Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany.
PharmaCenter Bonn, University of Bonn, Brühler Straße 7, Bonn D-53121, Germany.
J Med Chem. 2024 Sep 12;67(17):14986-15011. doi: 10.1021/acs.jmedchem.4c00535. Epub 2024 Aug 15.
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). 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 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 IC values in the low nanomolar range, / values of >100,000 M s and high antiviral activity. High-resolution X-ray cocrystal structures indicated an important role of -fluorobenzoyl substitution, forming a water network that stabilizes the inhibitor-bound enzyme. The most potent antiviral compound was the -ethoxy--fluorobenzoyl chloropyridyl ester (PSB-21110, , MW 296 g/mol; EC 2.68 nM), which may serve as a lead structure for broad-spectrum anticoronaviral therapeutics.
SARS-CoV-2 感染对脆弱患者构成高风险。在这项研究中，我们设计了带有各种取代基的苯甲酸卤代吡啶酯作为主要病毒蛋白酶 (M) 的不可逆抑制剂。总共合成了 55 种苯甲酰氯/溴代吡啶酯，苯甲酰部分的取代模式广泛变化。采用多参数优化工作流程，包括 SARS-CoV-2 和相关致病冠状病毒的 M 抑制测定、酶抑制的持续时间、化合物对谷胱甘肽的稳定性、细胞毒性和抗病毒活性。一些化合物表现出低纳摩尔范围内的 IC 值、/ 值>100,000 M s 和高抗病毒活性。高分辨率 X 射线共晶结构表明 -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 -乙氧基--氟苯甲酰氯吡啶酯 (PSB-21110,, MW 296 g/mol; EC 2.68 nM)，它可能作为广谱抗冠状病毒治疗的先导结构。
