Synthesis and biological evaluation of phosphate Prodrugs of 4-Phospho-D-erythronohydroxamic acid, an inhibitor of 6-phosphogluconate dehydrogenase

Gian Filippo Ruda, Vincent P. Alibu, Christos Mitsos, Olivier Bidet, Marcel Kaiser, Reto Brun, Michael P. Barrett, Ian H. Gilbert

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    We have previously reported the discovery of potent and selective inhibitors of 6-phosphogluconate dehydrogenase, the third enzyme of the phosphate pentose pathway, from Trypanosoma brucei, the causative organism of human African trypanosomiasis. These inhibitors were charged phosphate derivatives with restricted capacity to enter cells. Herein, we report the synthesis of five different classes of prodrugs: phosphoramidate; bis-S-acylthioethyl esters (bis-SATE); bis-pivaloxymethyl (bis-POM); CycloSaligenyl; and phenyl, S-acyl thioethyl mixed phosphate esters (mix-SATE). Prodrugs were studied for stability and activity against the intact parasites. Most prodrugs caused inhibition of the growth of the parasites. The activity of the prodrugs against the parasites appeared to be related to their stability in aqueous buffer.

    Original languageEnglish
    Pages (from-to)1169-1180
    Number of pages12
    Issue number8
    Publication statusPublished - Aug 2007

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