Rational Design and Multibiological Profiling of Novel Donepezil–Trolox Hybrids against Alzheimer’s Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties,ACS Chemical Neuroscience

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Rational Design and Multibiological Profiling of Novel Donepezil–Trolox Hybrids against Alzheimer’s Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2017-08-25 00:00:00 , DOI: 10.1021/acschemneuro.7b00257
Pei Cai ₁ , Si-Qiang Fang ₁ , Xue-Lian Yang ₁ , Jia-Jia Wu ₁ , Qiao-Hong Liu ₁ , Hao Hong ₁ , Xiao-Bing Wang ₁ , Ling-Yi Kong ₁

Affiliation

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer’s disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC₅₀ = 0.54 μM) and hMAO-B (IC₅₀ = 4.3 μM), significant antioxidant activity (41.33 μM IC₅₀ by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aβ_1–42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H₂O₂, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl₃ induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer’s drug.

中文翻译：

具有抗胆碱能，抗氧化，神经保护和认知增强特性的新型多奈哌齐-特罗洛克斯抗阿尔茨海默氏病杂种的合理设计和多生物学分析

设计，合成和评估了一系列新的多奈哌齐-trolox杂种，作为对抗阿尔茨海默氏病（AD）的多功能配体。生物学测定表明，这些衍生物对乙酰胆碱酯酶（AChE）和单胺氧化酶B（MAO-B）具有中等至良好的抑制活性，并具有显着的抗氧化作用。最佳化合物6d表现出平衡的功能，对h AChE（IC ₅₀ = 0.54μM）和h MAO-B（IC ₅₀ = 4.3μM）具有良好的抑制作用，具有显着的抗氧化活性（通过DPPH方法测得的IC ₅₀为41.33μMIC 50、1.72和1.79 trolox当量通过ABTS和ORAC方法），优异的铜螯合和_Aβ1–42聚集抑制作用。此外，细胞测试表明6d具有极低的毒性，并且能够抵抗氧化毒素（H ₂ O ₂，鱼藤酮和寡霉素-A）引起的神经毒性。最重要的是，在小鼠模型中口服6d表现出对东pol碱引起的急性记忆缺陷以及d-半乳糖（d -gal）和AlCl ₃引起的慢性氧化应激的认知和空间记忆的显着改善，而没有急性毒性和肝毒性。总之，体外和体内结果均表明6d 是开发安全有效的抗阿尔茨海默氏病药物的有价值的候选药物。

更新日期：2017-08-25

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