Barbituric Acid Derivatives as Covalent Inhibitors of <i>Leishmania braziliensis</i> Dihydroorotate Dehydrogenase.

ABSTRACT: Covalent drug design applied to parasite proteins enables selective therapies by targeting nucleophilic residues of macromolecules. We present the first covalent inhibitors of Leishmania braziliensis dihydroorotate dehydrogenase (LbDHODH), a key enzyme in pyrimidine biosynthesis with a reactive cysteine (Cys¹³¹) in its active site. From barbituric acid derivatives, we discovered 2i as a LbDHODH inhibitor with leishmanicidal activity, exhibiting an IC₅₀ of 0.5 ± 0.1 μM, a K_inact/KI of 767 M^-1s^-1, no inhibition of the human ortholog, and an EC₅₀ of 11 ± 5 μM in L. braziliensis promastigotes, with no cytotoxicity in THP-1 cells and good passive permea

SUBMITTER: Froes TQ 

PROVIDER: S-EPMC12481576 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature