title: Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase.
abstract: Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.
authors: Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.
authors: Shahienaz E
authors: SE
authors: Hampton
authors: Beatriz
authors: B
authors: Baragaña
authors: Alessandro
authors: A
authors: Schipani
authors: Cristina
authors: C
authors: Bosch-Navarrete
authors: J Alexander
authors: JA
authors: Musso-Buendía
authors: Eliseo
authors: E
authors: Recio
authors: Marcel
authors: M
authors: Kaiser
authors: Jean L
authors: JL
authors: Whittingham
authors: Shirley M
authors: SM
authors: Roberts
authors: Mikhail
authors: M
authors: Shevtsov
authors: James A
authors: JA
authors: Brannigan
authors: Pia
authors: P
authors: Kahnberg
authors: Reto
authors: R
authors: Brun
authors: Keith S
authors: KS
authors: Wilson
authors: Dolores
authors: D
authors: González-Pacanowska
authors: Nils Gunnar
authors: NG
authors: Johansson
authors: Ian H
authors: IH
authors: Gilbert
mesh_terms: D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D009705:Nucleosides; D011755:Pyrophosphatases; C010574:biphenyl; C020020:dUTP pyrophosphatase