Selective inhibition of Trypanosoma brucei 6-phosphogluconate dehydrogenase by high-energy intermediate and transition-state analogues

Christophe Dardonville, Eliana Rinaldi, Michael P. Barrett, Reto Brun, Ian H. Gilbert, Stefania Hanau

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    Two series of compounds were designed to mimic the transition state and high-energy intermediates (HEI) of the enzymatic reaction of 6-phosphogluconate dehydrogenase (6PGDH). Sulfoxide analogues (7-11) were designed to mimic the transition state during the oxidation of the substrate to 3-keto-6-phosphogluconate, an enzyme-bound intermediate of the enzyme. Hydroxamate and amide derivatives Of D-erythronic acid were designed to mimic the 1,2-cis-enediol HEI of the 6PGDH reaction. These two series of compounds were assayed as competitive inhibitors of the Trypanosoma brucei and sheep liver enzymes, and their selectivity value (ratio sheep/parasite) was calculated. The sulfoxide transition-state analogues showed weak and selective inhibition of the T. brucei enzyme. The hydroxamic derivatives showed potent and selective inhibition of the T brucei 6PGDH with a K-i in the nanomolar range.

    Original languageEnglish
    Pages (from-to)3427-3437
    Number of pages11
    JournalJournal of Medicinal Chemistry
    Issue number13
    Publication statusPublished - 17 Jun 2004

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