Dimkovski Aleksandar, Dobričić Vladimir, Simić Milena R, Jurhar Pavlova Maja, Mihajloska Evgenija, Sterjev Zoran, Poceva Panovska Ana
Institute for Pharmaceutical Chemistry, Faculty of Pharmacy, Ss Cyril and Methodius University in Skopje, 1000 Skopje, North Macedonia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, 11221 Belgrade, Serbia.
Molecules. 2025 May 11;30(10):2121. doi: 10.3390/molecules30102121.
A series of 21 novel coumarin-triazole-isatin hybrids was synthesized and evaluated for their potential as multitarget agents in Alzheimer's disease (AD). The compounds featured variations in alkyl linker length that connects coumarin and triazole and substitution at the 5-position of the isatin ring. Several derivatives showed potent butyrylcholinesterase (BChE) inhibition with selectivity over acetylcholinesterase (AChE). The lead compound, , exhibited strong BChE inhibition (IC = 1.74 μM), surpassing donepezil. Enzyme kinetics revealed a mixed-type mechanism, while molecular docking studies confirmed dual binding at catalytic and peripheral sites. Structure-activity relationship (SAR) analysis highlighted the influence of linker flexibility and steric/electronic effects of substituents. The observed BChE selectivity, combined with favorable in vitro profiles, identifies these hybrids as promising leads for AD drug development.
合成了一系列21种新型香豆素-三唑-异吲哚酮杂合物，并评估了它们作为阿尔茨海默病（AD）多靶点药物的潜力。这些化合物的特点是连接香豆素和三唑的烷基连接链长度不同，以及异吲哚酮环5位的取代情况不同。几种衍生物表现出对丁酰胆碱酯酶（BChE）的强效抑制作用，且对乙酰胆碱酯酶（AChE）具有选择性。先导化合物 表现出强烈的BChE抑制作用（IC = 1.74 μM），超过多奈哌齐。酶动力学揭示了一种混合型机制，而分子对接研究证实了在催化位点和外周位点的双重结合。构效关系（SAR）分析突出了连接链灵活性以及取代基的空间/电子效应的影响。所观察到的BChE选择性，结合良好的体外特性，确定这些杂合物是AD药物开发的有前景的先导化合物。
