria residing in macrophages. However, it was not pursued because of its poor pharmacokinetics and toxicity profile. Our goal was to design and synthesize new antimycobacterial BM212 analogs with lower toxicity and better pharmacokinetic profile. Using the scaffold hopping approach, three structurally diverse heterocycles - 2,3-disubstituted imidazopyridines, 2,3-disubstituted benzimidazoles and 1,2,4-trisubstituted imidazoles emerged as promising antitubercular agents. All compounds were synthesized through easy and convenient methods and their structures confirmed by IR, ¹H NMR, ¹³C NMR and MS. In-vitro cytotoxicity studies on normal kidney monkey cell lines and HepG2 cell lines, as well as metabolic stability studies on rat liver microsomes for some of the most active compounds, established that these compounds have negligible cytotoxicity and are metabolically stable. Interestingly the benzimidazole compound (4a) is as potent as the parent molecule BM212 (MIC 2.3μg/ml vs 0.7-1.5μg/ml), but is devoid of the toxicity against HepG2 cell lines (IC₅₀ 203.10µM vs 7.8µM).

1,2,4-Trisubstituted imidazoles; 2,3-Disubstituted benzimidazoles; 2,3-Disubstituted imidazopyridines; Anti-tubercular activity; BM212; Microplate alamar blue assay; Mycobacterium tuberculosis; Scaffold hopping.