Multitarget hybrid small molecules for metal chelation with additive cholinesterase inhibitory and antioxidant properties in alzheimer’s disease

Alzheimer’s disease (AD) is strongly associated with the misfolding and aggregation of amyloid-β (Aβ) peptides, a process significantly influenced by metal dyshomeostasis. In particular, copper ions play a crucial role by modulating aggregation pathways and promoting oxidative stress through redox cycling. Recent studies have shown that small molecules capable of interacting with metal ions can effectively influence Aβ aggregation, not through simple chelation but by modulating metal-protein interactions under biologically relevant conditions. These compounds are able to alter aggregation kinetics, reduce the formation of toxic oligomeric species, and mitigate metal-induced oxidative damage. This approach highlights the potential of metal-targeting small molecules as a strategy to control Aβ-related toxicity and provides a mechanistic framework for the development of new disease-modifying agents in AD. Starting from lead compounds reported in recently published studies, we have designed and synthesized hybrid molecules with a multitarget profile incorporating chelating moieties. The inclusion, within their structures, of pharmacophoric elements derived from well-known drugs such as donepezil, rivastigmine, and tacrine allowed us to retain activity toward classical targets, particularly cholinesterases, while simultaneously addressing metal-mediated pathological pathways. The obtained results are very encouraging, highlighting a well-defined selectivity trend toward Fe (III), Cu (II), and Zn (II). Moreover, the compounds retain inhibitory activity against one or both cholinesterases and, in some cases, exhibit significant antioxidant properties, further supporting their potential as multifunctional agents in AD therapy.