title: Acyclic nucleoside analogues as inhibitors of Plasmodium falciparum dUTPase.
abstract: We report the discovery of novel uracil-based acyclic compounds as inhibitors of deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), an enzyme involved in nucleotide metabolism that has been identified as a promising target for the development of antimalarial drugs. Compounds were assayed against both P.falciparum dUTPase and intact parasites. A good correlation was observed between enzyme inhibition and cellular assays. Acyclic uracil derivatives were identified that showed greater or similar potency and in general increased selectivity compared to previously reported inhibitors. The most active compound reported here against the P. falciparum enzyme had a K(i) of 0.2 microM. Molecular modeling studies provided a good rationale for the observed activities. Preliminary ADME studies indicated that some of the lead compounds are drug-like molecules. These compounds are useful tools for further investigating P. falciparum dUTPase for the development of much-needed novel antimalarial drugs.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3XF, UK.
authors.forename: Corinne
authors.initials: C
authors.lastname: Nguyen
authors.forename: Gian Filippo
authors.initials: GF
authors.lastname: Ruda
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: Ganasan
authors.initials: G
authors.lastname: Kasinathan
authors.forename: Isabel
authors.initials: I
authors.lastname: Leal
authors.forename: Alexander
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-Pérez
authors.forename: Britt-Louise
authors.initials: BL
authors.lastname: Sahlberg
authors.forename: Nils Gunnar
authors.initials: NG
authors.lastname: Johansson
authors.forename: Dolores
authors.initials: D
authors.lastname: Gonzalez-Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014320:Triphenylmethyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D009705:Nucleosides; D014320:Triphenylmethyl Compounds; D014498:Uracil; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase