The epidemic coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has now spread worldwide and efficacious therapeutics are urgently needed. 3-Chymotrypsin-like cysteine protease (3CL^pro) is an indispensable protein in viral replication and represents an attractive drug target for fighting COVID-19. Herein, we report the discovery of 9,10-dihydrophenanthrene derivatives as non-peptidomimetic and non-covalent inhibitors of the SARS-CoV-2 3CL^pro. The structure-activity relationships of 9,10-dihydrophenanthrenes as SARS-CoV-2 3CL^pro inhibitors have carefully been investigated and discussed in this study. Among all tested 9,10-dihydrophenanthrene derivatives, C1 and C2 display the most potent SARS-CoV-2 3CL^pro inhibition activity, with IC₅₀ values of 1.55 ± 0.21 μM and 1.81 ± 0.17 μM, respectively. Further enzyme kinetics assays show that these two compounds dose-dependently inhibit SARS-CoV-2 3CL^pro via a mixed-inhibition manner. Molecular docking simulations reveal the binding modes of C1 in the dimer interface and substrate-binding pocket of the target. In addition, C1 shows outstanding metabolic stability in the gastrointestinal tract, human plasma, and human liver microsome, suggesting that this agent has the potential to be developed as an orally administrated SARS-CoV-2 3CL^pro inhibitor.

由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的流行性冠状病毒病 2019 (COVID-19) 现已在全球蔓延，迫切需要有效的治疗方法。3-胰凝乳蛋白酶样半胱氨酸蛋白酶 (3CL ^pro ) 是病毒复制中不可或缺的蛋白质，是对抗 COVID-19 的有吸引力的药物靶点。^{在此，我们报告了 9,10-二氢菲衍生物作为 SARS-CoV-2 3CL pro}的非拟肽和非共价抑制剂的发现。本研究仔细研究和讨论了9,10-二氢菲作为 SARS-CoV-2 3CL ^{pro抑制剂的构效关系。}在所有测试的 9,10-二氢菲衍生物中，C1和C2显示出最有效的 SARS-CoV-2 3CL^促抑制活性，IC ₅₀值分别为 1.55 ± 0.21 μM 和 1.81 ± 0.17 μM。进一步的酶动力学分析表明，这两种化合物通过混合抑制方式剂量依赖性地抑制 SARS-CoV-2 3CL ^{pro 。} 分子对接模拟揭示了C1在二聚体界面和目标底物结合口袋中的结合模式。此外，C1在胃肠道、人体血浆和人体肝微粒体中表现出出色的代谢稳定性，表明该药物具有开发为口服SARS-CoV-2 3CL ^pro抑制剂的潜力。