Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment

摘要

Abstract A novel series of 9-amino-1,2,3,4-tetrahydroacridine and 5,6-dichloronicotinic acid moiety were conjugated with different linkers. Afterwards new derivatives were evaluated as potential multifunctional acetylcholinesterase inhibitors (AChEIs), anti-Alzheimer's disease (AD) drug candidates. All the compounds were synthesized and tested for capacity for the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes. Specifically, the most promising derivative 3b (IC 50 ?=?1.02?nM) had higher inhibitory potency compared to the reference drug, tacrine. Consequently, kinetic studies of 3b compound showed a mixed-type inhibition of both AChE and BuChE. Afterwards the best potent AChE inhibitor has been examined on amyloid β (Aβ) self-induced aggregation. Furthermore, 3b compound was tested in various concentrations and had moderate activity against Aβ aggregation. Inhibition of Aβ aggregation was 46.63% and 19.41% at 50?μM and 5??μM concentrations, respectively. Moreover, no cytotoxicity was observed for the mentioned concentrations. Therefore, 3b compound is a promising multipotent agent for the treatment of AD. Graphical abstract Display Omitted Highlights ? Tetrahydroacridine derivatives with 5,6-dichloronicotinic acid are ChE inhibitors. ? Compounds possess higher inhibitory activity towards ChE than reference drug, tacrine. ? The most active compound ( 3b ) shows a mixed-type inhibition of AChE and BuChE. ? Compound 3b inhibits β-amyloid aggregation. ? Novel compound may be considering as promising drugs in Alzheimer's disease treatment.