3-Amidocoumarins as Potential Multifunctional Agents against Neurodegenerative Diseases.
Monoamine oxidase (MAO) generates reactive oxygen species (ROS), which cause neuronal cell death, causing neurodegeneration. Agents that are able to concurrently inhibit MAO and scavenge free radicals represent promising multifunctional neuroprotective agents that could be used to delay or slow the progression of neurodegenerative diseases. In this work, variously substituted 3-amidocoumarins are described that exert neuroprotection in vitro against hydrogen peroxide in rat cortical neurons, as well as antioxidant activity in a 1,1-diphenyl-2-picrylhydrazyl (DPPH⋅) radical scavenging assay. Selective and reversible inhibitors of the MAO-B isoform were identified. Interestingly, in the case of the 3-benzamidocoumarins, substitution at position 4 with a hydroxy group abolishes MAO-B activity, but the compounds remain active in the neuroprotection model. Further evaluation of 3-heteroarylamide derivatives indicates that it is the nature of the heterocycle that determines the neuroprotective effects. Evaluation in a parallel artificial membrane permeability assay (PAMPA) highlighted the need to further improve the blood-brain barrier permeability of this compound class. However, the compounds described herein adhere to Lipinski's rule of five, suggesting that this novel scaffold has desirable properties for the development of potential drug candidates.
CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portugal. mariacmatos@gmail.com.
Maria João
http://orcid.org/0000-0002-3470-8299
MJ
Matos
Departamento de Farmacología, CIMUS, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Fernanda
F
Rodríguez-Enríquez
CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007, Porto, Portugal. fborges@fc.up.pt.
Fernanda
F
Borges
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Lourdes
L
Santana
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Eugenio
E
Uriarte
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
Martín
M
Estrada
Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006, Madrid, Spain.
María Isabel
MI
Rodríguez-Franco
Departamento de Farmacología, CIMUS, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Reyes
R
Laguna
Departamento de Farmacología, CIMUS, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain. mdolores.vina@usc.es.
Dolores
D
Viña
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D051381:Rats
D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; C030123:coumarin; D006861:Hydrogen Peroxide; D008995:Monoamine Oxidase
Parkinson′s disease; coumarin; inhibitors; monoamine oxidase; neuroprotection