Alkyloxyphenyl furano pyrimidines as potent and selective anti-VZV agents with enhanced water solubility

We have previously reported bicyclic furanopyrimidines as potent and selective inhibitors of varicella zoster virus (VZV) with subnanomolar activity for p-alkylphenyl substituted analogues. These compounds are highly lipophilic and of limited water solubility. In an effort to address this issue, and with a view to oral dosing, we have sought to enhance water solubility whilst retaining high antiviral potency and we herein report a novel series of p-alkyloxyphenyl compounds which contain a phenolic ether atom intended to boost hydrophilicity. We report the synthesis, characterisation and antiviral evaluation of this series and note the retention of extremely high antiviral potency, with EC50 values as low as 1 nanomolar