Show simple item record

dc.contributor.authorOliveira C.
dc.contributor.authorCagide F.
dc.contributor.authorTeixeira J.
dc.contributor.authorAmorim R.
dc.contributor.authorSequeira L.
dc.contributor.authorMesiti F.
dc.contributor.authorSilva T.
dc.contributor.authorGarrido J.
dc.contributor.authorRemião F.
dc.contributor.authorVilar S.
dc.contributor.authorUriarte E.
dc.contributor.authorOliveira P.J.
dc.contributor.authorBorges F.
dc.date.accessioned2020-09-02T22:24:47Z
dc.date.available2020-09-02T22:24:47Z
dc.date.issued2018
dc.identifier10.3389/fchem.2018.00126
dc.identifier.citation6, APR, -
dc.identifier.issn22962646
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5649
dc.descriptionAlzheimer'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. © 2018 Oliveira, Cagide, Teixeira, Amorim, Sequeira, Mesiti, Silva, Garrido, Remião, Vilar, Uriarte, Oliveira and Borges.
dc.language.isoen
dc.publisherFrontiers Media S. A
dc.subjectAcetyl and butyrylcholinesterase
dc.subjectCholinesterase inhibitors
dc.subjectHydroxybenzoic acids
dc.subjectMitochondria-targeted antioxidants
dc.subjectOxidative stress
dc.titleHydroxybenzoic acid derivatives as dual-target ligands: Mitochondriotropic antioxidants and cholinesterase inhibitors
dc.typeArticle


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record