Design, synthesis and evaluation of OA-tacrine hybrids as cholinesterase inhibitors with low neurotoxicity and hepatotoxicity against Alzheimer's disease.

设计,OA - 他克林杂种作为胆碱酯酶抑制剂的合成和评价 ， 对阿尔茨海默病具有低神经毒性和肝毒性。

• 影响指数: 5.756
• 发表时间: Dec 2023
• 来源期刊: J Enzyme Inhib Med Chem
• DOI: 10.1080/14756366.2023.2192439
• PMID: 36950955
• 文章类型: Journal Article
• 中科院分区: Q3
• 方向: 生物
• 作者列表: Yang H,Jia H,Deng M,Zhang K,Liu Y,Liu Y,Cheng M,Xiao W

关键词: Alzheimer’s disease; Oleanolic acid; cholinesterase inhibitors; low-toxicity; tacrine

Mesh: Humans; Tacrine / pharmacology; Cholinesterase Inhibitors / pharmacology; Alzheimer Disease / drug therapy; Acetylcholinesterase / metabolism; Structure-Activity Relationship; Chemical and Drug Induced Liver Injury

Abstract

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 (hAChE, IC50 = 14.37 ± 1.89 nM; SI > 695.89) and D4 (hAChE, IC50 = 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.

摘要

设计了一系列带有烷基胺接头的OA-他克林杂化物，合成，并评价其作为治疗阿尔茨海默病(AD)的有效胆碱酯酶抑制剂。生物学活性结果表明，某些杂种对乙酰胆碱酯酶（AChE）具有显着的抑制活性。其中,化合物B4(hAChE,IC50=14.37±1.89nM；SI>695.89）和D4（hAChE，IC50=0.18±0.01nM；SI=3374.44）显示出对AChE的优异抑制活性和选择性以及低神经细胞毒性。此外，化合物B4和D4在细胞活力方面表现出比他克林更低的肝毒性，凋亡，和HepG2细胞的细胞内ROS产生。化合物B4和D4的这些性质表明它们作为用于AD的预期治疗的有希望的药剂值得进一步研究。