Benzimidazole-based compounds kill Mycobacterium tuberculosis

•Seventy new benzimidazole-based compounds were designed and synthesized.•All of the compounds were evaluated for activity against replicating and non-replicating Mycobacterium tuberculosis in vitro.•Compounds 49, 67, 68, 69, 70 and 72 exhibited high potency and acceptable selectivity indices.•Several nitrofuranyl benzimidazoles were selectively bactericidal for mycobacteria and killed Mtb in primary human macrophages.•The SOS chromotest indicated that compound 70 had a very low mutagenic potential.

Tuberculosis remains one of the deadliest infectious diseases, killing 1.4 million people annually and showing a rapid increase in cases resistant to multiple drugs. New antibiotics against tuberculosis are urgently needed. Here we describe the design, synthesis and structure–activity relationships of a series of benzimidazole-based compounds with activity against Mycobacterium tuberculosis (Mtb) in a replicating state, a physiologically-induced non-replicating state, or both. Compounds 49, 67, 68, 69, 70, and 72, which shared a 5-nitrofuranyl moiety, exhibited high potency and acceptable selectivity indices (SI). As illustrated by compound 70 (MIC90 < 0.049 μg/mL, SI > 512), the 5-nitrofuranyl group was compatible with minimal cytotoxicity and good intra-macrophage killing, although it lacked non-replicating activity when assessed by CFU assays. Compound 70 had low mutagenic potential by SOS Chromotest assay, making this class of compounds good candidates for further evaluation and target identification.

Graphical abstractA series of novel benzimidazole-based compounds were designed and synthesized. Several nitrofuranyl benzimidazoles are selectively bactericidal for mycobacteria and kill Mtb in primary human macrophages. The most potent compound 70 has a very low mutagenic potential. Figure optionsDownload full-size imageDownload as PowerPoint slide