The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu²⁺–Aβ Aggregation and Reactive Oxygen Species

Alzheimer's disease (AD) is a neurological disorder characterized by a spectrum of symptoms such as memory loss and cognitive decline. AD is a multifaceted disease, and designing multipotent ligands is an effective strategy for AD treatment. In this regard, the pharmacophore moiety of clioquinol (CQ, metal chelator) was employed to design the multifunctional phenol-triazole derivatives 4(a-p). In particular, 4k with an o-I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency 4k = 90.5%, IC₅₀ = 6.51 ± 0.01 μM) against Aβ₄₂ aggregation as compared to 38.1% noted for CQ. Furthermore, 4k significantly disassembled the preformed Aβ₄₂ fibrils (Aβf, 92.5%), chelated Cu²⁺ ions, and inhibited Cu²⁺-mediated Aβ₄₂ aggregation. Compound 4k ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound 4k has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ₄₂ aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ₄₂ in the presence of 4k, we resorted to transmission electron microscopy (TEM), dynamic light scattering (DLS), and circular dichroism (CD), respectively. The molecular dynamics (MD) simulations depicted a notable reduction in the conformational transformations in the Aβ₄₂ monomer (Aβm) and Aβf on the incorporation of 4k. Compound 4k modulates Aβ₄₂ fibrillation by maintaining a helix conformation and simultaneously reduces the sampling of β-sheet structures in Aβm, consistent with the CD results. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis depicted a favorable binding of 4k to Aβm (-42.12 ± 7.14 kcal/mol) and Aβf (-74.42 ± 4.98 kcal/mol) with a significant contribution of van der Waals interactions to the binding free energy. The 4k-induced deformation in Aβf chains noted in the conformational snapshots depicts its destabilization potential against Aβf. Finally, our results uncovered the potential of phenol-triazole derivatives as a promiscuous ligand for targeting various pathological conditions in AD. The key insights into the prevention of conformational transitions in Aβm and destabilization of Aβf by 4k illuminated by experimental and computational studies are central to unraveling the molecular understanding of amyloid aggregation as well as designing future therapeutic candidates against multifaceted AD.