Anti-norovirus activity of C7-modified 4-amino-pyrrolo[2,1-f][1,2,4]triazine C-nucleosides

Synthetic nucleoside analogues characterized by a C–C anomeric linkage form a family of promising therapeutics against infectious and malignant diseases. Herein, C-nucleosides comprising structural variations at the sugar and nucleobase moieties were examined for their ability to inhibit both murine and human norovirus RNA-dependent RNA polymerase (RdRp). We have found that the combination of 4-amino-pyrrolo[2,1-f][1,2,4]triazine and its 7-halogenated congeners with either a D-ribose or 2′-C-methyl-D-ribose unit resulted in analogues with good antiviral activity against murine norovirus (MNV), albeit coupled with a significant cytotoxicity. Among this series, 4-aza-7,9-dideazaadenosine notably retained a strong antiviral effect in a human norovirus (HuNoV) replicon assay with an EC50 = 0.015 μM. This study demonstrates that C-nucleosides can be used as viable starting scaffolds for further optimization towards the development of nucleoside-based inhibitors of norovirus replication.