β-Branched acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase

Abstract

We report a series of β-branched acyclic tritylated deoxyuridine analogues as inhibitors of Plasmodium falciparum deoxyuridine-5′-triphosphate nucleotidohydrolase ( PfdUTPase), an enzyme involved in nucleotide metabolism that acts as first line of defence against uracil incorporation into DNA. Compounds were assayed against both PfdUTPase and intact parasites showing a correlation between enzyme inhibition and cellular assays. β-Branched acyclic uridine analogues described here showed equal or slightly better potency and selectivity compared with previously reported analogues. The best inhibitor gave a K i of 0.5 μM against PfdUTPase with selectivity greater than 200-fold compared to the corresponding human enzyme and sub-micromolar growth inhibition of P. falciparum (EC 50 0.6 μM). A crystal structure of the complex of PfdUTPase with one of the inhibitors shows that this acyclic derivative binds to the active site in a similar manner to that previously reported for a tritylated cyclic deoxyuridine derivative.