Publication Type Journal Article
Title Donepezil-based hybrids as multifunctional anti-Alzheimer s disease chelating agents: Effect of positional isomerization
Authors Marina Costa Romane Josselin Diana F. Silva Sandra M. Cardoso V May Sílvia Chaves M. Amélia Santos
Groups BIOIN
Journal JOURNAL OF INORGANIC BIOCHEMISTRY
Year 2020
Month May
Volume 206
Number
Pages
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.
DOI http://dx.doi.org/10.1016/j.jinorgbio.2020.111039
ISBN
Publisher
Book Title
ISSN 0162-0134
EISSN 1873-3344
Conference Name
Bibtex ID ISI:000528630900014
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