8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies

Autor: Maria J. Matos, Paula Novo, Lucía Mayán, Iria Torres, Eugenio Uriarte, Matilde Yáñez, José Ángel Fontenla, Francesco Ortuso, Stefano Alcaro, Francesca Procopio, María Isabel Rodríguez-Franco, Cristina Val, María I. Loza, José Brea, Fernanda Borges, Dolores Viña
Přispěvatelé: Ministerio de Ciencia e Innovación (España), Fundação para a Ciência e a Tecnologia (Portugal), Xunta de Galicia, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Consejo Superior de Investigaciones Científicas (España), Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica, Universidade de Santiago de Compostela. Departamento de Química Orgánica
Rok vydání: 2023
Předmět:
Zdroj: European Journal of Medicinal Chemistry. 248:115091
ISSN: 0223-5234
Popis: Psychiatric 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 (IC = 15.0 nM and IC = 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 t of 6.84 min, an intrinsic clearance of 195.63 μL min mg 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.
This research was funded by Consellería de Cultura, Educacion ´ e Ordenacion ´ Universitaria (EM2014/016), Ministerio de Ciencia e Innovacion ´ (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundaçao ˜ para a Ciˆencia e Tecnologia (PTDC/ASP-PES/28397/ 2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020 and EXPL/BIA-BQM/0492/2021). Financial support from the Xunta de Galicia (Centro de investigacion ´ de Galicia accreditation 2019–2022) and the European Union (European Regional Development Fund - ERDF), is also gratefully acknowledged. M.I.R.-F. acknowledges the economic support from the Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grant PID2021-122650OB-I00) and from CSIC (PIE202080E118).
Databáze: OpenAIRE
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