|作者：||Zhu Jie, Yang Hongyu, Chen Yao, Lin Hongzhi, Li Qi, Mo Jun, Bian Yaoyao, Pei Yuqiong, Sun Haopeng|
1a Department of Medicinal Chemistry , China Pharmaceutical University , Nanjing , China.
2b School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
3c School of Nursing , Nanjing University of Chinese Medicine , Nanjing , China.
|刊名：||Journal of enzyme inhibition and medicinal chemistry, 2018, Vol.33 (1), pp.496-506|
|关键词：||Alzheimer’s disease; Cholinesterase inhibitor; Molecular docking; Multi-target ligand; Tacrine-ferulic hybrid;|
|原始语种摘要：||The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM).... Besides, it inhibited amyloid β-protein self-aggregation by 65.49% at 25 μM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.|