Synthesis and biological evaluation of phosphate prodrugs of 4-phospho-D-erythronohydroxamic acid, an inhibitor of 6-phosphogluconate dehydrogenase.

Abstract

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.

• Authors: Gian Filippo Ruda, Vincent P Alibu, Christos Mitsos, Olivier Bidet, Marcel Kaiser, Reto Brun, Michael P Barrett, Ian H Gilbert
• Journal: ChemMedChem (ChemMedChem) Vol. 2 Issue 8 Pg. 1169-80 (Aug 2007) ISSN: 1860-7187 [Electronic] Germany
• PMID: 17615587 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-phosphoerythronohydroxamic acid
• Enzyme Inhibitors
• Hydroxamic Acids
• Prodrugs
• Sugar Phosphates
• Phosphogluconate Dehydrogenase

Topics

• Animals
• Enzyme Inhibitors (pharmacology)
• Hydroxamic Acids (pharmacology)
• Phosphogluconate Dehydrogenase (antagonists & inhibitors)
• Prodrugs (chemical synthesis, pharmacology)
• Sugar Phosphates (pharmacology)
• Trypanosoma brucei brucei (drug effects)