Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

作者：D. Xu, Ying Gong, Lianju Zhang, Xiao Fu, Xinran Wang, Ji Qin, Lin Tan, Teng Yang, Zeng Lin, Zhongliang Xu, Xiujuan Liu, Fuling Xiao, Feili Zhang, Feng Tang, Jianping Zuo, Xiaomin Luo, Wei Huang, Li Yang, Weibo Yang · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00319 · 被引用次数：8 · 研究领域：Influenza Virus Research Studies、Click Chemistry and Applications、interferon and immune responses

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 EC 50 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 .