Synthesis and Anti-Hepatitis B Activities of 3'-Fluoro-2'-Substituted Apionucleosides

Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2'-hydroxy- and 2'-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2'-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC₅₀ value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC₅₀ value of 7.8 nM.