title: Investigation of acyclic uridine amide and 5'-amido nucleoside analogues as potential inhibitors of the Plasmodium falciparum dUTPase.
abstract: Previously we have shown that trityl and diphenyl deoxyuridine derivatives and their acyclic analogues can inhibit Plasmodium falciparum dUTPase (PfdUTPase). We report the synthesis of conformationally restrained amide derivatives as inhibitors PfdUTPase, including both acyclic and cyclic examples. Activity was dependent on the orientation and location of the amide constraining group. In the case of the acyclic series, we were able to obtain amide-constrained analogues which showed similar or greater potency than the unconstrained analogues. Unfortunately these compounds showed lower selectivity in cellular assays.
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, UK.
authors.forename: Shahienaz E
authors.initials: SE
authors.lastname: Hampton
authors.forename: Alessandro
authors.initials: A
authors.lastname: Schipani
authors.forename: Cristina
authors.initials: C
authors.lastname: Bosch-Navarrete
authors.forename: Eliseo
authors.initials: E
authors.lastname: Recio
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Pia
authors.initials: P
authors.lastname: Kahnberg
authors.forename: Dolores
authors.initials: D
authors.lastname: González-Pacanowska
authors.forename: Nils Gunnar
authors.initials: NG
authors.lastname: Johansson
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000577:Amides / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014529:Uridine / Q000737:chemistry
chemical_list: D000577:Amides; D000962:Antimalarials; D004791:Enzyme Inhibitors; D009705:Nucleosides; D015800:Protozoan Proteins; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D014529:Uridine
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