Development of MmpL3 inhibitors for tuberculosis treatment

Tuberculosis (TB) is the leading cause of death worldwide from a single infectious agent, with an estimated 10 million new cases of active TB and approximately 1.3 million deaths in 2017. Despite several new or repurposed drugs being in advanced stages of clinical trials, low treatment success rates for MDR- and XDR-TB and HIV co-infections demonstrate the necessity for development of new anti-tubercular drugs as well as the discovery and characterization of novel druggable targets. In this book chapter we describe one of our medicinal chemistry projects on the development of a class of 1,5-diphenyl pyrroles active against the causative agent Mycobacterium tuberculosis (Mtb) to outline our experience in developing new anti-mycobacterials. We have identified an initial “soft-hit” (BM212) by the more reliable whole-cell screening assay; BM212 underwent chemical modifications that brought by several active hits. Next, the hit-to-lead program provided an improved lead BM635, active against both replicating and non-replicating bacilli, and efficacious in a murine model of tuberculosis infection. Further medicinal chemistry efforts included diverse strategies for improving the lead-like properties of this class of compounds. Meanwhile, we have elucidated target and mode of action of this class of compounds.