Multifunctional Mono-Triazole Derivatives Inhibit Aβ₄₂ Aggregation and Cu²⁺-Mediated Aβ₄₂ Aggregation and Protect Against Aβ₄₂-Induced Cytotoxicity

Abstract

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 [<b>4(a-x)</b>], the triazole derivative <b>4v</b> 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 <b>4v</b> 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, <b>4v</b> significantly inhibited Cu²⁺-induced Aβ₄₂ aggregation and disassembled the Cu²⁺-induced Aβ₄₂ protofibrils as compared to the reference compound clioquinol (CQ). Importantly, <b>4v</b> did not show cytotoxicity and was able to inhibit the toxicity induced by Aβ₄₂ aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of <b>4v</b> with Aβ₄₂ monomer and Aβ₄₂ protofibril structure. The experimental and molecular docking results highlighted that <b>4v</b> is a promising multifunctional lead compound for AD.