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). In vitro studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for hMAO-B. In particular, compound 5c presented the most balanced potential for ChE inhibition (BuChE: IC₅₀ = 5.24 μM; AChE: IC₅₀ = 0.37 μM) and hMAO-B selectivity (IC₅₀ = 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that 5c 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 5c could penetrate the blood–brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound 5c might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.

中文翻译：

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色酮和多奈哌齐杂种作为新型多能胆碱酯酶和单胺氧化酶抑制剂，可潜在治疗阿尔茨海默氏病

设计，合成并评估了一系列色酮和多奈哌齐杂化物，作为多能胆碱酯酶（ChE）和单胺氧化酶（MAO）抑制剂，可用于治疗阿尔茨海默氏病（AD）。体外研究表明，这些化合物中的绝大多数对BuChE和AChE表现出有效的抑制活性，并且对h MAO-B具有明显的选择性抑制作用。特别地，化合物5c呈现出对ChE抑制的最平衡的电位（BuChE：IC ₅₀ = 5.24μM； AChE：IC ₅₀ = 0.37μM）和h MAO-B选择性（IC ₅₀ = 0.272μM，SI = 247）。分子建模和动力学研究表明5c是一种混合型抑制剂，可同时与AChE的外围和活性位点结合。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5c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。总而言之，这些结果表明化合物5c可能是希望的多靶点候选药物，可能对阿尔茨海默氏病的治疗产生影响。