Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro),European Journal of Medicinal Chemistry

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Discovery of quinazolin-4-one-based non-covalent inhibitors targeting the severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro)
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-05-24 , DOI: 10.1016/j.ejmech.2023.115487
Kuojun Zhang ₁ , Tianyu Wang ₁ , Maotian Li ₂ , Mu Liu ₃ , He Tang ₁ , Lin Wang ₁ , Ke Ye ₁ , Jiamei Yang ₁ , Sheng Jiang ₁ , Yibei Xiao ₁ , Youhua Xie ₃ , Meiling Lu ₂ , Xiangyu Zhang ₄

Affiliation

The COVID-19 pandemic caused by SARS-CoV-2 continues to pose a great threat to public health while various vaccines are available worldwide. Main protease (M) has been validated as an effective anti-COVID-19 drug target. Using medicinal chemistry and rational drug design strategies, we identified a quinazolin-4-one series of nonpeptidic, noncovalent SARS-CoV-2 M inhibitors based on baicalein, 5,6,7-trihydroxy-2-phenyl-4-chromen-4-one. In particular, compound exhibits superior inhibitory activity against SARS-CoV-2 M relative to baicalein (IC = 0.085 ± 0.006 and 0.966 ± 0.065 μM, respectively), as well as improved physicochemical and drug metabolism and pharmacokinetics (DMPK) properties. In addition, inhibits viral replication in SARS-CoV-2-infected Vero E6 cells more effectively than baicalein (EC = 1.10 ± 0.12 and 5.15 ± 1.64 μM, respectively) with low cytotoxicity (CC ＞ 50 μM). An X-ray co-crystal structure reveals a non-covalent mechanism of action, and a noncanonical binding mode not observed by baicalein. These results suggest that represents a promising lead for development of more effective SARS-CoV-2 M inhibitors and anti-COVID-19 drugs.

中文翻译：

发现针对严重急性呼吸综合征冠状病毒 2 主要蛋白酶（SARS-CoV-2 Mpro）的喹唑啉 4-一基非共价抑制剂

尽管全球有多种疫苗可供使用，但由 SARS-CoV-2 引起的 COVID-19 大流行继续对公众健康构成巨大威胁。主蛋白酶 (M) 已被验证为有效的抗 COVID-19 药物靶点。利用药物化学和合理的药物设计策略，我们鉴定了一系列基于黄芩素、5,6,7-三羟基-2-苯基-4-chromen-4的喹唑啉-4-one系列非肽、非共价SARS-CoV-2 M抑制剂-一。特别是，与黄芩素相比，该化合物对 SARS-CoV-2 M 表现出优异的抑制活性（IC50 分别为 0.085 ± 0.006 和 0.966 ± 0.065 μM），并改善了理化、药物代谢和药代动力学 (DMPK) 特性。此外，在抑制 SARS-CoV-2 感染的 Vero E6 细胞中的病毒复制方面，比黄芩素（EC 分别为 1.10 ± 0.12 和 5.15 ± 1.64 μM）更有效，且细胞毒性较低（CC ＞ 50 μM）。 X 射线共晶结构揭示了黄芩素未观察到的非共价作用机制和非规范结合模式。这些结果表明，这为开发更有效的 SARS-CoV-2 M 抑制剂和抗 COVID-19 药物提供了有希望的先导。

更新日期：2023-05-24

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