Novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide derivatives as potent and selective influenza virus fusion inhibitors

Hemagglutinin is the surface protein of the influenza virus that mediates both binding and penetration of the virus into host cells. We here report on the synthesis and structure–activity relationship of some novel N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)‐carboxamide compounds carrying the 5‐chloro‐2‐methoxybenzamide structure, designed as influenza virus fusion inhibitors. The carboxamides ( 1a–h, 2a–h ) have a similar backbone structure as the fusion inhibitors that we reported on previously. Compounds 2b and 2d displayed inhibitory activity against influenza A/H3N2 virus replication (average antiviral EC₅₀: 2.1 µM for 2b and 3.4 µM for 2d ). Data obtained in the hemolysis inhibition assay supported that these compounds act as inhibitors of the influenza virus hemagglutinin‐mediated fusion process.