Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity.
R MM, Shandil R, Panda M, Sadler C, Ambady A, Panduga V, Kumar N, Mahadevaswamy J, Sreenivasaiah M, Narayan A, Guptha S, Sharma S, Sambandamurthy VK, Ramachandran V, Mallya M, Cooper C, Mdluli K, Butler S, Tommasi R, Iyer PS, Narayanan S, Chatterji M, Shirude PS.
We report a novel benzimidazole (BI) based DprE1 inhibitor 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 noncovalent inhibition of the decaprenylphosphoryl-β-d-ribose-2'-epimerase (DprE1). The representative compounds from the 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 modeling 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.