Chen Yao, Zhu Jie, Mo Jun, Yang Hongyu, Jiang Xueyang, Lin Hongzhi, Gu Kai, Pei Yuqiong, Wu Liang, Tan Renxiang, Hou Jing, Chen Jingyi, Lv Yang, Bian Yaoyao, Sun Haopeng
a School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
b Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization , Nanjing University of Chinese Medicine , Nanjing , China.
J Enzyme Inhib Med Chem. 2018 Dec;33(1):290-302. doi: 10.1080/14756366.2017.1412314.
Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid β-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC = 10.2 ± 1.2, 16.5 ± 1.7, and 15.3 ± 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.
小分子胆碱酯酶抑制剂（ChEI）为治疗阿尔茨海默病（AD）提供了一种有效的治疗策略。目前，发现具有多靶点效应的新型ChEI仍然非常重要。在此，我们报道了一系列他克林-肉桂酸杂化物作为新型ChEI的合成、构效关系研究及生物学评价。对所有目标化合物进行了体外胆碱酯酶抑制活性评价。对在胆碱酯酶上表现出强效活性的代表性化合物进行了淀粉样β蛋白自聚集抑制及体内试验评价。最优化合物19、27和30（人AChE IC分别为10.2±1.2、16.5±1.7和15.3±1.8 nM）在改善东莨菪碱诱导的认知障碍方面表现良好，且在肝毒性评价中具有初步安全性。这些化合物值得进一步评估以开发抗AD的新型治疗药物。
