Show simple item record

dc.contributor.authorMatos, Maria J.
dc.contributor.authorNovo, Paula
dc.contributor.authorMayán, Lucía
dc.contributor.authorTorres, Iria
dc.contributor.authorUriarte, Eugenio
dc.contributor.authorYáñez, Matilde
dc.contributor.authorFontenla, José Ángel
dc.contributor.authorOrtuso, Francesco
dc.contributor.authorAlcaro, Stefano
dc.contributor.authorProcopio, Francesca
dc.contributor.authorRodríguez-Franco, María Isabel
dc.contributor.authorVal, Cristina
dc.contributor.authorLoza, María I.
dc.contributor.authorBrea, José
dc.contributor.authorBorges, Fernanda
dc.contributor.authorViña, Dolores
dc.date.accessioned2024-04-18T07:33:08Z
dc.date.available2024-04-18T07:33:08Z
dc.date.issued2023
dc.identifier10.1016/j.ejmech.2023.115091
dc.identifier.issn02235234
dc.identifier.urihttps://hdl.handle.net/20.500.12728/11212
dc.description.abstractPsychiatric and neurological disorders affect millions of people worldwide. Currently available treatments may help to improve symptoms, but they cannot cure the diseases. Therefore, there is an urgent need for potent and safe therapeutic solutions. 8-Amide and 8-carbamatecoumarins were synthetized and evaluated as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Comparison between both scaffolds has been established, and we hypothesized that the introduction of different substituents can modulate hMAO activity and selectivity. N-(7-Hydroxy-4-methylcoumarin-8-yl)-4-methylbenzamide (9) and ethyl N-(7-hydroxy-4-methylcoumarin-8-yl)carbamate (20) proved to be the most active and selective hMAO-A inhibitors (IC50 = 15.0 nM and IC50 = 22.0 nM, respectively), being compound 9 an irreversible hMAO-A inhibitor twenty-four times more active in vitro than moclobemide, a drug used in the treatment of depression and anxiety. Based on PAMPA assay results, both compounds proved to be good candidates to cross the blood-brain barrier. In addition, these compounds showed non-significant cytotoxicity on neuronal viability assays. Also, the best compound proved to have a t1/2 of 6.84 min, an intrinsic clearance of 195.63 μL min−1 mg−1 protein, and to be chemically stable at pH 3.0, 7.4 and 10.0. Docking studies were performed to better understand the binding affinities and selectivity profiles for both hMAO isoforms. Finally, theoretical drug-like properties calculations corroborate the potential of both scaffolds on the search for new therapeutic solutions for psychiatric disorders as depression. © 2023 The Authorses_ES
dc.description.sponsorshipSpanish Research Agency; Ministerio de Ciencia, Innovación y Universidades, MCIU; European Commission, EC; Fundação para a Ciência e a Tecnologia, FCT, (CEECIND/02423/2018, EXPL/BIA-BQM/0492/2021, LA/P/0056/2020, PTDC/ASP-PES/28397/2017, UIDB/00081/2020); Consejo Superior de Investigaciones Científicas, CSIC, (PIE-202080E118); Ministerio de Ciencia e Innovación, MICINN, (PID2020-116076RJ-I00/AEI/10.13039/501100011033); Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia, (EM2014/016); European Regional Development Fund, ERDF, (PID2021-122650OB-I00); Xunta de Galiciaes_ES
dc.language.isoenes_ES
dc.publisherElsevier Masson s.r.l.es_ES
dc.subjectAmidocoumarinses_ES
dc.subjectCarbamatecoumarinses_ES
dc.subjectDepressiones_ES
dc.subjectDockinges_ES
dc.subjectMonoamine oxidase Aes_ES
dc.title8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studieses_ES
dc.typeArticlees_ES


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record