4-Benzyloxy-gamma-sultone derivatives: discovery of a novel family of non-nucleoside inhibitors of human cytomegalovirus and varicella zoster virus.

We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the 4-keto-1,2-oxathiole-2,2-dioxide (beta-keto-gamma-sultone) heterocyclic system. Several 4- and 5-substituted-5H-1,2-oxathiole-2,2-dioxide derivatives were found to have a selective inhibitory activity against human cytomegalovirus (HCMV) and varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a benzyl at the 5 position and a benzyloxy substituent at the 4 position are a prerequisite for anti-HCMV and VZV activity. The novel compounds do not show cross-resistance against a wide variety of mutant drug-resistant HCMV strains, pointing to a novel mechanism of antiviral action.