To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a new series of 1,2,3-triazole-chromenone derivatives were designed and synthesized based on the multi target-directed ligands approach. The in vitro biological activities included acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibition as well as anti-Aβ aggregation, neuroprotective effects, and metal-chelating properties. The results indicated a highly selective BuChE inhibitory activity with an IC50 value of 21.71 μM for compound 10h as the most potent compound. Besides, compound 10h could inhibit self-induced Aβ1–42 aggregation and AChE-induced Aβ aggregation with 32.6% and 29.4% inhibition values, respectively. The Lineweaver–Burk plot and molecular modeling study showed that compound 10h targeted both the catalytic active site (CAS) and peripheral anionic site (PAS) of BuChE. It should be noted that compound 10h was able to chelate biometals. Thus, the designed scaffold could be considered as multifunctional agents in AD drug discovery developments.

中文翻译：

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设计和合成可用于阿尔茨海默氏病的多目标定向1,2,3-三唑-二甲基氨基丙烯酰基-色酮衍生物

为了发现用于治疗阿尔茨海默氏病（AD）的多功能剂，基于多靶标定向配体方法设计并合成了一系列新的1,2,3-三唑-色酮衍生物。体外生物学活性包括乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）抑制以及抗Aβ聚集，神经保护作用和金属螯合特性。结果表明，作为最有效的化合物，化合物10h的IC50值为21.71μM，具有高度选择性的BuChE抑制活性。此外，化合物10h可以抑制自诱导的Aβ1-42聚集和AChE诱导的Aβ聚集，抑制值分别为32.6％和29.4％。Lineweaver-Burk图和分子建模研究表明，化合物10h既靶向BuChE的催化活性位点（CAS），又靶向外周阴离子位点（PAS）。应当指出，化合物10h能够螯合生物金属。因此，设计的支架可以被认为是AD药物开发中的多功能药物。