A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer’s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and β–amyloid (Aβ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of Aβ-induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

The intricate and multifactorial nature of Alzheimer´s disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid-β peptide (Aβ) and metal dyshomeostasis.In order to continue the search for new anti-AD drugs, a design strategy was followed based on repositioning donepezil (DNP), by attaching a benzylpiperidine mimetic of DNP moiety at different (ortho, para) attachment points of a hydroxyphenyl-benzimidazole (BIM) chelating unit. Herein, two compounds (1 and 2) are compared in terms of their potential multiple properties: both present good AChE inhibition (low micromolar range) and are moderate/good inhibitors of Aβ self-and Cu-mediated aggregation; although compound 1 has a higher chelating capacity towards Cu 2+ (pCu = 14.3, pZn = 6.4, pH 7.4, CL/CM = 10, CM = 10 −6 M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Aβ-induced cell toxicity.

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