Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain

In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancemen t of the antiviral potency by inclusion of a phenyl:group in the side chain of these compounds. The target structures were prepared by the Pd-catalyze d coupling of a series of para-substituted arylacetylenes with 5-iodo-2'-de oxyuridine, to give intermediate Ei-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index va lues greater than or equal to 1 000 000. From a range of DNA and RNA viruse s tested, only VZV was inhibited by these compounds indicating their extrem e selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, I makes them of consider able interest for potential drug development for VZV infections.