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

• Type: Article in International Scientific Journal
• Date: 2018

Authors

Oliveira, C (Author) Other; Fernando Cagide (Author) FCUP; Teixeira, J (Author) Other; Amorim, R (Author) Other; Sequeira, L (Author) Other; Mesiti, F (Author) Other; Silva, T (Author) Other; Garrido, J (Author) Other; Fernando Remiao (Author) FFUP; Vilar, S (Author) Other; Uriarte, E (Author) Other; Oliveira, PJ (Author) Other; Fernanda Borges (Author) FCUP

Journal

Title: Frontiers in Chemistry

Vol. 6

ISSN: 2296-2646

Publisher: FRONTIERS MEDIA SA

Indexing

ISI Web of Knowledge - 30 Citations

Scopus - 29 Citations

Other information

Authenticus ID: P-00N-X92

DOI: 10.3389/fchem.2018.00126

Abstract (EN): 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 twomitochondriotropic antioxidants AntiOxBEN(1) (catechol derivative), and AntiOxBEN(2) (pyrogallol derivative) and compounds 15-18, which have longer spacers. Compounds AntiOxBEN(1) 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 weremore effective AChE inhibitors (IC50 = 7.7 +/- 0.4 and 7.2 +/- 0.5 mu M, 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 A beta-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, themitochondriotropic antioxidant AntiOxBEN(1) is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 17