拟肽四氢吡咯螺二氢吲哚酮作为sars - cov - 23cl蛋白酶抑制剂的设计、合成及生物学评价

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-04-14 eCollection Date: 2025-05-08 DOI:10.1021/acsmedchemlett.4c00637

Liuyan Hu, Zhi Zhao, Shujing Zhang, Lei Yang, Wenjie Cui, Tianwen Hu, Jin Suo, Haiguo Sun, Qiumeng Zhang, Leike Zhang, Weiliang Zhu, Zhijian Xu, Yumin Zhang, Xiangrui Jiang, Yan Zhang, Jingshan Shen

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引用次数: 0

摘要

SARS-CoV-2的3CL蛋白酶（3CLpro）是介导病毒复制和转录的关键酶。在这项研究中，我们合成并评价了一系列含有四氢吡咯螺二氢吲哚酮片段的拟肽化合物。其中13c和17d表现出明显的3CLpro抑制活性，IC50分别为3.71和6.21 nM。在肝微粒体代谢稳定性测试中，化合物13c在人肝微粒体中表现出较好的稳定性。此外，13c在Vero E6细胞中表现出显著的抗sars - cov -2活性和较高的安全性（EC50 = 19.26 nM, SI bb0 400）。进一步的研究表明，13c对HCoV-OC43具有较强的活性，并且在Huh7细胞中具有良好的安全性（EC50 = 61 nM, SI bb0 100）。这些发现表明，化合物13c是开发新型3CLpro抑制剂的一个有前景的先导化合物。

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Design, Synthesis, and Biological Evaluation of Peptidomimetic Tetrahydropyrrole Spirodihydroindolones as SARS-CoV-2 3CL Protease Inhibitors.

The 3CL protease (3CL^pro) of SARS-CoV-2 is a key enzyme that plays an essential role in mediating viral replication and transcription. In this study, we synthesized and evaluated a series of peptidomimetic compounds containing a tetrahydropyrrole spirodihydroindolone moiety. Among the target compounds, 13c and 17d exhibited obvious 3CL^pro inhibitory activities with IC₅₀ = 3.71 and 6.21 nM, respectively. In metabolic stability testing of liver microsomes, compound 13c showed improved stability in human liver microsomes. In addition, 13c displayed significant anti-SARS-CoV-2 activity and high safety in Vero E6 cells (EC₅₀ = 19.26 nM, SI > 400). Further investigations indicated that 13c showed potent activity against HCoV-OC43 and favorable safety in Huh7 cells (EC₅₀ = 61 nM, SI > 100). These findings suggest that compound 13c is a promising lead compound in the development of novel 3CL^pro inhibitors.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.