Design, synthesis, in vitro and in vivo evaluation of tacrine-cinnamic acid hybrids as multi-target acetyl-and butyrylcholinesterase inhibitors against Alzheimer's disease

作者：Chen, Yao; Lin, Hongzhi; Zhu, Jie; Gu, Kai; Li, Qi; He, Siyu; Lu, Xin; Tan, Renxiang; Pei, Yuqiong; Wu, Liang; Bian, Yaoyao^*; Sun, Haopeng^*

来源：RSC Advances, 2017, 7(54): 33851-33867.

DOI：10.1039/c7ra04385f

• BETA-AMYLOID AGGREGATION
• TARGET-DIRECTED LIGANDS
• MULTIFUNCTIONAL AGENTS
• OXIDATIVE STRESS
• HUMAN ACETYLCHOLINESTERASE
• CHOLINESTERASE-INHIBITORS
• CHOLINERGIC HYPOTHESIS
• DRUGS
• DERIVATIVES
• NEURODEGENERATION

Previously, we have reported tacrine-ferulic acid hybrids as multi-target cholinesterase inhibitors against Alzheimer's disease. However, the detailed structure-activity relationship (SAR), especially regarding the ferulic acid moiety, has yet to be elucidated. Herein we report the structural modification of the ferulic acid moiety, which is replaced by cinnamic acid with different substitutions. The target compounds are synthesized and evaluated for their in vitro cholinesterase inhibitory activities, inhibition of amyloid beta-protein self-aggregation, cyto-protective effects against hydrogen peroxide and antiproliferative activity in PC-12 cells. The optimal compounds 35 and 36 are subsequently selected for in vivo assays. 36 shows much better performance in ameliorating the scopolamine-induced cognition impairment and less hepatotoxicity than tacrine. The compound serves as a good lead compound for further optimization.

• 出版日期2017
• 单位中国药科大学; 南京中医药大学