MultifunctionalMono-Triazole Derivatives InhibitAβ 42 Aggregation and Cu 2+ -Mediated Aβ 42 Aggregation and Protect Against Aβ 42 -InducedCytotoxicity

Amyloid beta (Aβ) peptide aggregation is considered as one of the key hallmarks of Alzheimer’s disease (AD). Moreover, Aβ peptide aggregation increases considerably in the presence of metal ions and triggers the generation of reactive oxygen species (ROS), which ultimately leads to oxidative stress and neuronal damage. Based on the ‘multitarget-directed ligands’ (MTDLs) strategy, we designed, synthesized, and evaluated a novel series of triazole-based compounds for AD treatment via experimental and computational methods. Among the designed MTDLs [4(a–x)], the triazole derivative 4v exhibited the most potent inhibition of self-induced Aβ42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 μM and also disassembled the preformed Aβ42 aggregates significantly. In addition, compound 4v showed excellent metal chelating ability and maintained copper in the redox-dormant state to prevent the generation of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aβ42 aggregati...