Geraiely_2026_RSC.Adv__

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by several hallmarks, including cholinergic dysfunction, aggregation of amyloid beta (Abeta), oxidative stress, and metal ion dyshomeostasis. A series of donepezil-derived chalcones 7a-q were synthesized and tested for their ability to inhibit cholinesterase (ChE) and amyloid beta (Abeta) aggregation, antioxidant properties, and metal chelation. Of these, compound 7j with a 2-chloroaryl moiety showed moderate anti-AChE activity (IC(50) = 17.96 microM) and showed potent inhibition of Abeta aggregation, both in the presence of self-induced (72.5%) and AChE-induced (77.6%) conditions, and had good Cu(2+) chelation ability, which was confirmed by ultraviolet-visible (UV-vis) spectroscopy. Compound 7p, an analog containing furan, exhibited both anti-ChE activity (IC(50) = 22.70 microM for AChE and 19.14 microM for BuChE, respectively) and moderate anti-Abeta aggregation activity, as well as moderate antioxidant activity. The two compounds were found to be safe, also in PC12 cells and SH-SY5Y cells. Their results are all encouraging for their use as multi-target directed ligands (MTDLs) against AD. Finally, the molecular dynamics simulations in the active site of AChE of compound 7j showed stable binding for 100 nanoseconds. In vivo experiments in zebrafish showed that compound 7p markedly enhanced locomotor and exploratory behavior, with a therapeutic profile compared to the standard drug donepezil, and compound 7j exhibited moderate therapeutic effects.