Cen Juan, Guo Huiyan, Hong Chen, Lv Jianwu, Yang Yacheng, Wang Ting, Fang Dong, Luo Wen, Wang Chaojie
Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng 475004, China.
Huaihe Hospital, Henan University, Kaifeng 475000, China.
Eur J Med Chem. 2018 Jan 20;144:128-136. doi: 10.1016/j.ejmech.2017.12.005. Epub 2017 Dec 5.
A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation.
合成了一系列新型他克林-联苯双酯（THA-DDB）缀合物（7a-e），并将其作为潜在的抗阿尔茨海默病药物进行评估。这些化合物表现出强大的胆碱酯酶和自诱导β-淀粉样蛋白（Aβ）聚集抑制活性。Lineweaver-Burk图和分子模拟研究表明，这些化合物可以靶向乙酰胆碱酯酶（AChE）的催化活性位点（CAS）和外周阴离子位点（PAS）。与THA相比，缀合物7d对PC12和HepG2细胞的细胞毒性以及对人肝细胞系（HL-7702）的肝毒性要小得多。此外，用7d处理在小鼠中未表现出明显的肝毒性。最后，体内研究证实，7d可显著改善东莨菪碱处理的ICR小鼠的认知表现。因此，7d在治疗阿尔茨海默病方面具有很高的潜力，值得进一步研究。
