ABSTRACT
We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.
Subject(s)
Antiviral Agents/chemical synthesis , Azides/chemical synthesis , Hepacivirus/drug effects , Organophosphorus Compounds/chemical synthesis , Uridine/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azides/chemistry , Azides/pharmacology , Cell Line, Tumor , Hepacivirus/genetics , Humans , Models, Molecular , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Replicon , Stereoisomerism , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine/pharmacologyABSTRACT
Thieno analogues of the potent and selective furo-pyrimidine anti-VZV nucleoside family bearing a p-alkylphenyl side chain have been synthesised and tested for their antiviral activity against Varicella-Zoster virus (VZV). While the alkyl chain analogues were shown to retain full antiviral activity against VZV, these new analogues did not when compared to their furo parent nucleosides.
