Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships exploration

被引：1

作者：

Zhang, Heng ^{[1
]}

Li, Jing ^{[1
]}

Toth, Karoly ^{[2
,3
]}

Tollefson, Ann E. ^{[2
,3
]}

Jing, Lanlan ^{[1
]}

Gao, Shenghua ^{[1
]}

Liu, Xinyong ^{[1
]}

Zhan, Peng ^{[1
]}

机构：

[1] Shandong Univ, Cheeloo Coll Med, Sch Pharmaceut Sci, Dept Med Chem,Key Lab Chem Biol,Minist Educ, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China

[2] St Louis Univ, Dept Mol Microbiol & Immunol, Sch Med, St. Louis, MO 63104 USA

[3] St Louis Univ Inst Drug & Biotherapeut Innovat, St. Louis, MO 63104 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2023年 / 96卷

基金：

中国博士后科学基金;

关键词：

SARS-CoV-2; Main protease; Drug design; Ebselen; Bioactivity evaluation; DISCOVERY;

D O I：

10.1016/j.bmc.2023.117531

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The main protease (Mpro) represents one of the most effective and attractive targets for designing anti-SARS-CoV2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the Mpro active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 Mpro inhibition assay, with IC50 values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar Mpro activity (IC50 = 364 nM) and low micromolar antiviral activity (EC50 = 8.01 mu M), comparable to that of Ebselen (IC50 = 339 nM, EC50 = 3.78 mu M). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against Mpro.

引用

页数：11

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