College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang, China.
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, China.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):69-85. doi: 10.1080/14756366.2021.1993845.
A novel series of chalcone-Vitamin E-donepezil hybrids was designed and developed based on multitarget-directed ligands (MTDLs) strategy for treating Alzheimer's disease (AD). The biological results revealed that compound showed good AChE inhibitory potency (AChE IC = 0.41 µM; AChE IC = 1.88 µM). Both the kinetic analysis and docking study revealed that was a mixed type AChE inhibitor. was also a good antioxidant (ORAC = 3.3 ), selective metal chelator and MAO-B inhibitor (IC = 8.8 µM). Moreover, it showed remarkable inhibition of self- and Cu-induced A aggregation with a 78.0 and 93.5% percentage rate at 25 µM, respectively, and disassembled self-induced and Cu-induced aggregation of the accumulated A fibrils with 72.3 and 84.5% disaggregation rate, respectively. More importantly, exhibited a good neuroprotective effect on HO-induced PC12 cell injury and presented good blood-brain barrier permeability . Thus, was a promising multi-target-directed ligand for treating AD.
基于多靶点药物设计（MTDL）策略，我们设计并合成了一系列新型查尔酮-维生素 E-多奈哌齐杂合分子，用于治疗阿尔茨海默病（AD）。生物学结果表明，化合物 表现出良好的乙酰胆碱酯酶抑制活性（AChE IC = 0.41 μM；AChE IC = 1.88 μM）。动力学分析和对接研究均表明，化合物 是一种混合类型的乙酰胆碱酯酶抑制剂。 还具有良好的抗氧化（ORAC = 3.3）、选择性金属螯合和 MAO-B 抑制活性（IC = 8.8 μM）。此外，它对自发诱导和 Cu 诱导的 A 聚集具有显著的抑制作用，在 25 μM 时分别达到 78.0%和 93.5%的抑制率，并且对自诱导和 Cu 诱导聚集的 A 纤维的解聚率分别达到 72.3%和 84.5%。更重要的是，化合物 对 HO 诱导的 PC12 细胞损伤具有良好的神经保护作用，并且具有良好的血脑屏障通透性。因此，化合物 是一种有前途的多靶点药物，可用于治疗 AD。
