AI Article Synopsis
- The study focuses on creating phosphonooxymethyl derivatives of the antifungal compound ravuconazole, specifically BMS-379224 and BMS-315801, as potential water-soluble prodrugs.
- Both derivatives were successfully synthesized and showed high water solubility, with the ability to convert back to ravuconazole in certain conditions, such as in the presence of alkaline phosphatase and in vivo in rats.
- BMS-379224 emerged as the more stable and promising prodrug compared to BMS-315801, and is currently undergoing clinical evaluation for intravenous use.
Article Abstract
Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole.
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| http://dx.doi.org/10.1016/j.bmcl.2003.08.029 | DOI Listing |
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