Exploring Flavonoids Rutin and Morin as Multi‐Target–Directed Ligands for Metal Chelation, Amyloid Interaction, and AChE‐Induced Amyloid Inhibition

ABSTRACT Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder characterized by amyloid‐beta (Aβ) aggregation, metal dyshomeostasis, oxidative stress, and neurotransmitter depletion. Multi‐target–directed ligands (MTDLs) are emerging as promising therapeutic candidates to address these diverse pathological features. This study evaluates the anti‐AD potential of two naturally occurring flavonoids, rutin and morin, focusing on the unexplored aspects of their ability to chelate Cu 2 + ions, inhibit Aβ aggregation, and mitigate oxidative stress. Using spectro‐potentiometric techniques, their Cu 2 + binding stoichiometry, acidity constants (p K a ), and copper complex stability constants were studied. UV–visible spectroscopy indicated their capacity to compete for Cu 2 + from Aβ‐Cu 2 + complexes. Thioflavin T (ThT) fluorescence assays and transmission electron microscopy (TEM) demonstrated significant inhibition of both metal‐free and metal‐induced Aβ aggregation. Additionally, rutin and morin exhibited potent antioxidant activity in ABTS and DPPH assays, even in the presence of Cu 2 + highlighting their ability to play a role in overcoming oxidative stress. Their favorable partition coefficient values further enhance their therapeutic potential. These comprehensive in vitro findings position rutin and morin as promising candidates for combating AD, warranting further investigation for therapeutic development.