Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization

Costa, Marina and Josselin, Romane and Silva, Diana F. and Cardoso, Sandra M. and May, Nóra V. (2020) Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization. JOURNAL OF INORGANIC BIOCHEMISTRY, 206. pp. 1-34. ISSN 0162-0134

Preview

Text MS_PositionalBIM_Real.pdf Download (1MB) | Preview

Abstract

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 (A beta) 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 mu molar range) and are moderate/good inhibitors of A beta self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the p-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu2+ and Zn2+ (pCu = 14.3, pZn = 6.4, pH 7.4, C-I/C-M = 10, C-M = 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 Ali-induced cell toxicity.

Actions (login required)

Edit Item