Wu Xiuyuan, Ze Xiaotong, Qin Shuai, Zhang Beiyu, Li Xinnan, Gong Qi, Zhang Haiyan, Zhu Zheying, Xu Jinyi
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
Molecules. 2024 Apr 14;29(8):1782. doi: 10.3390/molecules29081782.
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 (, AChE: IC = 0.223 μM) with pyrimidone compound (GSK-3: IC = 3 μM) 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 (GSK-3). The optimal compound possessed potent dual AChE/GSK-3 inhibition (AChE: IC = 0.047 ± 0.002 μM, GSK-3: IC = 0.930 ± 0.080 μM). 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 μM. 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.
阿尔茨海默病（AD）是一种复杂的神经退行性疾病，可导致认知功能丧失。AD的进展受多种信号通路及其相关靶点的调控。因此，多靶点策略在理论上具有更大的治疗AD的潜力。在本研究中，以半胱胺或胱胺基团为连接体，通过他克林（AChE：IC = 0.223 μM）与嘧啶酮化合物（GSK-3：IC = 3 μM）杂交设计并合成了一系列新的杂合物。生物学评价结果表明，大多数化合物对乙酰胆碱酯酶（AChE）和糖原合酶激酶3（GSK-3）表现出中度至良好的抑制活性。最佳化合物具有强效的双重AChE/GSK-3抑制作用（AChE：IC = 0.047 ± 0.002 μM，GSK-3：IC = 0.930 ± 0.080 μM）。进一步的分子对接和酶动力学研究表明，该化合物可同时占据AChE的催化阴离子位点和外周阴离子位点。结果还表明，在浓度高达25 μM时，该化合物对SH-SY5Y神经母细胞瘤细胞没有毒性。总的来说，本研究探索了具有硫插入连接体的新型四氢吖啶杂合物的构效关系，为新型多靶点抗AD药物的进一步研发提供了参考。
