Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

Frontiers in Chemistry

卷:6

Fernanda Borges¹  Catarina Oliveira¹  Fernando Cagide¹  Lisa Sequeira¹  José Teixeira²  Ricardo Amorim²  Paulo J. Oliveira²  Tiago Silva²  Santiago Vilar³  Jorge Garrido⁴  Francesco Mesiti⁵  Eugenio Uriarte⁶  Fernando Remião⁷ 

[1] CIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal;

[2] CNC, Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Cantanhede, Portugal;

[3] Departamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, Spain;

[4] Department of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, Porto, Portugal;

[5] Department of “Scienze della Salute”, University “Magna Græcia” of Catanzaro, Catanzaro, Italy;

[6] Instituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, Santiago, Chile;

[7] UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal;

关键词: hydroxybenzoic acids;    oxidative stress;    mitochondria-targeted antioxidants;    cholinesterase inhibitors;    acetyl and butyrylcholinesterase;   

DOI  :  10.3389/fchem.2018.00126

来源: DOAJ

【 摘 要 】

Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

【 授权许可】

Unknown