New series of aromatic amides hybrids derivatives as anti-Alzheimer's drugs: Design, synthesis, biological activity and computational studies

IF 4.2 Q2 CHEMISTRY, MULTIDISCIPLINARY Results in Chemistry Pub Date : 2025-03-01 DOI:10.1016/j.rechem.2025.102138

Lin Chen , Si-Lu Sun , He-Yang Zhong , Dan Wan , Fei Feng , Shuai Huang , Xian-Li Zhou

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Abstract

Alzheimer's disease (AD) is a degenerative disease of the central nervous system with complex pathogenesis there is an urgent need to develop more relevant agents. Since Gx-50 has some anti-AD activity and its cinnamic acid fragment can be regarded as an advantaged fragment, it was suggested to splice it and similar fragment to compound 3 which showed anti-AD activities in previous work. Then 20 compounds were obtained and among them, compound 1b has better acetylcholinesterase inhibitory activity (IC₅₀ = 0.29 μM), which was equivalent to the positive drug donepezil, and its molecular docking showed cinnamic acid part of compound 1b provide more bind possibilities with hAChE. Also, compound 1b showed neuroprotection effect (cell survival rate is 76.72 % at 12.5 μM), and revealed by ROS analysis and immunofluorescence, its neuroprotection activity may act by reducing ROS-induced oxidative stress. Besides, 10b also exhibits activity in inhibiting acetylcholinesterase (IC₅₀ = 0.31 μM) and Aβ aggregation (IC₅₀ = 25.0 μM), making it potential for further development. In summary, it studied the feasibility of molecular hybridization, adn provided new promising multi-functional agent for anti-AD.

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抗阿尔茨海默病新系列芳香酰胺杂化衍生物：设计、合成、生物活性及计算研究

阿尔茨海默病（AD）是一种发病机制复杂的中枢神经系统退行性疾病，迫切需要开发更多的相关药物。由于Gx-50具有一定的抗ad活性，其肉桂酸片段可视为有利片段，因此在前期工作中建议将其与具有抗ad活性的化合物3的类似片段拼接。得到20个化合物，其中化合物1b具有较好的乙酰胆碱酯酶抑制活性（IC50 = 0.29 μM），与阳性药物多奈哌齐相当，其分子对接表明化合物1b的肉桂酸部分与hAChE结合的可能性更大。化合物1b具有一定的神经保护作用（12.5 μM下细胞存活率为76.72%），ROS分析和免疫荧光分析表明，化合物1b的神经保护作用可能是通过降低ROS诱导的氧化应激来实现的。此外，10b还具有抑制乙酰胆碱酯酶（IC50 = 0.31 μM）和Aβ聚集（IC50 = 25.0 μM）的活性，具有进一步开发的潜力。综上所述，研究了分子杂交的可行性，为抗ad提供了新的有前景的多功能药物。

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