Discovery of aminothiazole derivatives as novel human enterovirus A71 capsid protein inhibitors.

A series of novel enterovirus A71 inhibitors with an aminothiazole scaffold were identified. The best compound 12s displayed low- to sub-micromolar activity against enterovirus replication without significant cytotoxicity. Microscale thermophoresis (MST) experiment and co-localization assay indicated that 12s exhibited antiviral activity by targeting EV-A71 capsid protein (K d = 0.149 μM) and disturbing the binding between VP1 and receptor hSCARB2. [Display omitted] • A series of novel enterovirus A71 inhibitors with an aminothiazole scaffold were identified. • 12 s showed broad-spectrum anti-enterovirus activity (low to sub-micromolar) without significant cytotoxicity. • Systematic mechanism studies showed that 12 s might interact with the EV-A71 capsid protein by disturbing the binding between VP1 and the host receptor hSCARB2. Enterovirus A71 (EV-A71), one of the major pathogens that causes hand, foot and mouth disease (HFMD), has seriously threatened the health and safety of young children. In this study, aminothiazole derivatives were synthesized and screened against EV-A71 in Rhabdomyosarcoma (RD) cells. The best compound (12 s), with a biphenyl group, showed activity against EV-A71 (EC 50 : 0.27 μM) but also against a series of different human enteroviruses without significant cytotoxicity (CC 50 > 56.2 μM). Mechanistic studies including time-of-drug-addition assays, viral entry assays and microscale thermophoresis (MST) experiments, showed that 12 s binds to EV-A71 capsid and blocks the binding between the viral protein VP1 and the relevant human scavenger receptor class B member 2 (hSCARB2). [ABSTRACT FROM AUTHOR]