Evaluation of novel phosphoramidate ProTides of the 2'-fluoro derivatives of apotent anti-varicella zoster virus bicyclic nucleoside analogue.

摘要

BACKGROUND: Recently, the synthesis and antiviral activity of a series of2'-fluoro derivatives of the most potent anti-varicella zoster virus (VZV) agentreported to date, the bicyclic nucleoside analogue Cf1743, have been reported.METHODS: Here, we present molecular modelling studies for the interaction ofthese compounds with VZV-encoded thymidine kinase (TK) and we report thesynthesis of a series of phosphoramidate ProTides of these compounds designed tobypass the nucleoside kinase dependence of the parent nucleoside analogues.RESULTS: The phosphoramidate prodrugs were equally effective as their parentcompounds against VZV in cell culture, but lost antiviral potency againstTK-deficient VZV strains.CONCLUSIONS: ProTide-based kinase bypass is not successful in this case.