Synthesis and evaluation of NHC derivatives and 4'-fluorouridine prodrugs.

β-D-N 4 -Hydroxycytidine (NHC) derivatives with structural modifications at the C 4 ', O 4 ' or C 6 position and 4'-fluorouridine prodrugs were synthesized and evaluated for their antiviral activities against respiratory syncytial virus (RSV) or influenza virus (IFV) in vitro . The NHC derivatives were found inactive, but 4'-fluorouridine and its prodrugs had potent anti-RSV and anti-IFV activities. 4'-Fluorouridine was proved to be a nucleoside with poor stability, but the tri-ester prodrugs exhibited enhanced stability, especially tri-isobutyrate ester 1a. This prodrug also showed excellent oral pharmacokinetic properties in rats, with potential to be an oral antiviral candidate.