| 杨燕,陈旭飞,张前,袁旭芳,何希瑞.化学通报,2022,85(4):460-469. |
| 基于AChE和BuChE靶标的查尔酮衍生物的合成及生物活性研究 |
| Synthesis and Biological Evaluation of Chalcone Derivatives as AChE and BuChE Inhibitors |
| 投稿时间：2021-07-27 修订日期：2021-08-22 |
| DOI： |
| 中文关键词: 阿尔兹海默病 查尔酮衍生物 AChE BuChE 生物活性 |
| 英文关键词:AD, Chalcone derivatives, AChE, BuChE, Biological activity |
| 基金项目:贵州省科技计划项目 (黔科合基础–ZK[2021]一般550)；贵州省科技计划项目 (黔科合平台人才[2018]5772-074)；贵州省科技计划项目(黔科合平台人才[2019]－017)；遵义市科技计划项目(遵市科合HZ字(2020)78 号) |
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| 中文摘要: |
| 为了探寻治疗阿尔兹海默病（AD）的潜在双靶标活性化合物，本研究设计合成了5个新的查耳酮衍生物，并对它们的生物活性进行了评价。酶活性测定结果表明，化合物C1-C5对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）均具有显著的抑制活性。其中，化合物C4对AChE和BuChE有明显的抑制作用，IC50分别为6.00和2.63 μM。细胞实验表明，化合物C4对Glu、H2O2和Aβ1-42诱导的神经母细胞瘤SH-SY5Y损伤具有显著的保护作用，且呈剂量依赖性。Y迷宫和Morris水迷宫研究结果表明，C4能改善东莨菪碱诱导的小鼠的认知障碍和背景记忆能力，且对小鼠自主活动无影响，具有毒副作用小的优点。此外，C4能显著降低小鼠皮层总胆碱酯酶（T-CHE）和丙二醛（MDA）含量，提高谷胱甘肽过氧化物酶（GSH-Px）和超氧化物歧化酶（SOD）含量。分子模拟显示，化合物C4能够结合AChE和BuChE的催化活性位点和外周阴离子位点。因此，化合物C4可能是一种很有前途的双靶向活性分子，值得做进一步的结构优化和活性评价，以期为发现安全高效的AD治疗药物奠定基础。 |
| 英文摘要: |
| Five novel chalcone derivatives were designed, synthesized and evaluated as dual-target agents for the treatment of Alzheimer’s disease (AD). In vitro enzyme activity determination displayed that all the synthesized compounds showed impressive inhibitory activity against AChE and BuChE. Particularly, significant AChE and BuChE inhibition was demonstrated by compound C4 with IC50 value of 6.00 and 2.63 μM, respectively. Results of the cell experimentsexhibited that compound C4 showed lower cytotoxicity and good neuroprotective effects against Glu, H2O2 and Aβ1-42 induced damage in SH-SY5Y in a dose-dependent manner. The Y maze and Morris water maze studies revealed that C4 improve the cognitive impairment and contextual memory in scopolamine-induced mice, and it has no effect on the autonomous activities of mice, showing the advantages of less toxicity and side effect. Furthermore, our investigation proved that compound 4 significantly reduce T-CHE and MDA levels, and increased content of GSH-Px and SOD in the cortex of scopolamine-induced memory impairment mice. Molecular modeling indicated that C4 could bind to the catalytic active site and peripheral anionic site of AChE and BuChE. Taken together, these results revealed that compound C4 might be a potential promising dual-targeted agent for the treatment of AD, and deserved to do further structure optimization and activity evaluation, offering a foundation for the discovery of safe and efficient drugs for the treatment of AD. |
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