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dc.contributor.authorOliveira, Catarina
dc.contributor.authorBagetta, Donatella
dc.contributor.authorCagide, Fernando
dc.contributor.authorTeixeira, José
dc.contributor.authorAmorim, Ricardo
dc.contributor.authorSilva, Tiago
dc.contributor.authorGarrido, Jorge
dc.contributor.authorRemião, Fernando
dc.contributor.authorUriarte Villares, Eugenio
dc.contributor.authorOliveira, Paulo J.
dc.contributor.authorAlcaro, Stefano
dc.contributor.authorOrtuso, Francesco
dc.contributor.authorBorges, Fernanda
dc.date.accessioned2020-04-02T06:36:37Z
dc.date.available2020-04-02T06:36:37Z
dc.date.issued2019
dc.identifier.citationOliveira, C., Bagetta, D., Cagide, F., Teixeira, J., Amorim, R., Silva, T., Garrido, J., Remião, F., Uriarte, E., Oliveira, P., Alcaro, S., Ortuso, F. and Borges, F., 2019. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents. European Journal of Medicinal Chemistry, 174, 116-129
dc.identifier.issn0223-5234
dc.identifier.urihttp://hdl.handle.net/10347/21077
dc.description.abstractThe discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer's disease therapy. Therefore, a small library of benzoic based amide nitrones (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes. SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern. In general, tert-butyl derivatives effectively inhibited AChE, being compound 33 the most potent (IC50 = 8.3 ± 0.3 μM; Ki 5.2 μM). The data pointed to a non-competitive inhibition mechanism of action, which was also observed for the standard donepezil. None of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data, confirming that the binding mode of nitrones 33 and 38 towards AChE has the most favourable binding free energy. The tert-butylnitrones 33 and 38 were not cytotoxic on different cell lines (SH-SY5Y and HepG2). Moreover, compound 33 was able to prevent t-BHP-induced oxidative stress in SH-SY5Y differentiated cells. Due to its AChE selectivity and promising cytoprotective properties, as well as its appropriate drug-like profile pointing toward blood-brain barrier permeability, compound 33 is proposed as a valid lead for a further optimization step
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, POCI-01-0145-FEDER-016659, and PTDC/DTP-FTO/2433/2014). C. Oliveira (SFRH/BD/88773/2012, NORTE-01-0145-FEDER-000028), F. Cagide (SFRH/BPD/74491/2010, NORTE-01-0145-FEDER-000028), J. Teixeira (PTDC/DTP-FTO/2433/2014, NORTE-01-0145-FEDER-000028) grants are supported by FCT, POPH and QREN. This article is based upon work supported by the COST Action CA15135
dc.language.isoeng
dc.publisherElsevier
dc.rights© 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectBenzoic acid
dc.subjectNitrones
dc.subjectSpin traps
dc.subjectAlzheimer's disease
dc.subjectCholinesterase inhibitors
dc.subjectAcetylcholinesterase
dc.subjectOxidative stress
dc.titleBenzoic acid-derived nitrones: a new class of potential acetylcholinesterase inhibitors and neuroprotective agents
dc.typejournal article
dc.identifier.doi10.1016/j.ejmech.2019.04.026
dc.relation.publisherversionhttps://doi.org/10.1016/j.ejmech.2019.04.026
dc.type.hasVersionVoR
dc.identifier.essn1768-3254
dc.rights.accessRightsopen access
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Química Orgánica
dc.description.peerreviewedSI
dc.relation.projectIDinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88773%2F2012/PT


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© 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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 © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)





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