Discovery Of 2 '-Alpha-C-Methyl-2 '-Beta-C-Fluorouridine Phosphoramidate Prodrugs As Inhibitors Of Hepatitis C Virus

2'-alpha-C-Methyl-2'-beta-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 +/- 0.19, 0.88 +/- 0.12, and 2.24 +/- 0.22 mu M, respectively. The docking study revealed that the recognition of the 2'-beta-F by Arg158, 3'-OH by N291, and the Watson Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.