Benzimidazoquinazolines as new potent anti-TB chemotypes: Design, synthesis, and biological evaluation

Abstract

In search for new molecular entities as anti-TB agents, the benzimidazoquinazoline polyheterocyclic scaffold has been designed adopting the scaffold hopping strategy. Thirty-two compounds have been synthesized through an improved tandem decarboxylative nucleophilic addition cyclocondensation reaction of o-phenylenediamine with isatoic anhydride followed by further cyclocondensation of the intermediately formed 2-(o-aminoaryl)benzimidazole with trialkyl orthoformate/acetate. The resultant benzimidazoquinazolines were evaluated in vitro for anti-TB activity against M. tuberculosis H₃₇Rv (ATCC27294 strain). Fourteen compounds exhibiting MIC values in the range of 0.4-6.25 µg/mL were subjected to cell viability test against RAW 264.7 cell lines and were found to be non-toxic (<30% inhibition at 50 µg/mL). The active compounds were further evaluated against INH resistant Mtb strains. The most active compound 6x [MIC (H37Rv) of 0.4 µg/mL] and the compound 6d [MIC (H37Rv) of 0.78 µg/mL] were also found to be active against INH resistant Mtb strain with MIC values of 12.5 and 0.78 µg/mL, respectively.

Keywords: Anti-TB (H37Rv) activity; Benzimidazoquinolines; INH resistant-Mtb; New anti-TB chemotypes; Polyheterocycle.