State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK.
Molecules. 2022 May 11;27(10):3090. doi: 10.3390/molecules27103090.
Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive decline as well as behavioral problems. It is a progressive and well recognized complex disease; therefore, it is very urgent to develop novel and effective anti-AD drugs. In this study, a series of novel isochroman-4-one derivatives from natural (±)-7,8-dihydroxy-3-methyl-isochroman-4-one [(±)-XJP] were designed and synthesized, and their anti-AD potential was evaluated. Among them, compound [()-3-acetyl-1-benzyl-4-((6,7-dimethoxy-4-oxoisochroman-3-ylidene)methyl)pyridin-1-ium bromide] possessed potent anti-acetylcholinesterase (AChE) activity as well as modest antioxidant activity. Further molecular modeling and kinetic investigations revealed that compound was a dual-binding inhibitor that binds to both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the enzyme AChE. In addition, compound exhibited low cytotoxicity and moderate anti-A aggregation efficacy. Moreover, the in silico screening suggested that these compounds could pass across the blood-brain barrier with high penetration. These findings show that compound was a promising lead from a natural product with potent AChE inhibitory activity and deserves to be further developed for the prevention and treatment of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，可导致记忆和认知能力下降以及行为问题。它是一种进行性和公认的复杂疾病；因此，开发新型有效的抗 AD 药物非常紧迫。在这项研究中，设计并合成了一系列来自天然（±）-7,8-二羟基-3-甲基异色满-4-酮[(±)-XJP]的新型异色满-4-酮衍生物，并评估了它们的抗 AD 潜力。其中，化合物 [()-3-乙酰基-1-苄基-4-((6,7-二甲氧基-4-氧代异色满-3-亚基)甲基)吡啶-1-翁溴化物]具有很强的乙酰胆碱酯酶（AChE）抑制活性和适度的抗氧化活性。进一步的分子建模和动力学研究表明，化合物 是一种双重结合抑制剂，可与 AChE 的催化阴离子部位（CAS）和外周阴离子部位（PAS）结合。此外，化合物 表现出低细胞毒性和适度的抗 A 聚集功效。此外，计算机筛选表明这些化合物可以具有高穿透性穿过血脑屏障。这些发现表明，化合物 是一种有前途的天然产物先导化合物，具有很强的 AChE 抑制活性，值得进一步开发用于预防和治疗 AD。
