The Synergistic Potential of Rationally Designed Phenol-Triazole Derivatives to Attenuate Aβ/Cu-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 (-). In particular, with an -I group on the phenyl ring displayed a noteworthy higher inhibition (inhibition efficiency = 90.5%, IC = 6.51 ± 0.01 μM) against Aβ aggregation as compared to 38.1% noted for CQ. Furthermore, significantly disassembled the preformed Aβ fibrils (Aβf, 92.5%), chelated Cu ions, and inhibited Cu-mediated Aβ aggregation. Compound ceases the production of reactive oxygen species (ROS) as it acts as an antioxidant due to the presence of a phenolic hydroxyl group. Compound has a sufficient safety-efficacy profile and alleviates the cytotoxicity by Aβ aggregates in PC-12 cells. For studying the modulation in the fibrillary architecture, hydrodynamic size, and structural transition of Aβ in the presence of , 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 Aβ monomer (Aβm) and Aβf on the incorporation of . Compound modulates Aβ 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 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 -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 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.