Utilize este identificador para referenciar este registo:
https://hdl.handle.net/10316/103683
Título: | Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases | Autor: | Chavarria, Daniel Da Silva, Ophelie Benfeito, Sofia Barreiro, Sandra Garrido, Jorge Cagide, Fernando Soares, Pedro Remião, Fernando Brazzolotto, Xavier Nachon, Florian Oliveira, Paulo J. Dias, José Borges, Fernanda |
Palavras-chave: | neurodegenerative diseases; piperine; triphenylphosphonium; cholinesterases; monoamine oxidase; mitochondria-targeted antioxidants | Data: | 23-Fev-2021 | Editora: | MDPI | Projeto: | UIDB/00081/2020 PTDC/MED-QUI/29164/2017 POCI-01-0145-FEDER- 29164 PTDC/BIA-MOL/28607/2017 POCI-01-0145-FEDER-028607 Direction Générale de l’Armement (DGA) and Service de Santé des Armées (SSA) of the French Ministry of Armed Forces |
Título da revista, periódico, livro ou evento: | Antioxidants | Volume: | 10 | Número: | 2 | Resumo: | Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP+) conjugates (compounds 2-5), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (eqBChE) and moderate electric eel acetylcholinesterase (eeAChE) inhibitors, with catechols 4 and 5 presenting lower IC50 values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds 2-5 towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds 2-5 in complex with human ChEs (hChEs) showed that these compounds exhibit different binging modes to hAChE and hBChE. Unlike AntiOXCINs, compounds 2-5 displayed moderate human monoamine oxidase (hMAO) inhibitory activity. Moreover, compounds 4 and 5 presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion. | URI: | https://hdl.handle.net/10316/103683 | ISSN: | 2076-3921 | DOI: | 10.3390/antiox10020329 | Direitos: | openAccess |
Aparece nas coleções: | I&D CNC - Artigos em Revistas Internacionais |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
---|---|---|---|---|
antioxidants-10-00329-v3.pdf | 2.39 MB | Adobe PDF | Ver/Abrir |
Este registo está protegido por Licença Creative Commons