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dc.contributor.author | Oliveira, Catarina |
dc.contributor.author | Bagetta, Donatella |
dc.contributor.author | Cagide, Fernando |
dc.contributor.author | Teixeira, José |
dc.contributor.author | Amorim, Ricardo |
dc.contributor.author | Silva, Tiago |
dc.contributor.author | Garrido, Jorge |
dc.contributor.author | Remião, Fernando |
dc.contributor.author | Uriarte Villares, Eugenio |
dc.contributor.author | Oliveira, Paulo J. |
dc.contributor.author | Alcaro, Stefano |
dc.contributor.author | Ortuso, Francesco |
dc.contributor.author | Borges, Fernanda |
dc.date.accessioned | 2020-04-02T06:36:37Z |
dc.date.available | 2020-04-02T06:36:37Z |
dc.date.issued | 2019 |
dc.identifier.citation | Oliveira, 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.issn | 0223-5234 |
dc.identifier.uri | http://hdl.handle.net/10347/21077 |
dc.description.abstract | The 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.sponsorship | This 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.iso | eng |
dc.publisher | Elsevier |
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.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ |
dc.subject | Benzoic acid |
dc.subject | Nitrones |
dc.subject | Spin traps |
dc.subject | Alzheimer's disease |
dc.subject | Cholinesterase inhibitors |
dc.subject | Acetylcholinesterase |
dc.subject | Oxidative stress |
dc.title | Benzoic acid-derived nitrones: a new class of potential acetylcholinesterase inhibitors and neuroprotective agents |
dc.type | journal article |
dc.identifier.doi | 10.1016/j.ejmech.2019.04.026 |
dc.relation.publisherversion | https://doi.org/10.1016/j.ejmech.2019.04.026 |
dc.type.hasVersion | VoR |
dc.identifier.essn | 1768-3254 |
dc.rights.accessRights | open access |
dc.contributor.affiliation | Universidade de Santiago de Compostela. Departamento de Química Orgánica |
dc.description.peerreviewed | SI |
dc.relation.projectID | info:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F88773%2F2012/PT |
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