Synthesis and evaluation of NHC derivatives and 4 & PRIME;-fluorouridine prodrugs

beta-d-N-4-Hydroxycytidine (NHC) derivatives with structural modifications at the C-4 & PRIME;, O-4 & PRIME; or C-6 position and 4 & PRIME;-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 & PRIME;-fluorouridine and its prodrugs had potent anti-RSV and anti-IFV activities. 4 & PRIME;-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.