Design and Synthesis of Benzenesulfonamide Derivatives as Potent Anti-Influenza Hemagglutinin Inhibitors

摘要

Structural optimization of salicylamide-based hemagglutinin (HA) inhibitor >1 resulted in the identification of cis-3-(5-hydroxy-1,3,3-trimethylcyclohexylmethylamino)benzenesulfonamide >28 and its derivatives as potent anti-influenza agents. The lead compound >28 and its 2-chloro analogue >40 can effectively prevent cytopathic effects (CPE) caused by infection of influenza A/Weiss/43 strain (H1N1) with EC50 values of 210 and 86 nM, respectively. Mechanism of action studies indicate that >40 and its analogues inhibit the virus fusion with host endosome membrane by binding to HA and stabilizing the prefusion HA structure. With significantly improved metabolic stability, the reported series represents the first generation of orally bioavailable HA inhibitors that have a good selectivity window and potential for further development as novel anti-influenza agents.