Insight into the functional and structural properties of 3-arylcoumarin as an interesting scaffold in monoamine oxidase B inhibition.
The design, synthesis, pharmacological evaluation, and theoretical studies of a new series of halogenated 3-arylcoumarins were carried out with the aim of finding new structural and biological features. This series displays several alkyl, hydroxy, halogen, and/or alkoxy groups in both benzene rings of the 3-arylcoumarin scaffold. Most of the compounds studied show high affinity and selectivity for the human monoamine oxidase B (hMAO-B) isoenzyme, with IC50 values in the low nanomolar and picomolar range. Most of the evaluated compounds display higher MAO-B inhibitory activity and selectivity than selegiline (the reference compound). Coumarin 12 (3-(3-bromophenyl)-6-methylcoumarin) is the most active compound (IC50 =134 pM), being 140-fold more active than selegiline and showing the highest specificity for hMAO-B. To better understand the structure-activity relationships, docking experiments were carried out on human monoamine oxidase (A and B) structures. Finally, the prediction of passive blood-brain partitioning, based on in silico derived physicochemical descriptors, was performed.
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela (Spain). mariacmatos@gmail.com.
Maria João
MJ
Matos
Santiago
S
Vilar
Verónica
V
García-Morales
Nicholas P
NP
Tatonetti
Eugenio
E
Uriarte
Lourdes
L
Santana
Dolores
D
Viña
D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D003374:Coumarins; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; C030123:coumarin; D008995:Monoamine Oxidase
coumarins; enzymes; inhibitors; oxidases; structure-activity relationships