Costa_2020_J.Inorg.Biochem_206_111039

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 beta (Abeta) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low mumolar range) and are moderate/good inhibitors of Abeta self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the beta-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu(2+) and Zn(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 Abeta-induced cell toxicity.