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, EC(99)=49 ± 38 μM and 23b, EC(99)≥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.
Welsh School of Pharmacy, Cardiff University, UK.
Silvia
S
Meneghesso
Evelien
E
Vanderlinden
Annelies
A
Stevaert
Christopher
C
McGuigan
Jan
J
Balzarini
Lieve
L
Naesens
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000254:growth & development; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; D014764:Viral Proteins; D012321:DNA-Directed RNA Polymerases