Design, Synthesis and Evaluation of Novel Tacrine-3-n-butylphthalide Hybrids as Multifunctional Cholinesterase Inhibitors

A series of tacrine-3-n-butylphthalide hybrids have been designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The result showed that all the target compounds exhibited inhibitory activity on acetylcholinesterase (AChE) and butylcholinesterase (BuChE). Especially, 3-butyl-6-((7-((1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)oxy)isobenzofuran-1(3H)-one (10b) displayed the greatest ability to inhibit AChE (IC50=38.65 nmol.L-1), which was 5-fold greater than that of tacrine (IC50=200.70 nmol.L-1). 3-Butyl-6-((8-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)oxy)isobenzofuran-1(3H)-one (10g) displayed the greatest ability to inhibit BuChE (IC50=33.69 nmol.L-1), which was close to tacrine (IC50=27.12 nmol.L-1) and 220-fold greater than that of donepezil (IC50=7530 nmol.L-1). In rat A beta-induced injury model of hippocampal neurons, the effect of compounds on reactive oxygen species (ROS) levels in rat hippocampal have been evaluated, and the results indicated that most of these compounds had potent inhibitory activity for rat hippocampal neuronal cells secreting ROS induced by A beta(1-42).