Design, Synthesis, and Biological Evaluation of 5,8-Dimethyl Shikonin Oximes as SARS-CoV-2 M^pro Inhibitors.

IF 4.2 2区化学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecules Pub Date : 2025-03-14 DOI:10.3390/molecules30061321

Jiahua Cui, Shouyan Xiang, Qijing Zhang, Shangqing Xiao, Gaoyang Yuan, Chenwu Liu, Shaoshun Li

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引用次数: 0

Abstract

We have designed, synthesized, and characterized a small library of shikonin derivatives and demonstrated their inhibitory activity against the main protease, M^pro, of SARS-CoV-2. One analog, 5,8-dimethyl shikonin oxime (15), exhibited the highest activity against SARS-CoV-2 M^pro with an IC₅₀ value of 12.53 ± 3.59 μM. It exhibited much less toxicity as compared with the parent compound, shikonin, in both in vitro and in vivo models. Structure-activity relationship analysis indicated that the oxime moieties on the naphthalene ring and the functional groups attached to the oxygen atom on the side chain play a pivotal role in enzymatic inhibitory activity. Molecular docking results implied that the inhibitor 15 is perfectly settled in the core of the substrate-binding pocket of M^pro by possibly interacting with three catalytic residues, His41, Cys145, and Met165. Overall, the shikonin oxime derivative 15 deserves further investigation as an antiviral agent against SARS-CoV-2.

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5,8-二甲基紫草素肟作为SARS-CoV-2 Mpro抑制剂的设计、合成及生物学评价

我们设计、合成并鉴定了一个小的紫草素衍生物文库，并证明了它们对SARS-CoV-2主要蛋白酶Mpro的抑制活性。其中一种类似物5,8-二甲基紫草素肟（15）对SARS-CoV-2 Mpro的活性最高，IC50值为12.53±3.59 μM。在体外和体内模型中，与母体化合物紫草素相比，它的毒性要小得多。构效关系分析表明，萘环上的肟基团和侧链上氧原子上的官能团在酶抑制活性中起关键作用。分子对接结果表明，抑制剂15可能通过与三个催化残基His41、Cys145和Met165相互作用，完美地沉淀在Mpro底物结合口袋的核心。总之，紫草素肟衍生物15作为抗病毒药物值得进一步研究。

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

Molecules 化学-有机化学

CiteScore

7.40

自引率

8.70%

发文量

7524

审稿时长

1.4 months

期刊介绍： Molecules (ISSN 1420-3049, CODEN: MOLEFW) is an open access journal of synthetic organic chemistry and natural product chemistry. All articles are peer-reviewed and published continously upon acceptance. Molecules is published by MDPI, Basel, Switzerland. Our aim is to encourage chemists to publish as much as possible their experimental detail, particularly synthetic procedures and characterization information. There is no restriction on the length of the experimental section. In addition, availability of compound samples is published and considered as important information. Authors are encouraged to register or deposit their chemical samples through the non-profit international organization Molecular Diversity Preservation International (MDPI). Molecules has been launched in 1996 to preserve and exploit molecular diversity of both, chemical information and chemical substances.