Monoamine oxidase (MAO) inhibitory activity: 3-phenylcoumarins versus 4-hydroxy-3-phenylcoumarins.
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.
Department of Life Sciences & Environment, Section of Pharmaceutical Sciences, University of Cagliari, Palazzo delle Scienze, Via Ospedale, 72, 09124 Cagliari (Italy). delogug@unica.it.
Giovanna L
GL
Delogu
Silvia
S
Serra
Elias
E
Quezada
Eugenio
E
Uriarte
Santiago
S
Vilar
Nicholas P
NP
Tatonetti
Dolores
D
Viña
D001665:Binding Sites; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; C030123:coumarin; D008995:Monoamine Oxidase
3-arylcoumarins; inhibitors; molecular docking; monoamine oxidases