Tetrahydroacridine derivatives with dichloronicotinic acid moiety as attractive, multipotent agents for Alzheimer's disease treatment.
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 (IC50 = 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.
['Czarnecka|Kamila|K|', 'Chufarova|Nina|N|', 'Halczuk|Krzysztof|K|', 'Maciejewska|Karolina|K|', 'Girek|Małgorzata|M|', 'Skibiński|Robert|R|', 'Jończyk|Jakub|J|', 'Bajda|Marek|M|', 'Kabziński|Jacek|J|', 'Majsterek|Ireneusz|I|', 'Szymański|Paweł|P|']
D000110:Acetylcholinesterase D000166:Acridines D000544:Alzheimer Disease D016229:Amyloid beta-Peptides D000818:Animals D002091:Butyrylcholinesterase D002800:Cholinesterase Inhibitors D004305:Dose-Response Relationship, Drug D004593:Electrophorus D006736:Horses D006801:Humans D008958:Models, Molecular D015394:Molecular Structure D009539:Nicotinic Acids D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
Multipotent agent Alzheimer's disease Acetylcholinesterase inhibitors Molecular modeling Multifunctional drugs