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

Abstract

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.

The Playbooks of Medicinal Chemistry Design Moves

“…Balabon et al . recently published two articles reporting the optimization of a series of hydantoin-based compounds as DprE1 inhibitors against Mycobacterium tuberculosis. , Their work focused on SAR exploration around the nitrile substituent of compound 1 (Figure a). They reported 30 replacements with the primary sulfonamide, achieving the best overall profile.…”

“…All 30 replacements used by Balabon et al , are part of the SureChEMBL transformations with 24 (80%) of them even being part of the high-frequency set (Table ). Some of the common replacements were not used in Balabon et al’s work, , unsurprisingly as they mostly correspond to highly lipophilic (phenyl, t -Bu, etc.) substituents or substituents very similar to others that were used (Figure b).…”

“…Recovery of nitrile-related medicinal chemistry design moves reported in two publications from Balabon et al . , (a) Starting compound for optimization. One of the optimization sites was the aromatic ring substituted with a nitrile.…”

“… a Nitrile → X transformations reported in refs and , which were found in nitrile → X transformations extracted from the SureChEMBL transformation database. X is any fragment. …”

Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities

“…Recently, several structurally diverse noncovalent inhibitors of DprE1 have been described in the literature, most notably TBA-7371 and TCA1 (Figure ). ,− These compounds have the additional bonus of avoiding the nitro group used in BTZs, a well-established structural alert, and show the potential for further development. 1,4-Azaindole TBA-7371 has entered clinical development, and the structure–activity relationship (SAR) of this series has been fully explored and is well understood. , TCA1 was identified via a cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria, which has bactericidal activity against replicating and nonreplicating M.…”