title: Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase.
abstract: The ubiquitous enzyme dUTP nucleotidohydrolase (dUTPase) catalyses the hydrolysis of dUTP to dUMP and can be considered as the first line of defence against incorporation of uracil into DNA. Inhibition of this enzyme results in over-incorporation of uracil into DNA, leading to DNA fragmentation and cell death and is therefore lethal. By taking advantage of structural differences between the human and Plasmodium dUTPase, selective inhibitors of the enzyme can be designed and synthesised with the aim of being developed into novel anti-parasitic drugs. Analogue based design was used to target the Plasmodium falciparum dUTPase (PfdUTPase). The structures of previously discovered selective inhibitors of the PfdUTPase were modified by insertion of an amide bond. A series of tritylated uracil acetamide derivatives were synthesised and assessed for inhibition of the enzyme and parasite growth in vitro. These compounds were weak inhibitors of the PfdUTPase.
authors.affiliation: Welsh School of Pharmacy, University of Wales Cardiff, King Edward VII Avenue, Cardiff CF103XF, UK.
authors.forename: Orla
authors.initials: O
authors.lastname: McCarthy
authors.forename: Alex
authors.initials: A
authors.lastname: Musso-Buendia
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Perez
authors.forename: Nils Gunnar
authors.initials: NG
authors.lastname: Johansson
authors.forename: Dolores Gonzalez
authors.initials: DG
authors.lastname: Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000081:Acetamides; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; D014498:Uracil; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase