School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
Eur J Med Chem. 2011 Jun;46(6):2609-16. doi: 10.1016/j.ejmech.2011.03.058. Epub 2011 Apr 3.
A new series of heterobivalent tacrine derivatives were designed, synthesized and evaluated as potential multi-functional anti-Alzheimer agents for their inhibitory activity on cholinesterases, antioxidant activity and self-induced β-amyloid (Aβ) aggregation. All these synthesized compounds had potent inhibition activity on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) at nanomolar range. A Lineweaver-Burk plot and molecular modeling study showed that these compounds targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The compounds containing hydroxyl group showed potent peroxyl radical absorbance activity. In addition, compound 5j exhibited higher self-induced Aβ aggregation inhibitory activity than curcumin, which could become a multi-functional agent for further development for the treatment of AD.
设计、合成了一系列新的杂双价他克林衍生物，并将其作为潜在的多官能抗阿尔茨海默病药物进行评估，以评估其对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）的抑制活性、抗氧化活性和自诱导β-淀粉样蛋白（Aβ）聚集的抑制活性。所有合成的化合物均在纳摩尔范围内对乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BuChE）具有很强的抑制活性。Lineweaver-Burk 作图和分子模拟研究表明，这些化合物靶向 AChE 的催化活性位点（CAS）和外周阴离子位点（PAS）。含有羟基的化合物表现出很强的过氧自由基吸收活性。此外，化合物 5j 对 Aβ 自诱导聚集的抑制活性高于姜黄素，这可能使其成为进一步开发用于治疗 AD 的多官能药物。
