2,4-二酮内酰胺衍生物的设计、合成及其抑制Mpro活性筛选

doi:10.6023/cjoc202601032

有机化学 ›› 2026, Vol. 46 ›› Issue (8): 3104-3113.DOI: 10.6023/cjoc202601032 上一篇下一篇

研究论文

2,4-二酮内酰胺衍生物的设计、合成及其抑制Mpro活性筛选

敖选丽, 马超洁, 王淑冰, 何蕾, 赏宇, 朱锦阳, 李建秀, 张琴, 张荣平^*(), 侯博^*()

云南中医药大学中药学院暨云南省南药可持续利用研究重点实验室昆明 650500

收稿日期:2026-03-15 修回日期:2026-04-09 发布日期:2026-05-27
通讯作者: 张荣平, 侯博
基金资助:
国家自然科学基金(82360690); 云南省基础研究计划(202401AT070183); 中医药联合专项−面上项目(202301AZ070001-044); 中医药联合专项−面上项目(202401-AZ070001-024); 兴颠英才支持计划; 云南省重点领域科技计划(202303AC100025); 云南省科技厅重大科技专项计划(202402AA310027); 云南省教育厅科学研究基金(2025Y0598)

Design, Synthesis and Mpro Inhibitory Activity Screening of 2,4-Diketolactam Derivatives

Xuanli Ao, Chaojie Ma, Shubing Wang, Lei He, Yu Shang, Jinyang Zhu, Jianxiu Li, Qin Zhang, Rongping Zhang^*(), Bo Hou^*()

School of Chinese Materia Medica & Yunnan Key Laboratory of Southern Medicine Utilization, Yunnan University of Chinese Medicine, Kunming 650500

Received:2026-03-15 Revised:2026-04-09 Published:2026-05-27
Contact: Rongping Zhang, Bo Hou
Supported by:
National Natural Science Foundation of China(82360690); Yunnan Fundamental Research Projects(202401AT070183); Traditional Chinese Medicine (TCM) Joint Special Project-General Project(202301AZ070001-044); Traditional Chinese Medicine (TCM) Joint Special Project-General Project(202401-AZ070001-024); Yunnan Xingdian Talent Support Program; Yunnan Provincial Key Fields Science and Technology Program(202303AC100025); Major Science and Technology Special Project of Yunnan Provincial Department of Science and Technology(202402AA310027); Scientific Research Fund Project of the Department of Education of Yunnan Province(2025Y0598)

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摘要/Abstract

以β-丙氨酸乙酯盐酸盐和丙二酸单乙酯酰氯为原料合成2,4-二酮内酰胺衍生物, 获得25个2,4-二酮内酰胺衍生物t1~t25, 并评估其对主要蛋白酶(Mpro)的抑制活性. 化合物t5, t9和t18有较高的抑制率, 进一步对上述3个化合物梯度浓度抑制Mpro活性测试, 得到IC₅₀分别为0.445, 0.425, 0.088 μmol/L, 阳性对照奈玛特韦为0.426 μmol/L, 抑制活性显示t5, t9的IC₅₀与奈玛特韦相当, t18的IC₅₀更低, 分子对接揭示t5作用于His41关键氨基酸, t9, t18与Mpro靶蛋白活性位点的关键氨基酸Cys145/His41共同作用. 此研究表明2,4-二酮内酰胺片段可成为抑制Mpro靶点的分子砌块, 上述3个化合物对冠状病毒Mpro具有较强抑制作用，可作为开发抗冠状病毒药物潜力化合物, 并为进一步药效学评价提供物质基础.

关键词: 冠状病毒, 2,4-二酮内酰胺衍生物, 主要蛋白酶(Mpro), 抑制剂

Twenty-five 2,4-diketolactam derivatives t1~t25 were synthesized using β-alanine ethyl ester hydrochloride and monoethyl malonyl chloride as initial materials. The inhibitory activities of these compounds against the main protease (Mpro) were tested. The experimental results showed that t5, t9, and t18 exhibited relatively high Mpro inhibitory rates. Further gradient concentration assays of three compounds were conducted to evaluate the Mpro inhibitory activities. Their half-maximal inhibitory concentrations (IC₅₀) against Mpro were 0.445, 0.425, and 0.088 μmol/L, respectively, whereas the IC₅₀ value of nirmatrelvir was 0.426 μmol/L. The inhibitory activity showed that the IC₅₀ values of t5 and t9 were comparable to those of nirmatrelvir, while the IC₅₀ value of t18 was lower. Molecular docking revealed that t5 interacted with the key residue His41, while t9 and t18 interacted with both Cys145 and His41 in the active site of Mpro. This study demonstrates that the 2,4-diketolactam moiety can serve as a privileged building block for targeting the Mpro. The above three compounds exhibit potent inhibitory activity against coronavirus Mpro and represent promising candidates for the development of anti-coro- navirus agents, providing a material basis for further pharmacodynamic evaluations.

Key words: coronavirus, 2,4-diketolactam derivatives, main protease (Mpro), enzyme inhibitors

引用此文

敖选丽, 马超洁, 王淑冰, 何蕾, 赏宇, 朱锦阳, 李建秀, 张琴, 张荣平, 侯博. 2,4-二酮内酰胺衍生物的设计、合成及其抑制Mpro活性筛选[J]. 有机化学, 2026, 46(8): 3104-3113.

Xuanli Ao, Chaojie Ma, Shubing Wang, Lei He, Yu Shang, Jinyang Zhu, Jianxiu Li, Qin Zhang, Rongping Zhang, Bo Hou. Design, Synthesis and Mpro Inhibitory Activity Screening of 2,4-Diketolactam Derivatives[J]. Chinese Journal of Organic Chemistry, 2026, 46(8): 3104-3113.

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图/表 6

图式1. 化合物a1~a3合成路线

Scheme 1. Synthetic routes of compounds a1~a3

图式2. 化合物t1~t25通用合成路线(R为醛基分子砌块)

Scheme 2. General synthetic route of compounds t1~t25 (R=aldehyde building block)

表1. 化合物t1～t25的结构

Table 1. Structures of compounds t1～t25

图1. 化合物t1~t25对Mpro抑制率(阳性对照为黄芩素和奈玛特韦)

Figure 1. Inhibitory rates of compounds t1~t25 against Mpro (baicalein and nirmatrelvir as positive controls)

图2. 化合物t5, t9, t18, Nirmatrelvir对Mpro抑制曲线(n=6)

Figure 2. Inhibition curves of compounds t5, t9, t18 and nirmatrelvir against Mpro (n=6)

图3. 化合物t5 (A), t9 (B), t18 (C)和Nirmatrelvir (D)与Mpro分子的对接结果

Figure 3. Molecular docking diagrams of compounds t5 (A), t9 (B), t18 (C), and nirmatrelvir (D) with Mpro, respectively

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2,4-二酮内酰胺衍生物的设计、合成及其抑制Mpro活性筛选

Design, Synthesis and Mpro Inhibitory Activity Screening of 2,4-Diketolactam Derivatives

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