Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase

Huaqing Cui, Gian Filippo Ruda, Juana Carrero-Lerida, Luis M. Ruiz-Perez, Ian H. Gilbert, Dolores Gonzalez-Pacanowska

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    22 Citations (Scopus)

    Abstract

    Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (K-m = 51 mu M, k(cat)/K-m = 7.4 x 10(4) M-1 s(-1)), but can also use uridine, albeit less efficiently (K-m = 85 mu M, k(cat)/K-m = 306 M-1 s(-1)). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, K-i = 6 mu M). (C) 2010 Elsevier Masson SAS. All rights reserved.

    Original languageEnglish
    Pages (from-to)5140-5149
    Number of pages10
    JournalEuropean Journal of Medicinal Chemistry
    Volume45
    Issue number11
    DOIs
    Publication statusPublished - Nov 2010

    Keywords

    • Malaria
    • Purine nucleoside phosphorylase
    • Uridine phosphorylase
    • Transition state inhibitor
    • Drug discovery
    • TRANSITION-STATE ANALOG
    • URIDINE PHOSPHORYLASE
    • FORCE-FIELD
    • MALARIA
    • MAB

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