Novel Donepezil-Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer's Disease

• Autor(a) principal: Queda, Fausto
• Data de Publicação: 2021
• Outros Autores: Calò, Sonia, Gwizdala, Karolina, Magalhães, João D., Cardoso, Sandra M., Chaves, Sílvia, Piemontese, Luca, Santos, M. Amélia
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10316/105262; https://doi.org/10.3390/molecules26061658
• topic: arylsulfonamide; donepezil; anti-neurodegeneratives; Alzheimer´s disease; AChE inhibitors; Aβ aggregation; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Cell Line, Tumor; Cholinesterase Inhibitors; Donepezil; Humans; Ligands; Piperazines; Piperidines; Structure-Activity Relationship; Sulfonamides

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.