Scaffold Morphing To Identify Novel DprE1 Inhibitorswith Antimycobacterial Activity

We report a novel benzimidazole (BI) based DprE1 inhibitors that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a non-covalent inhibition of the decaprenylphosphoryl-¬β-D-ribose-2’-epimerase (DprE1). The representative compounds from new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modelling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.