RT Journal Article
T1 8-Amide and 8-carbamate substitution patterns as modulators of 7-hydroxy-4-methylcoumarin's antidepressant profile: Synthesis, biological evaluation and docking studies
A1 Matos, Maria João Correia Pinto Carvalho de
A1 Novo, Paula
A1 Mayán Santos, Lucía
A1 Torres, Iria
A1 Uriarte Villares, Eugenio
A1 Yáñez Jato, Matilde
A1 Ortuso, Francesco
A1 Alcaro, Stefano
A1 Procopio, Francesca
A1 Rodríguez Franco, María Isabel
A1 Val García, Cristina
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Borges, Fernanda
A1 Viña Castelao, María Dolores
A1 Fontenla Gil, José Ángel
K1 Amidocoumarins
K1 Carbamatecoumarins
K1 Monoamine oxidase A
K1 Depression
K1 Docking
AB 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 (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
PB Elsevier
SN 0223-5234
YR 2023
FD 2023
LK http://hdl.handle.net/10347/30291
UL http://hdl.handle.net/10347/30291
LA eng
NO European Journal of Medicinal Chemistry, 248 (2023) 115091. https://doi.org/10.1016/j.ejmech.2023.115091
NO This research was funded by Consellería de Cultura, Educación e Ordenación Universitaria (EM2014/016), Ministerio de Ciencia e Innovación (PID2020-116076RJ-I00/AEI/10.13039/501100011033) and Fundação para a Ciência 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 investigación 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 (PIE-202080E118)
DS Minerva
RD 24 abr 2026