Monoamine Oxidase (MAO) Inhibitory Activity: 3-Phenylcoumarins versus 4-Hydroxy-3-phenylcoumarins

Giovanna Delogu, Silvia Serra, Elias Quezada, Eugenio Uriarte, Santiago Vilar, Nicholas Tatonetti, Dolores Viña

Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs

Résumé

Monoamine oxidase (MAO) is a useful target in the treatment of neurodegenerative diseases and depressive disorders. Both isoforms, MAO-A and MAO-B, are known to play critical roles in disease progression, and as such, the identification of novel, potent and selective inhibitors is an important research goal. Here, two series of 3-phenylcoumarin derivatives were synthesized and evaluated against MAO-A and MAO-B. Most of the compounds tested acted preferentially on MAO-B, with IC50 values in the micromolar to nanomolar range. Only 6-chloro-4-hydroxy-3-(2'-hydroxyphenyl)coumarin exhibited activity against the MAO-A isoform, while still retaining good selectivity for MAO-B. 6-Chloro-3-phenylcoumarins unsubstituted at the 4 position were found to be more active as MAO-B inhibitors than the corresponding 4-hydroxylated coumarins. For 4-unsubstituted coumarins, meta and para positions on the 3-phenyl ring seem to be the most favorable for substitution. Molecular docking simulations were used to explain the observed hMAO-B structure-activity relationships for this type of compound. 6-Chloro-3-(3'-methoxyphenyl)coumarin was the most active compound identified (IC50 =0.001 μM) and is several times more potent and selective than the reference compound, R-(-)-deprenyl hydrochloride. This compound represents a novel tool for the further investigation of the therapeutic potential of MAO-B inhibitors.
langue originaleAnglais
Pages (de - à)1672-1676
Nombre de pages5
journalChemMedChem
Volume9
Numéro de publication8
Date de mise en ligne précoce29 avr. 2014
Les DOIs
Etat de la publicationPublié - 2014

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