Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, 620990, Ekaterinburg, Russia.
Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Chernogolovka, Russia.
ChemMedChem. 2022 May 18;17(10):e202200080. doi: 10.1002/cmdc.202200080. Epub 2022 Mar 23.
New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC to 0.224 μM) and butyrylcholinesterase (BChE, IC to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug-drug interactions in clinical use. The conjugates were mixed-type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE-induced β-amyloid aggregation. The new conjugates exhibited high ABTS -scavenging activity. N-(6-(1,2,3,4-Tetrahydroacridin-9-ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu , Fe and Zn . Thus, the new conjugates have displayed the potential to be multifunctional anti-AD agents for further development.
新型他克林和柳氮磺胺吡啶的亚烷基间隔物缀合物被合成并评估为治疗阿尔茨海默病（AD）的潜在多功能药物。这些化合物表现出对乙酰胆碱酯酶（AChE，IC to 0.224 μM）和丁酰胆碱酯酶（BChE，IC to 0.0104 μM）的高抑制活性。它们对羧酸酯酶的抑制作用也较弱，这表明在临床应用中潜在的药物相互作用的可能性较低。这些缀合物是对两种胆碱酯酶的混合类型可逆抑制剂，并且在分子对接中显示出对 AChE 的催化和外周阴离子部位的双重结合，这与碘化丙啶置换的实验结果一起表明它们有潜力阻止 AChE 诱导的β-淀粉样蛋白聚集。新的缀合物具有很高的 ABTS 清除活性。N-(6-(1,2,3,4-四氢吖啶-9-基氨基)己基)柳氮磺胺吡啶是一种先导化合物，它还表现出对 Cu、Fe 和 Zn 的金属螯合能力。因此，这些新的缀合物具有成为进一步开发的多功能抗 AD 药物的潜力。
