河北大学学报(自然科学版) ›› 2024, Vol. 44 ›› Issue (4): 382-389.DOI: 10.3969/j.issn.1000-1565.2024.04.006

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喹啉-三嗪衍生物的设计合成及体外丁酰胆碱酯酶抑制活性

董常娥1,李瑞1,薛轩熠1,张钊源1,史大华1,2   

  • 收稿日期:2023-04-27 出版日期:2024-07-25 发布日期:2024-07-12
  • 通讯作者: 史大华(1977—)
  • 作者简介:董常娥(1997—),女,江苏海洋大学在读硕士研究生,主要从事海洋化学合成研究.
    E-mail:1455667418@qq.com
  • 基金资助:
    江苏高校优势学科建设工程项目(PAPD)

Design and synthesis of quinoline-triazine derivatives and in vitro butyrylcholinesterase inhibitory activity

DONG Change1, LI Rui1, XUE Xuanyi1, ZHANG Zhaoyuan1, SHI Dahua1,2   

  1. 1. School of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China; 2. Jiangsu Henghai Pharmaceutical Research Institute Co., LTD, Lianyungang 222005, China
  • Received:2023-04-27 Online:2024-07-25 Published:2024-07-12

摘要: 以2-(氯甲基)喹啉的盐酸盐为原料,经氧化,亲核取代反应得到结构新颖的喹啉-三嗪衍生物(5a-5f).运用IR、1H NMR、13C NMR和HRMS等表征手段确证所有化合物结构与设计一致.采用Ellman方法对目标化合物进行体外抑制丁酰胆碱酯酶活性测试,结果显示:所有化合物在80 μmol/L下抑制率超过50%,其中化合物5e[IC50=(1.71±0.04)μmol/L]活性最佳,强于阳性对照物多奈哌齐[IC50=(12.69±0.07)μmol/L].进一步对5e与BuChE分子对接研究发现,结构中喹啉环和硫原子与酶活性位点残基Ser198、His438、Trp82和Thr120可通过氢键作用.因此,化合物5e是本研究中筛选出活性最好的结构,为阿尔茨海默病(AD)研究提供了新的结构方向.

关键词: 喹啉, 1,2,4-三嗪衍生物, 丁酰胆碱酯酶抑制剂, 阿尔茨海默病

Abstract: Using 2-(chloromethyl)quinoline hydrochloride as raw material, quinoline-triazine derivatives(5a-5f)with novel structures were obtained by oxidation and nucleophilic substitution reaction. The structure and design of all compounds were confirmed to be consistent using characterization methods such as IR, 1H NMR, 13C NMR, and HRMS. Ellman method was used to test the activity of the target compounds against butyrylcholinesterase in vitro. The results showed that all compounds inhibition rate were more than 50% at 80 μmol/L. Compound 5e[IC50=(1.71±0.04)μmol/L] had the best activity and was stronger than the positive control donepezil [IC50=(12.69±0.07)μmol/L]. Further studies on the molecular docking of 5e and BuChE showed that the quinoline ring and sulfur atom in the structure could interact with the residues Ser198, His438, Trp82 and Thr120 of the enzyme active site through hydrogen bonding. Thus, compound 5e is the most active structure screened in this study, which provides a new structural direction for Alzheimers disease(AD)research and is of significance for further research.

Key words: quinoline, 1,2,4-triazine derivatives, butyrylcholinesterase inhibitors, Alzheimers disease

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