Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus

Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC99 = 49 ± 38 μM and 23b, EC99 ⩾ 81 μM) while the corresponding nucleoside analogue (2′-fluoro-2′-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.

► Uridine 5′-triphosphate derivatives can inhibit influenza RNA polymerase.
► Application of ProTide approach to uridine-based nucleoside analogues is reported.
► Two ProTides derived from 2′-fluoro-2′-deoxyuridine show moderate antiviral activity whilst parent nucleoside is inactive.
► Slow processing of ProTide is causing relatively low antiviral activity.