ABSTRACT
Bicyclic furanopyrimidines were recently discovered by us to be potent and selective inhibitors of VZV. Related studies to investigate the role of the sugar in this activity uncovered dideoxy furanopyrimidines as inhibitors of HCMV and this led to the preparation of highly modified long alkyl chain furanopyrimidines from the N- and O-alkylation of their parent bases. Herein we describe their synthesis and subsequent biological evaluation against HCMV. O-alkylated derivatives were almost invariably found to be at least equiactive with their N-alkylated counterparts. At this point, little change in activity has been found with large variation in N- and O-substituent.
Subject(s)
Antiviral Agents/pharmacology , Cytomegalovirus Infections/drug therapy , Cytomegalovirus/metabolism , Furans/chemistry , Pyrimidines/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Models, Chemical , Phosphorylation , Pyrimidine Nucleosides/pharmacologySubject(s)
Antiviral Agents/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Herpesvirus 3, Human/drug effects , Pyrimidine Nucleosides/chemical synthesis , Acyclovir/pharmacology , Antiviral Agents/pharmacology , Bridged Bicyclo Compounds/pharmacology , Cell Line , Humans , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacologyABSTRACT
Bicyclic furano pyrimidine nucleosides have been found to be highly potent and selective inhibitors of varicella zoster virus (VZV). They are inactive against herpes simplex virus and have been known for several decades as (unwanted) synthetic by-products in the Pd-catalysed coupling of acetylenes to 5-iodo nucleosides. These fluorescent bicyclic nucleosides are now established as a new family of potent antivirals. They are unusual in that they exhibit complete specificity for VZV and require an alkyl (or alkylaryl) side-chain for biological activity. The latter requirement confers extremely high lipophilicities on these compounds, unknown amongst chemotherapeutic nucleosides, which may be of considerable importance in formulation, dosing and tissue distribution. The most potent compounds reported are p-alkylaryl compounds, with EC50 values below 1 nM versus VZV and selectivity index values of around 1,000,000. Here, we review the discovery, synthesis, characterization, antiviral profile, SAR, mechanism of action and development prospects for this new family of antivirals.