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Synthesis and Biological Evaluation of Phosphate Prodrugs of 4‐Phospho‐ D ‐erythronohydroxamic Acid, an Inhibitor of 6‐Phosphogluconate Dehydrogenase
Author(s) -
Ruda Gian Filippo,
Alibu Vincent P.,
Mitsos Christos,
Bidet Olivier,
Kaiser Marcel,
Brun Reto,
Barrett Michael P.,
Gilbert Ian H.
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700040
Subject(s) - prodrug , trypanosoma brucei , chemistry , biochemistry , pentose phosphate pathway , dehydrogenase , enzyme , phosphoramidate , phosphate , hydrolysis , glycolysis , gene
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‐acyl thioethyl 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.