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dc.contributor.authorOliveira, Catarina
dc.contributor.authorCagide, Fernando
dc.contributor.authorTeixeira, José
dc.contributor.authorAmorim, Ricardo
dc.contributor.authorSequeira, Lisa
dc.contributor.authorMesiti, Francesco
dc.contributor.authorSilva, Tiago
dc.contributor.authorGarrido, Jorge
dc.contributor.authorRemião, Fernando
dc.contributor.authorVilar Varela, Santiago
dc.contributor.authorUriarte Villares, Eugenio
dc.contributor.authorOliveira, Paulo J.
dc.contributor.authorBorges, Fernanda
dc.date.accessioned2020-05-26T19:07:04Z
dc.date.available2020-05-26T19:07:04Z
dc.date.issued2018
dc.identifier.citationOliveira C, Cagide F, Teixeira J, Amorim R, Sequeira L, Mesiti F, Silva T, Garrido J, Remião F, Vilar S, Uriarte E, Oliveira PJ and Borges F (2018) Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors. Front. Chem. 6:126. doi: 10.3389/fchem.2018.00126
dc.identifier.issn2296-2646
dc.identifier.urihttp://hdl.handle.net/10347/22614
dc.description.abstractAlzheimer'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.
dc.description.sponsorshipThis work was funded by FEDER funds through the Operational Programme Competitiveness Factors-COMPETE and national funds by FCT – Foundation for Science and Technology under research grants (QUI/UI0081/2013, NORTE-01-0145-FEDER-000028 and PTDC/DTP-FTO/2433/2014, POCI-01-0145-FEDER-016659, POCI-01-0145-FEDER-007440. CO (SFRH/BD/88773/2012), FC (SFRH/BPD/74491/2010), JT (PTDC/DTP-FTO/2433/2014 and NORTE-01-0145-FEDER000028) RA (PTDC/DTP-FTO/2433/2014) grants are supported by FCT, POPH, and QREN. The authors also thank the COST action CA15135 for support
dc.language.isoeng
dc.publisherFrontiers Media
dc.rightsCopyright © 2018 Oliveira, Cagide, Teixeira, Amorim, Sequeira, Mesiti, Silva, Garrido, Remião, Vilar, Uriarte, Oliveira and Borges. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHydroxybenzoic acids
dc.subjectOxidative stress
dc.subjectMitochondria-targeted antioxidants
dc.subjectCholinesterase inhibitors
dc.subjectAcetyl and butyrylcholinesterase
dc.titleHydroxybenzoic acid derivatives as dual-target ligands: mitochondriotropic antioxidants and cholinesterase inhibitors
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.3389/fchem.2018.00126
dc.relation.publisherversionhttps://doi.org/10.3389/fchem.2018.00126
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI


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Copyright © 2018 Oliveira, Cagide, Teixeira, Amorim, Sequeira, Mesiti, Silva, Garrido, Remião, Vilar, Uriarte, Oliveira and Borges. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms
Except where otherwise noted, this item's license is described as  Copyright © 2018 Oliveira, Cagide, Teixeira, Amorim, Sequeira, Mesiti, Silva, Garrido, Remião, Vilar, Uriarte, Oliveira and Borges. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms





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