School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
Eur J Med Chem. 2022 Apr 5;233:114216. doi: 10.1016/j.ejmech.2022.114216. Epub 2022 Feb 23.
With the aging of the population intensifying, finding a cure or reasonable treatment for Alzheimer' disease (AD) has become an urgent priority. To target the multi-facets of AD, a class of chrysin derivatives (1-4) were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, which were characterized by H NMR, C NMR, MS and elemental analysis. 1-4 showed inhibitory activities on reactive oxygen species, Aβ aggregation (self-, Cu-induced, AChE-induced). They were also potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with selectivity toward BuChE. Compound 1 as the most promising candidate exhibited the highest selective BuChE inhibition (SI = 15). Furthermore, the kinetic study suggested compound 1 to be a mixed type inhibitor. The results of docking study were consistent with the in vitro results. In addition, compound 1-4 showed favorable blood-brain barrier (BBB) penetration and drug-like property in silico prediction. The corresponding copper complexes of 1-4 have also been synthesized. 1-4 selectively chelated Cu, Fe, Zn and Al ions, while had no chelating ability to other biometals. The copper complexes also showed good AChE, BuChE and reactive oxygen species inhibitory activities. Notably, the single crystals of 1-Cu(II) complex [Cu(CHNO)] were prepared for the first time and characterized by X-ray single crystal diffraction. X-ray crystallography analysis of 1-Cu(II) complex provided a reliable structure-activity insight at the molecular level about the antioxidative and Aβ disaggregation activities. Compound 1 might be a good lead compound to develop promising candidate analogs as AD therapeutics.
随着人口老龄化的加剧，寻找阿尔茨海默病（AD）的治疗方法或合理的治疗方法已成为当务之急。为了针对 AD 的多方面问题，我们采用多靶点导向配体（MTDLs）策略，合理设计并合成了一类白杨素衍生物（1-4），并用 1 H NMR、13 C NMR、MS 和元素分析对其进行了表征。1-4 对活性氧、Aβ聚集（自聚集、Cu 诱导、AChE 诱导）具有抑制活性。它们也是乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的有效抑制剂，对 BuChE 具有选择性。化合物 1 作为最有前途的候选药物，对 BuChE 表现出最高的选择性抑制（SI=15）。此外，动力学研究表明，化合物 1 是一种混合类型抑制剂。对接研究结果与体外结果一致。此外，化合物 1-4 在体内外预测中均表现出良好的血脑屏障（BBB）渗透性和类药性。1-4 的相应铜配合物也已被合成。1-4 选择性螯合 Cu、Fe、Zn 和 Al 离子，而对其他生物金属没有螯合能力。铜配合物也表现出良好的 AChE、BuChE 和活性氧抑制活性。值得注意的是，首次制备了 1-4 的铜配合物[Cu(CHNO)]的单晶，并通过 X 射线单晶衍射进行了表征。1-Cu(II)配合物的 X 射线晶体学分析为抗氧化和 Aβ解聚活性提供了分子水平上可靠的结构-活性见解。化合物 1 可能是开发有希望的候选类似物作为 AD 治疗药物的良好先导化合物。
