Wang Xiao-Bing, Yin Fu-Cheng, Huang Ming, Jiang Neng, Lan Jin-Shuai, Kong Ling-Yi
Jiangsu Key Laboratory of Bioactive Natural Product Research and , State Key Laboratory of Natural Medicines , Department of Natural Medicinal Chemistry , School of Traditional Chinese Pharmacy , China Pharmaceutical University , 24 Tong Jia Xiang , Nanjing 210009 , People's Republic of China . Email:
RSC Med Chem. 2020 Jan 7;11(2):225-233. doi: 10.1039/c9md00441f. eCollection 2020 Feb 1.
A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for MAO-B. In particular, compound presented the most balanced potential for ChE inhibition (BuChE: IC = 5.24 μM; AChE: IC = 0.37 μM) and MAO-B selectivity (IC = 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound could penetrate the blood-brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.
设计、合成了一系列色酮与多奈哌齐的杂合物，并将其作为多效胆碱酯酶（ChE）和单胺氧化酶（MAO）抑制剂进行评估，用于阿尔茨海默病（AD）的潜在治疗。研究表明，这些化合物中的绝大多数对丁酰胆碱酯酶（BuChE）和乙酰胆碱酯酶（AChE）表现出强效抑制活性，并且对MAO-B具有明显的选择性抑制作用。特别是，化合物表现出最平衡的ChE抑制潜力（BuChE：IC = 5.24 μM；AChE：IC = 0.37 μM）和MAO-B选择性（IC = 0.272 μM，SI = 247）。分子模拟和动力学研究表明，是一种混合型抑制剂，同时结合到AChE的外周和活性位点。它也是一种竞争性抑制剂，占据了MAO-B的底物和入口腔。此外，化合物可以穿透血脑屏障（BBB），并且对大鼠嗜铬细胞瘤（PC12）细胞显示出低毒性。总之，这些结果表明化合物可能是一种有希望的多靶点药物候选物，对阿尔茨海默病治疗可能有影响。
