Qin Pengxia, Ran Yingying, Xie Fei, Liu Yujing, Wei Chao, Luan Xiaoyi, Wu Jingde
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, PR China.
Department of Pharmacy, Qilu Hospital of Shandong University, Jinan 250012, PR China.
Bioorg Med Chem. 2023 Feb 15;80:117178. doi: 10.1016/j.bmc.2023.117178. Epub 2023 Jan 21.
The multitarget-directed ligands approach represents a potential strategy to provide effective treatments for Alzheimer's disease (AD) given its multifactorial pathology. Herein, a series of N-benzyl piperidine derivatives were designed, synthesized, and biologically characterized for dual inhibitions of histone deacetylase (HDAC) and acetylcholinesterase (AChE). Among the compounds tested, d5 and d10 exhibited dual enzyme inhibitions (d5: HDAC = 0.17 μM, AChE = 6.89 μM, d10: HDAC = 0.45 μM, AChE = 3.22 μM), and both compounds showed activities on scavenging free radical, metal chelating, and inhibiting Aβ aggregations. More importantly, both compounds exhibited promising neuroprotective activities in PC-12 cells and good AChE selectivity. Collectively, the multifunctional profiles of compound d5 and d10 encourage further optimization and exploration to develop more potent analogues as potential treatments for AD.
鉴于阿尔茨海默病（AD）的多因素病理学特征，多靶点导向配体方法是一种为其提供有效治疗的潜在策略。在此，设计、合成了一系列N-苄基哌啶衍生物，并对其抑制组蛋白脱乙酰酶（HDAC）和乙酰胆碱酯酶（AChE）的双重活性进行了生物学表征。在所测试的化合物中，d5和d10表现出双重酶抑制作用（d5：HDAC = 0.17 μM，AChE = 6.89 μM；d10：HDAC = 0.45 μM，AChE = 3.22 μM），且两种化合物均表现出清除自由基、金属螯合和抑制Aβ聚集的活性。更重要的是，两种化合物在PC-12细胞中均表现出有前景的神经保护活性以及良好的AChE选择性。总体而言，化合物d5和d10的多功能特性鼓励进一步优化和探索，以开发更有效的类似物作为AD的潜在治疗药物。
