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.

A 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 as PowerPoint slide