Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot and mouth disease (HFMD) which seriously threatened the safety and lives of infants and young children. However, there are no licensed direct antiviral agents to cure the HFMD. In this study, a series of quinoline formamide analogues as effective enterovirus inhibitors were developed, subsequent systematic structure-activity relationship (SAR) studies demonstrated that these quinoline formamide analogues exhibited good potency to treat EV-A71 infection. As described, the most efficient EV-A71 inhibitor 6i showed good anti-EV-A71 activity (EC₅₀ = 1.238 μM) in RD cells. Furthermore, compound 6i could effectively prevent death of virus infected mice at dose of 6 mg/kg. When combined with emetine (0.1 mg/kg), this treatment could completely prevent the clinical symptoms and death of virus infected mice. Mechanism study indicated that compound 6i inhibited EV-A71 via targeting 2C helicase, thus impeding RNA remodeling and metabolism. Taken together, these data indicated that 6i is a promising EV-A71 inhibitor and worth extensive preclinical investigation as a lead compound.

肠病毒A71（EV-A71）是引起手足口病（HFMD）的人类病原体，严重威胁着婴幼儿的安全和生命。但是，没有获得许可的直接抗病毒药可以治愈手足口病。在这项研究中，开发了一系列喹啉甲酰胺类似物作为有效的肠病毒抑制剂，随后的系统结构活性关系（SAR）研究表明，这些喹啉甲酰胺类似物表现出了良好的治疗EV-A71感染的能力。如上所述，最有效的EV-A71抑制剂6i 在RD细胞中显示出良好的抗EV-A71活性（EC ₅₀ = 1.238μM）。此外，化合物6i可以有效预防6 mg / kg剂量的病毒感染小鼠的死亡。当与依替丁（0.1 mg / kg）联合使用时，这种治疗可以完全预防病毒感染小鼠的临床症状和死亡。机制研究表明，化合物6i通过靶向2C解旋酶抑制EV-A71，从而阻碍RNA重塑和代谢。综上所述，这些数据表明6i是一种有前途的EV-A71抑制剂，作为前导化合物值得进行广泛的临床前研究。