Design, Synthesis, and Evaluation of 5 '-Diphenyl Nucleoside Analogues as Inhibitors of the Plasmodium falciparum dUTPase

Shahienaz E. Hampton, Beatriz Baragana, Alessandro Schipani, Cristina Bosch-Navarrete, J. Alexander Musso-Buendia, Eliseo Recio, Marcel Kaiser, Jean L. Whittingham, Shirley M. Roberts, Mikhail Shevtsov, James A. Brannigan, Pia Kahnberg, Reto Brun, Keith S. Wilson, Dolores Gonzalez-Pacanowska, Nils Gunnar Johansson, Ian H. Gilbert

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    22 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)1816-1831
    Number of pages16
    JournalChemMedChem
    Volume6
    Issue number10
    DOIs
    Publication statusPublished - 4 Oct 2011

    Keywords

    • antiprotozoal agents
    • drug design
    • dUTPase
    • malaria
    • nucleosides
    • DRUG
    • TARGET

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