Polyphenolic Imidazopyridines as Multifunctional Modulators of Oxidative Stress, Metal Dyshomeostasis, and β1-42 Amyloid Aggregation in an In Vitro Model of Alzheimer's Disease.

Alzheimer's disease (AD) involves oxidative stress, metal dyshomeostasis, and toxic oligomers of the amyloid-β peptide (Aβ1-42), calling for multifunctional agents. We investigated a panel of imidazo[1,2-a]pyridines bearing catechol or resorcinol motifs previously designed as SIRT1-activating agents. Their antioxidant profile was evaluated using in vitro DPPH and ABTS assays, which revealed promising radical scavenging activities, and TBARS assays on rat brain homogenates showing inhibition of lipid peroxidation, strictly dependent on the phenolic pattern. UV-Vis studies revealed metal-binding properties, particularly Cu2+ and Fe2+ interactions. In Aβ1-42 aggregation assays, the most active derivatives appeared to promote fibril maturation and the growth of large, ThT-low aggregates with distinct morphological features observed by TEM. Notably, Aβ1-42 aggregates generated in the presence of these compounds exhibited reduced cytotoxicity, preserved cell viability, and induced lower ROS levels in RA-differentiated SH-SY5Y cells compared to aggregates formed in their absence. Imaging and FRET analyses further indicated reduced formation of membrane-binding toxic species. Overall, our data suggest that polyphenolic imidazo[1,2-a]pyridines can remodel Aβ1-42 aggregation, redirecting it toward structurally distinct and less toxic assemblies, while also counteracting oxidative and metal-associated damage. These findings highlight their potential as multifunctional agents capable of addressing several pathological hallmarks of AD.