Identification and Exploration of a Series of SARS-Cov-2 MPro Cyano-Based Inhibitors Revealing Ortho-Substitution Effects within the P3 Biphenyl Group

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-09-25 DOI:10.1021/acsmedchemlett.5c00301

Emma Clyde-Allen, , , Mikołaj Zmudzinski, , , Mohammad Afsar, , , Ciyana James, , , Anindita Nayak, , , Digant Nayak, , , Priscila dos Santos Bury, , , Dirk Jochmans, , , Johann Neyts, , , Christopher J. Scott, , , Shaun K. Olsen, , , Marcin Drag, , and , Rich Williams*,

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Abstract

Starting from a simple scaffold hopping exercise based on our previous exploration of cysteine protease inhibitors against legumain, compound 6a was identified as a starting point for the development of a SARS-CoV-2 main protease (M^Pro) inhibitor. Compound 6a displayed submicromolar biochemical potency in the ultrasensitive assay developed by Drag and co-workers. Through an iterative structure–activity relationship campaign, we discovered an unexpected improvement in both biochemical and cellular potency through the incorporation of an ortho substituent within the P3 benzamide. X-ray crystallography revealed that incorporation of the ortho substituent caused a subtle but important binding enhancement of the P1 glutamate group within the M^Pro S1 pocket. While incorporation of the ortho substituent improved the potency, the off-target selectivity against a panel of cysteine proteases and cell activity remained suboptimal. Further scanning of the P2 core revealed that incorporation of the 3.1.0 proline could address these issues and afford compound 22e, a highly potent and cellularly active M^Pro inhibitor.

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揭示P3联苯基团邻位取代效应的一系列SARS-Cov-2 MPro氰基抑制剂的鉴定和探索

基于我们之前对针对豆类的半胱氨酸蛋白酶抑制剂的探索，从简单的支架跳跃运动开始，化合物6a被确定为开发SARS-CoV-2主要蛋白酶（MPro）抑制剂的起点。在Drag和同事开发的超灵敏实验中，化合物6a显示出亚微摩尔的生化效力。通过反复的结构-活性关系运动，我们发现通过在P3苯酰胺中加入邻位取代基，在生化和细胞效力方面都有意想不到的改善。x射线晶体学显示，邻位取代基的掺入引起了MPro S1口袋内P1谷氨酸基团的微妙但重要的结合增强。虽然邻位取代基的加入提高了效力，但对一组半胱氨酸蛋白酶的脱靶选择性和细胞活性仍然不理想。对P2核心的进一步扫描表明，加入3.1.0脯氨酸可以解决这些问题，并获得高效且具有细胞活性的MPro抑制剂22e。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.