Design, synthesis and evaluation of novel uracil acetamide derivatives as potential inhibitors of Plasmodium falciparum dUTP nucleotidohydrolase

Orla McCarthy, Alex Musso-Buendia, Marcel Kaiser, Reto Brun, Luis M. Ruiz-Perez, Nils Gunnar Johansson, Dolores Gonzalez Pacanowska, Ian H. Gilbert

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    41 Citations (Scopus)

    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. (C) 2008 Elsevier Masson SAS. All rights reserved.

    Original languageEnglish
    Pages (from-to)678-688
    Number of pages11
    JournalEuropean Journal of Medicinal Chemistry
    Volume44
    Issue number2
    DOIs
    Publication statusPublished - Feb 2009

    Keywords

    • dUTP nucleotidohydrolase
    • Uracil acetamide
    • Anti-plasmodial
    • Anti-malarial
    • PYROPHOSPHATASE
    • ANALOGS
    • TARGET

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