Deoxyuridine triphosphate nucleotidohydrolase as a potential antiparasitic drug target

Corinne Nguyen, Ganasan Kasinathan, Isabel Leal-Cortijo, Alexander Musso-Buendia, Marcel Kaiser, Reto Brun, Luis M. Ruiz-Perez, Nils G. Johansson, Dolores Gonzalez-Pacanowska, Ian H. Gilbert

    Research output: Contribution to journalArticlepeer-review

    58 Citations (Scopus)

    Abstract

    NOTE: THE SYMBOLS/SPECIAL CHARACTERS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE ABSTRACT ON THE PUBLISHER’S WEBSITE FOR AN ACCURATE DISPLAY.This paper describes a structure-activity study to identify novel, small-molecule inhibitors of the enzyme deoxyuridine 5‘-triphosphate nucleotidohydrolase (dUTPase) from parasitic protozoa. The successful synthesis of a variety of analogues of dUMP is described in which the substituents are introduced at the 3‘- and 5‘-positions, together with variation in the heteroatom at the 5‘-position. The compounds were assayed against recombinant Plasmodium falciparum and Leishmania major enzymes and the human enzyme to give a measure of selectivity. The compounds were also tested in vitro against the intact parasites P. falciparum and L. donovani. A number of potent and selective inhibitors of the P. falciparum dUTPase that show drug-like properties and represent good leads for future development were identified. The best inhibitors included the compounds 5‘-tritylamino-2‘,5‘-dideoxyuridine (2j) (Ki = 0.2 µM) and 5‘-O-triphenylsilyl-2‘,3‘-didehydro-2‘,3‘-dideoxyuridine (5h) (Ki = 1.3 µM), with selectivity greater than 200-fold compared to the human enzyme. Structural features important for antiplasmodial activity were determined. The correlation observed between the inhibition of the enzyme and the inhibition of the parasite growth in vitro demonstrates that the P. falciparum dUTPase constitutes a valid and attractive novel target for the development of much-needed new antimalarial drugs.
    Original languageEnglish
    Pages (from-to)5942-5954
    Number of pages13
    JournalJournal of Medicinal Chemistry
    Volume48
    Issue number19
    DOIs
    Publication statusPublished - 2005

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