Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Nonpeptidic Irreversible Inhibitors of SARS-CoV-2 Main Protease with Potent Antiviral Activity
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-15 , DOI: 10.1021/acs.jmedchem.4c00535
Angelo Oneto _{1,

2} , Ghazl Al Hamwi _{1,

2} , Laura Schäkel _{1,

2} , Nadine Krüger ₃ , Katharina Sylvester _{1,

2} , Marvin Petry _{1,

2} , Rasha Abu Shamleh _{1,

2} , Thanigaimalai Pillaiyar _{1,

2} , Tobias Claff _{1,

2} , Anke C Schiedel _{1,

2} , Norbert Sträter ₄ , Michael Gütschow _{1,

2} , Christa E Müller _{1,

2}

Affiliation

SARS-CoV-2 infections pose a high risk for vulnerable patients. In this study, we designed benzoic acid halopyridyl esters bearing a variety of substituents as irreversible inhibitors of the main viral protease (M^pro). Altogether, 55 benzoyl chloro/bromo-pyridyl esters were synthesized, with broad variation of the substitution pattern on the benzoyl moiety. A workflow was employed for multiparametric optimization, including M^pro inhibition assays of SARS-CoV-2 and related pathogenic coronaviruses, the duration of enzyme inhibition, the compounds’ stability versus glutathione, cytotoxicity, and antiviral activity. Several compounds showed IC₅₀ values in the low nanomolar range, k_inact/K_i values of >100,000 M^–1 s^–1 and high antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of ortho-fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent antiviral compound was the p-ethoxy-o-fluorobenzoyl chloropyridyl ester (PSB-21110, 29b, MW 296 g/mol; EC₅₀ 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics.

中文翻译：

具有有效抗病毒活性的 SARS-CoV-2 主要蛋白酶非肽不可逆抑制剂

SARS-CoV-2 感染对弱势患者构成很高的风险。在这项研究中，我们设计了带有多种取代基的苯甲酸卤代吡啶酯作为主要病毒蛋白酶（M ^pro ）的不可逆抑制剂。总共合成了 55 种苯甲酰氯/溴吡啶酯，苯甲酰基部分的取代模式变化很大。采用工作流程进行多参数优化，包括 SARS-CoV-2 和相关致病性冠状病毒的 M ^pro抑制测定、酶抑制的持续时间、化合物相对于谷胱甘肽的稳定性、细胞毒性和抗病毒活性。几种化合物显示出低纳摩尔范围内的 IC ₅₀值、>100,000 M ^–1 s ^–1的k _inact / K值和高抗病毒活性。高分辨率 X 射线共晶结构表明邻氟苯甲酰取代的重要作用，形成稳定抑制剂结合酶的水网络。最有效的抗病毒化合物是对乙氧基邻氟苯甲酰氯吡啶酯（PSB-21110, 29b ，MW 296 g/mol；EC ₅₀ 2.68 nM），它可以作为广谱抗冠状病毒治疗的先导结构。

更新日期：2024-08-15

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南