Wan Dan, Wang Feng-Qin, Xie Jiang, Chen Lin, Zhou Xian-Li
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, P.R. China.
Affiliated Hospital of Southwest Jiaotong University & The Third People Hospital of Chengdu, Chengdu 610031, Sichuan, P.R. China.
ACS Omega. 2023 Jun 5;8(24):21802-21812. doi: 10.1021/acsomega.3c01427. eCollection 2023 Jun 20.
In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids (), DNP-benzylamine hybrids (), and DNP-phenylethylamine hybrids () were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound exhibited excellent acetylcholinesterase inhibitory activity with an IC value of 4.4 μM, higher than that of positive control DNP and significant neuroprotective effects against HO-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 μM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.
在本研究中，多奈哌齐（DNP）的活性基团苄基哌啶通过方酰胺与神经递质苯乙胺相连，其中苯乙胺的脂肪链缩短且苯环被取代。获得了一系列多功能杂化化合物，包括DNP-苯胺杂化物（）、DNP-苄胺杂化物（）和DNP-苯乙胺杂化物（），并测定了它们对胆碱酯酶的抑制活性以及对SH-SY5Y细胞系的神经保护作用。结果表明，化合物表现出优异的乙酰胆碱酯酶抑制活性，IC值为4.4 μM，高于阳性对照DNP，并且在12.5 μM时对SH-SY5Y细胞中过氧化氢诱导的氧化损伤具有显著的神经保护作用，存活率为80.11%，远高于模型组（存活率 = 53.1%）。通过分子对接、活性氧（ROS）和免疫荧光分析阐明了化合物的作用机制。结果表明，化合物可作为治疗阿尔茨海默病的先导化合物进一步研究。此外，分子对接研究表明方酰胺基团与靶蛋白形成了强相互作用。基于上述分析，我们认为方酰胺可能是抗AD药物中一个有趣的结构单元。
