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

• Published in: Archiv der Pharmazie (Weinheim) 2019-11, Vol.352 (11), p.e1900028-n/a
• Main Authors: Göktaş, Füsun, Özbil, Mehmet, Cesur, Nesrin, Vanderlinden, Evelien, Naesens, Lieve, Cesur, Zafer
• Format: Article
• Language: English
• Subjects: antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Aza Compounds - chemical synthesis; Aza Compounds - chemistry; Aza Compounds - pharmacology; cycloaddition; Dose-Response Relationship, Drug; Influenza; Influenza A Virus, H3N2 Subtype - drug effects; influenza virus; Microbial Sensitivity Tests; Molecular Docking Simulation; Molecular Structure; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; structure elucidation; Structure-Activity Relationship; synthesis; Virus Replication - drug effects
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201900028

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. A new series of N‐(1‐thia‐4‐azaspiro[4.5]decan‐4‐yl)carboxamide compounds carrying the 5‐chloro‐2‐methoxybenzamide structure were designed, synthesized and evaluated for antiviral activity. Compounds 2b, 2c, and 2d displayed inhibitory activity against influenza A/H3N2 virus, acting as inhibitors of the influenza virus hemagglutinin‐mediated fusion process.