title: 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.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Baragaña
authors.forename: Orla
authors.initials: O
authors.lastname: McCarthy
authors.forename: Paula
authors.initials: P
authors.lastname: Sánchez
authors.forename: Cristina
authors.initials: C
authors.lastname: Bosch-Navarrete
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Jean L
authors.initials: JL
authors.lastname: Whittingham
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Roberts
authors.forename: Xiao-Xiong
authors.initials: XX
authors.lastname: Zhou
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
authors.forename: Nils Gunnar
authors.initials: NG
authors.lastname: Johansson
authors.forename: Dolores
authors.initials: D
authors.lastname: González-Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D003857:Deoxyuridine