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 [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 aggregation and disassembled the Cu2+-induced Aβ42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v 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 4v with Aβ42 monomer and Aβ42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.

Attenuation of Oxidative Stress by Cannabinoids and Cannabis Extracts in Differentiated Neuronal Cells

“…It has been shown by several researchers that the interaction of Cu(II) with peptides and proteins leads to ROS formation [ 44 , 45 , 56 , 60 , 61 ]. Therefore, the Aβ-Cu(II) system can be used as an oxidative stress inducer in the SH-SY5Y in vitro model to mimic the AD-like oxidative stress condition [ 62 , 63 ]. Among the Aβ isoforms, Aβ 1–42 is more hydrophobic and fibrillogenic than Aβ 1–40 due to the addition of two hydrophobic residues at the N-terminus [ 64 ].…”

Serotonin and Melatonin Show Different Modes of Action on Aβ42 Protofibril Destabilization

“…Until now, an effective treatment for AD does not yet exist. It is crucial to find effective inhibitors for the treatment of AD. − A large number of experimental studies reported that several different types of potential inhibitors, including nanoparticles, , short peptides, − small molecules, , multitarget-directed ligands, − and antibodies, , are able to dissociate Aβ fibrils and/or inhibit Aβ aggregation. Inspired by those experimental studies, several computational groups investigated the inhibitory mechanisms − using MD simulations.…”

Alizarin and Purpurin from Rubia tinctorum L. Suppress Insulin Fibrillation and Reduce the Amyloid-Induced Cytotoxicity

“…Specifically, the cell survival rate increased to 73.7% and 90.5%, respectively, when the concentrations of alizarin/purpurin were 200 μM. Therefore, it was concluded that alizarin and purpurin had a significant inhibitory effect on insulin aggregates-induced cytotoxicity, which was attributed to their effective inhibition of insulin aggregation. , …”

“…Therefore, it was concluded that alizarin and purpurin had a significant inhibitory effect on insulin aggregates-induced cytotoxicity, which was attributed to their effective inhibition of insulin aggregation. 40,41 Effects of Alizarin/Purpurin on Insulin Amyloid Defibrillation. In addition to the inhibition ability of alizarin/purpurin on the formation of amyloid fibrils, whether the two anthraquinone compounds could destroy and clear the preformed insulin fibrils was unknown.…”