Novel Benzosuberone/Indanone-Linked Thiazoles as Small-Molecule SARS-CoV-2 Main Protease Inhibitors.

IF 3.5 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-04-01 DOI:10.1002/ddr.70081

Thoraya A Farghaly, Elham N Bifari, Mariam A Al-Sheikh, Afaf Y Khormi, Hanadi Y Medrasi, Jihan Qurban, Hanan Gaber Abdulwahab

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引用次数: 0

Abstract

Herein, novel benzosuberone/indanone-linked thiazoles were designed and synthesized as small-molecule SARS-CoV-2 Main protease (M^pro) inhibitors with potential anti-COVID activity. All thiazole derivatives were synthesized from the reaction of thiosemicarbazone derivatives with α-halocarbonyl derivatives. The structures of novel benzosuberone/indanone-linked thiazoles were confirmed based on their spectral data. Thiazolyl-benzosuberone 9d and thiazolyl-indanone 14 were the most potent against M^pro displaying one-digit IC₅₀ values of 5.94 and 8.47 µM, respectively, compared to ritonavir (IC₅₀ = 2.4 µM). Moreover, antiviral assay revealed the ability of compounds 9d and 14 to inhibit the replication of SARS-CoV-2 in Vero cells at EC₅₀ values of 9.33 and 28.75 µM, respectively, relative to ritonavir (EC₅₀ = 1.72 µM). Cytotoxicity assay in Vero cells was also conducted. 9d and 14 showed CC₅₀ values of 289.63 and 229.42 µM and SI of 31.0 and 7.9, respectively. In addition, a docking study revealed proper orientation and well-fitting of title compounds into the binding pocket of SARS-CoV-2 M^pro.

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在此，我们设计并合成了新型苯并琥珀酰/茚酮连接噻唑类化合物，作为具有潜在抗COVID活性的小分子SARS-CoV-2主要蛋白酶（Mpro）抑制剂。所有噻唑衍生物都是由硫代氨基甲酸酯衍生物与 α-卤代羰基衍生物反应合成的。根据光谱数据确认了新型苯并琥珀酰/茚酮连接噻唑的结构。与利托那韦（IC50 = 2.4 µM）相比，噻唑基苯并环戊酮 9d 和噻唑基茚满酮 14 对 Mpro 的药效最强，其 IC50 值分别为 5.94 和 8.47 µM。此外，抗病毒试验显示，相对于利托那韦（EC50 = 1.72 µM），化合物 9d 和 14 能够抑制 SARS-CoV-2 在 Vero 细胞中的复制，其 EC50 值分别为 9.33 µM 和 28.75 µM。还在 Vero 细胞中进行了细胞毒性试验。9d 和 14 的 CC50 值分别为 289.63 和 229.42 µM，SI 分别为 31.0 和 7.9。此外，一项对接研究显示，标题化合物在 SARS-CoV-2 Mpro 的结合口袋中有正确的定向和良好的拟合。

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

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.