State Key Laboratory of New-tech for Chinese Medicine Pharmaceutical Process, Jiangsu Kanion Pharmaceutical Co., Ltd, Jiangsu, Lianyungang, China.
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, China.
J Enzyme Inhib Med Chem. 2023 Dec;38(1):2192439. doi: 10.1080/14756366.2023.2192439.
A series of OA-tacrine hybrids with the alkylamine linker was designed, synthesized, and evaluated as effective cholinesterase inhibitors for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some hybrids possessed significant inhibitory activities against acetylcholinesterase (AChE). Among them, compounds B4 (AChE, IC = 14.37 ± 1.89 nM; SI > 695.89) and D4 (AChE, IC = 0.18 ± 0.01 nM; SI = 3374.44) showed excellent inhibitory activities and selectivity for AChE as well as low nerve cell toxicity. Furthermore, compounds B4 and D4 exhibited lower hepatotoxicity than tacrine in cell viability, apoptosis, and intracellular ROS production for HepG2 cells. These properties of compounds B4 and D4 suggest that they deserve further investigation as promising agents for the prospective treatment of AD.
设计、合成并评价了一系列具有烷胺连接基的 OA-他克林杂合体，作为治疗阿尔茨海默病（AD）的有效胆碱酯酶抑制剂。生物活性结果表明，一些杂合体对乙酰胆碱酯酶（AChE）具有显著的抑制活性。其中，化合物 B4（AChE，IC = 14.37 ± 1.89 nM；SI > 695.89）和 D4（AChE，IC = 0.18 ± 0.01 nM；SI = 3374.44）对 AChE 具有优异的抑制活性和选择性，且神经细胞毒性低。此外，与他克林相比，化合物 B4 和 D4 在 HepG2 细胞活力、细胞凋亡和细胞内 ROS 产生方面对肝毒性的影响更小。化合物 B4 和 D4 的这些特性表明，它们值得进一步研究，作为有前途的 AD 治疗药物。
