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. We reported the synthesis and anti-RSV or anti-IFV activities of NHC derivatives and 4′-fluorouridine prodrugs, which were evaluated for their chemical stability and PK properties. Tri-isobutyrate ester 1a has potential to be as an antiviral agent.