Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds

Gian Filippo Ruda, Pui Ee Wong, Vincent P. Alibu, Suzanne Norval, Kevin D. Read, Michael P. Barrett, Ian H. Gilbert

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    Abstract

    RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood.
    Reprinted with permission from Ruda, GF, Wong, PE, Alibu, VP, Norval, S, Read, KD, Barrett, MP & Gilbert, IH 2010, 'Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds' Journal of Medicinal Chemistry, vol 53, no. 16, pp. 6071-6078.. Copyright 2010 American Chemical Society.

    Original languageEnglish
    Pages (from-to)6071-6078
    Number of pages8
    JournalJournal of Medicinal Chemistry
    Volume53
    Issue number16
    DOIs
    Publication statusPublished - 2010

    Keywords

    • 6-PHOSPHOGLUCONATE DEHYDROGENASE
    • PRODRUGS
    • D4T
    • NUCLEOTIDES
    • DERIVATIVES
    • INHIBITORS
    • DISCOVERY
    • DELIVERY
    • SERIES

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