Synthesis of multivalent difluorinated zanamivir analogs as potent antiviral inhibitors

Abstract

An efficient synthesis of mono-, di-, tetra-, and octa-valent difluorinated zanamivir analogs as potent inhibitors of influenza virus is reported. The mono difluorinated zanamivir with an azide linker attached at the C-7 position was synthesized in good yield from sialic acid using Selectfluor® and (diethylaminosulfur trifluoride) DAST as the fluorination reagent. This key intermediate was attached on various alkynlated scaffolds via “Click Chemistry” to afford multivalent glycoclusters. A neuraminidase inhibition assay was used to evaluate the compounds for their inhibitory activity using H7N9 virus like particle. These multivalent sialosides show enhanced inhibition with IC50 values ∼100-fold better than the monomer indicative of the strength of using a multivalent approach.