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

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 Aβ aggregation, metal-induced Aβ 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 ± 0.129 μM) against Aβ42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50 = 6.385 ± 0.009 μM). Compound 6n disassembled preformed Aβ42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aβ42 aggregation and disassembled preformed Cu2+-induced Aβ42 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 Aβ42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aβ42 monomer and Aβ42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aβ42 that play a critical role in Aβ42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.