Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base

We herein report the discovery of an entirely new category of potent antivi ral agents based on novel deoxynucleoside analogues with unusual bicyclic b ase moieties. Target structures, previously known as byproducts in Pd-catal yzed coupling of terminal alkynes with 5-iodo-nucleosides, are recognized h erein for the first time to be potent and selective inhibitors of varicella -zoster virus (VZV) in vitro. As an unusual structure-activity relationship we noted the absolute requirement of a long alkyl side chain, with an opti mum length of C-8-C-10, for antiviral activity. We thus report the synthesi s and characterization of a series of chain-modified analogues and their ex tensive in vitro evaluation. The lead compounds have a ca. 300-fold enhance ment in anti-VZV activity over the reference compound acyclovir, with no de tectable in vitro cytotoxicity. The novel structure of these compounds, cou pled with their ease of synthesis, excellent antiviral profile, and promisi ng physical properties, makes them of great interest for possible antiviral drug development.