title: Design and synthesis of benzenesulfonamide derivatives as potent anti-influenza hemagglutinin inhibitors.
abstract: 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.
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Tang
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Xianfeng
authors.initials: X
authors.lastname: Lin
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Zongxing
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Li
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Wang
authors.affiliation: WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Li
authors.affiliation: WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
authors.forename: Haodong
authors.initials: H
authors.lastname: Li
authors.affiliation: WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Lin
authors.affiliation: WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yang
authors.affiliation: WuXi Apptec Co., Ltd. , Shanghai, 200131, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Guo
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Jim Z
authors.initials: JZ
authors.lastname: Wu
authors.affiliation: Roche R&D Center China , Shanghai, 201203, China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Yang
keywords: Anti-influenza; benzenesulfonamide; hemagglutinin; inhibitor