Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease
文献类型：期刊论文
| 作者 | Wu, Xiuyuan3; Ze, Xiaotong3; Qin, Shuai3; Zhang, Beiyu2; Li, Xinnan3; Gong, Qi1; Zhang, Haiyan1 ; Zhu, Zheying2; Xu, Jinyi3
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| 刊名 | MOLECULES
 |
| 出版日期 | 2024-04-01 |
| 卷号 | 29期号:8页码:17 |
| 关键词 | Alzheimer's disease tacrine cystamine MTDLs inhibitors molecular modeling |
| DOI | 10.3390/molecules29081782 |
| 通讯作者 | Zhu, Zheying(zheying.zhu@nottingham.ac.uk) ; Xu, Jinyi(jinyixu@china.com) |
| 英文摘要 | Alzheimer's disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 mu M) with pyrimidone compound 5 (GSK-3 beta: IC50 = 3 mu M) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3 beta (GSK-3 beta). The optimal compound 18a possessed potent dual AChE/GSK-3 beta inhibition (AChE: IC50 = 0.047 +/- 0.002 mu M, GSK-3 beta: IC50 = 0.930 +/- 0.080 mu M). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 mu M. Collectively, this work explored the structure-activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs. |
| WOS关键词 | TARGET-DIRECTED LIGANDS ; GLYCOGEN-SYNTHASE KINASE-3-BETA ; ACETYLCHOLINESTERASE INHIBITORS ; DISCOVERY ; PATHOPHYSIOLOGY ; EXPRESSION ; CHOLINESTERASE ; PATHOGENESIS ; CHALLENGES ; NEURONS |
| 资助项目 | National Natural Science Foundation of China |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001221402400001 |
| 出版者 | MDPI |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311337]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhu, Zheying; Xu, Jinyi |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China 2.Univ Nottingham, Sch Pharm, Therapeut & Formulat, Univ Pk Campus, Nottingham NG7 2RD, England 3.China Pharmaceut Univ, Dept Med Chem, State Key Lab Nat Med, 24 Tong Jia Xiang, Nanjing 210009, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Xiuyuan,Ze, Xiaotong,Qin, Shuai,et al. Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease[J]. MOLECULES,2024,29(8):17. |
| APA | Wu, Xiuyuan.,Ze, Xiaotong.,Qin, Shuai.,Zhang, Beiyu.,Li, Xinnan.,...&Xu, Jinyi.(2024).Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.MOLECULES,29(8),17. |
| MLA | Wu, Xiuyuan,et al."Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease".MOLECULES 29.8(2024):17. |
入库方式： OAI收割
来源：上海药物研究所
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