Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer's disease.

ABSTRACT

A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aß aggregation, metal-induced Aß aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC50 = 8.065 ±â€¯0.129 µM) against Aß42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50 = 6.385 ±â€¯0.009 µM). Compound 6n disassembled preformed Aß42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aß42 aggregation and disassembled preformed Cu2+-induced Aß42 aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aß42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aß42 monomer and Aß42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aß42 that play a critical role in Aß42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.