Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC₅₀ value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

中文翻译：

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模块化仿生策略使肟大环化合物作为甲型流感病毒 (H1N1) 抑制剂的发现和 SAR 探索成为可能


尽管疫苗接种仍然是控制甲型流感病毒（IAV）感染的普遍预防手段，但具有新作用机制的新型结构抗病毒小分子药物治疗 IAV 仍然非常令人期待。在此，我们描述了一种模块化仿生策略，以快速实现一类以肟为特征的新型大环化合物，该大环化合物可能靶向血凝素（HA）介导的IAV进入宿主细胞。 SAR 分析表明，大环化合物的大小和连接基在提高效力方面发挥着重要作用。特别是，37作为14元大环肟，对IAV H1N1表现出有效的抑制活性，EC ₅₀ 值为23 nM，细胞毒性较低，可减轻H1N1感染后的细胞病变效应，明显保护细胞存活。此外，37在体外与神经氨酸酶抑制剂奥司他韦表现出显着的协同活性。