Synthesis and Anti-HCV Activity of a Novel 2′,3′-Dideoxy-2′-α-fluoro-2′-β‑<i>C</i>‑methyl Guanosine Phosphoramidate Prodrug

A novel 2′,3′-dideoxy-2′-α-fluoro-2′-β-<i>C</i>-methyl-6-methoxy guanosine (<b>8</b>) and its phosphoramidate prodrug (<b>1</b>) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (<b>1</b>) displayed nanomolar level antiviral activity (EC₅₀ = 0.39–1.1 μM) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons