Benzimidazole-based compounds kill Mycobacterium tuberculosis

Abstract 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 (MIC 90  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.