Synthesis and Biological Evaluation of 4‑Substituted Fluoronucleoside Analogs for the Treatment of Hepatitis B Virus Infection

A series
of 4-substituted fluoronucleosides have been synthesized
in order to address the toxicity issue of the parent compound 7, and after in vitro evaluation, the cyclopropylamino analog 1f was selected for in vivo study. In mice, this compound
exhibited a significantly improved toxicity profile. Administered
orally, compound 1f was well-tolerated at a dose up to
3 g/kg and showed insignificant toxicity on white blood cells and
a low mutagenic effect at dosages up to 80 mg/kg (single) or 20 mg/kg/day
(5 days). In duck HBV (DHBV)-infected duck models, both the serum
and liver DHBV DNA levels (74.2 and 82.1%, respectively) were markedly
reduced by the treatment of 1f at a dose of 1 mg/kg/day
for 10 days. In addition, both the viral DNA levels had a lower degree
of recovery after withdrawal of the test compound for 3 days.