Barbituric acid derivatives as covalent inhibitors of Leishmania braziliensis dihydroorotate dehydrogenase

by Quadros Froes T, Omowumi Alegbejo Price T, Fleck Godoi B, Menezes Vaidergorn M, dos Santos T, Ivo Palacio Leite P, Gedder Silva D, Dias da Purificação A, Loch L, Schenkman S, Kratz JM, da Silva Emery F, Cristina Nonato M. Journal of Medicinal Chemistry 2025, 68(18):18869–18884. doi: 10.1021/acs.jmedchem.5c00462

Summary: The authors of this manuscript present the first covalent inhibitors of Leishmania braziliensis dihydroorotate dehydrogenase, a key enzyme in pyrimidine biosynthesis with a reactive cysteine (Cys¹³¹) in its active site. A barbituric acid derivative was discovered that demonstrated remarkable potency, with an IC₅₀ of 0.5 ± 0.1 μM, significant antiparasitic activity against Leishmania braziliensis promastigote, and no cytotoxicity in mammalian cells. X-ray crystallography confirmed covalent bond formation with Cys¹³¹ and revealed active-site rearrangements, supporting the proposed covalent inhibition mechanism and providing structural insights for further optimization. This study validates LbDHODH as a promising target for leishmaniasis therapy and highlights the potential of covalent inhibition in antiparasitic drug discovery.