Identification and Profiling of HydantoinsA Novel Class of Potent Antimycobacterial DprE1 Inhibitors

Tuberculosis
is the leading cause of death worldwide from infectious diseases.
With the development
of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action.
Herein, we report the discovery and profiling of a novel hydantoin-based
family of antimycobacterial inhibitors of the decaprenylphospho-β-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared
a library of more than a 100 compounds and evaluated them for their
biological and physicochemical properties. The series is characterized
by high enzymatic and whole-cell activity, low cytotoxicity, and a
good overall physicochemical profile. In addition, we show that the
series acts via reversible inhibition of the DprE1 enzyme. Overall,
the novel compound family forms an attractive base for progression
to further stages of optimization and may provide a promising drug
candidate in the future.