Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β‑d‑Ribose Oxidase (DprE1) Inhibitors

In search of novel drugs against
tuberculosis, we previously discovered
and profiled a novel hydantoin-based family that demonstrated highly
promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1,
a subunit of decaprenylphosphoryl-β-d-ribose-2′-epimerase.
This protein, localized in the periplasmic space of the mycobacterial
cell wall, was shown to be an essential and vulnerable antimycobacterial
drug target. Here, we report the further SAR exploration of this chemical
family through more than 80 new analogues. Among these, the most active
representatives combined submicromolar cellular potency and nanomolar
target affinity with balanced physicochemical properties and low human
cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being
the target of the hydantoins. Overall, the hydantoin family of DprE1
inhibitors represents a promising noncovalent lead series for the
discovery of novel antituberculosis agents.