Author(s):
Piemontese, Luca ; Tomás, Daniel ; Hiremathad, Asha ; Capriati, Vito ; Candeias, Emanuel ; Cardoso, Sandra M. ; Chaves, Sílvia ; Santos, M. Amélia
Date: 2018
Persistent ID: https://hdl.handle.net/10316/107711
Origin: Estudo Geral - Universidade de Coimbra
Subject(s): Alzheimer’s disease; multipotent drugs; donepezil mimetics; AChE inhibitors; anti-Aβ aggregation; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Caco-2 Cells; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Humans; Indans; Models, Molecular; Molecular Structure; Piperidines; Protein Aggregates; Structure-Activity Relationship
Description
A new series of multifunctional hybrids, based on the structure of the donepezil (DNP) drug, have been developed and evaluated as potential anti Alzheimer's disease (AD) agents. The rationale of this study was the conjugation of a benzylpiperidine/benzylpiperazine moiety with derivatives of bioactive heterocyclics (benzimidazole or benzofuran), to mimic the main structure of DNP and to endow the hybrids with additional relevant properties such as inhibition of amyloid beta (Aβ) peptide aggregation, antioxidant activity and metal chelation. Overall, they showed good activity for AChE inhibition (IC50=4.0-30.0 μΜ) and moderate ability for inhibition of Aβ1-42 self-mediated aggregation. The hybrids containing chelating groups showed improvement in the inhibition of Cu-induced Aβ42 aggregation and the antioxidant capacity. Moreover, neuroprotective effects of these compounds were evidenced in neuroblastoma cells after Aβ1-42 induced toxicity. Structure-activity relationship allowed the identification of some promising compounds and the main determinant structural features for the targeted properties.
