Postovsky Institute of Organic Synthesis, Urals Branch of Russian Academy of Sciences, Yekaterinburg 620990, Russia.
Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka 142432, Russia.
Biomolecules. 2022 Oct 24;12(11):1551. doi: 10.3390/biom12111551.
Alzheimer's disease (AD) is considered a modern epidemic because of its increasing prevalence worldwide and serious medico-social consequences, including the economic burden of treatment and patient care. The development of new effective therapeutic agents for AD is one of the most urgent and challenging tasks. To address this need, we used an aminoalkylene linker to combine the well-known anticholinesterase drug tacrine with antioxidant 2-tolylhydrazinylidene-1,3-diketones to create 3 groups of hybrid compounds as new multifunctional agents with the potential for AD treatment. Lead compounds of the new conjugates effectively inhibited acetylcholinesterase (AChE, IC 0.24-0.34 µM) and butyrylcholinesterase (BChE, IC 0.036-0.0745 µM), with weak inhibition of off-target carboxylesterase. Anti-AChE activity increased with elongation of the alkylene spacer, in agreement with molecular docking, which showed compounds binding to both the catalytic active site and peripheral anionic site (PAS) of AChE, consistent with mixed type reversible inhibition. PAS binding along with effective propidium displacement suggest the potential of the hybrids to block AChE-induced β-amyloid aggregation, a disease-modifying effect. All of the conjugates demonstrated metal chelating ability for Cu, Fe, and Zn, as well as high antiradical activity in the ABTS test. Non-fluorinated hybrid compounds and also showed Fe reducing activity in the FRAP test. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters acceptable for potential lead compounds at the early stages of anti-AD drug development.
阿尔茨海默病（AD）被认为是一种现代流行病，因为它在全球的发病率不断上升，并且具有严重的医学和社会后果，包括治疗和患者护理的经济负担。开发治疗 AD 的新有效治疗剂是最紧迫和最具挑战性的任务之一。为了满足这一需求，我们使用氨基亚烷基 linker 将众所周知的抗胆碱酯酶药物他克林与抗氧化剂 2- 甲苯基腙基-1,3-二酮结合起来，创造了 3 组具有治疗 AD 潜力的新型多功能杂化物。新缀合物的先导化合物有效地抑制了乙酰胆碱酯酶（AChE，IC 0.24-0.34 µM）和丁酰胆碱酯酶（BChE，IC 0.036-0.0745 µM），对非靶标羧基酯酶的抑制作用较弱。与分子对接一致，随着亚烷基间隔物的延长，抗 AChE 活性增加，表明化合物结合到 AChE 的催化活性位点和外周阴离子位点（PAS），符合混合型可逆抑制。PAS 结合以及有效置换丙啶表明，这些杂化物具有阻断 AChE 诱导的β-淀粉样蛋白聚集的潜力，从而具有疾病修饰作用。所有的缀合物都表现出对 Cu、Fe 和 Zn 的金属螯合能力，以及在 ABTS 测试中的高抗自由基活性。非氟代杂化物 和 还在 FRAP 测试中表现出对 Fe 的还原活性。预测的 ADMET 和缀合物的物理化学性质表明，它们具有良好的中枢神经系统生物利用度和安全性参数，可作为抗 AD 药物开发早期的潜在先导化合物。
