Autor(es):
Poliseno, Viviana ; Chaves, Sílvia ; Brunetti, Leonardo ; Loiodice, Fulvio ; Carrieri, Antonio ; Laghezza, Antonio ; Tortorella, Paolo ; Magalhães, João D. ; Cardoso, Sandra M. ; Santos, M. Amélia ; Piemontese, Luca
Data: 2021
Identificador Persistente: https://hdl.handle.net/10316/103766
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Alzheimer’s disease; tenuazonic acid; donepezil; neurodegenerative; metal chelation; multifunctional drugs; acetylcholinesterase; antioxidant; amyloid; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; Donepezil; Free Radical Scavengers; Humans; Hydrogen-Ion Concentration; Metals; Molecular Docking Simulation; Neuroprotection; Neuroprotective Agents; Protein Aggregates; Spectrophotometry; Tenuazonic Acid
Descrição
Alzheimer's disease (AD) is generally recognized as a multifactorial neurodegenerative pathology with an increasing impact on society. Tenuazonic acid (TA) is a natural compound that was recently identified as a potential multitarget ligand with anti-cholinesterase, anti-amyloidogenic and antioxidant activities. Using its structure as a chemical scaffold, we synthesized and evaluated new derivatives (1-5), including tenuazonic-donepezil (TA-DNP) hybrids (4 and 5) due to the clinical importance of the anti-AD drug donepezil. These novel compounds all achieved activity in the micromolar range towards all selected targets and demonstrated to be potentially orally absorbed. Moreover, a selected compound (1) was further investigated as a chelating agent towards copper (II), zinc (II) and iron (III) and showed good chelating ability (pFe = 16.6, pCu = 11.6, pZn = 6.0 at pH 7.4). Therefore, the TA motif can be considered an interesting building block in the search for innovative multi-functional anti-neurodegenerative drugs, as exemplified by hybrid 5, a promising non-cytotoxic lead compound adequate for the early stages of AD, and capable of ameliorating the oxidative status of SH-SY5Y human neuroblastoma cells.
