设计、合成及 4-氨基烷基-1(2H)-酞嗪酮类化合物的体外评价作为潜在的多功能抗老年痴呆症药物。
Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer's disease agents.
机构信息
Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Department of Medicinal Chemistry, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
出版信息
Bioorg Chem. 2021 Jun;111:104895. doi: 10.1016/j.bioorg.2021.104895. Epub 2021 Apr 8.
A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC = 0.7 µM and 6.4 µM respectively), moderate inhibition towards AChE (IC = 8.2 µM), and good activities against self- and Cu-induced Aβ aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.
一系列 4-氨基烷基-1(2H)-酞嗪酮衍生物被设计并合成，作为治疗阿尔茨海默病（AD）的潜在多功能药物。体外生物测定结果表明，大多数合成化合物表现出显著的乙酰胆碱酯酶抑制作用，对单胺氧化酶 A 和单胺氧化酶 B 具有中等至高的抑制活性，以及良好的抗血小板聚集能力。其中，化合物 15b 对 MAO-B 和 MAO-A 的抑制活性最高（IC 50 值分别为 0.7 µM 和 6.4 µM），对乙酰胆碱酯酶的抑制活性中等（IC 50 值为 8.2 µM），对自身诱导和 Cu 诱导的 Aβ 聚集以及血小板聚集具有良好的抑制活性。此外，15b 还表现出抗氧化能力、神经保护作用、抗神经炎症和血脑屏障通透性。这些优异的结果表明，化合物 15b 可能值得进一步研究，以作为一种有前途的多功能候选药物，用于治疗 AD。
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