Inhibition of monoamine oxidases by coumarin-3-acyl derivatives: biological activity and computational study.
A series of coumarin-3-acyl derivatives have been synthesized and investigated for the ability to inhibit selectively monoamine oxidases. The coumarin-3-carboxylic acids, 2a-e, proved to be reversible and selective inhibitors of the MAO-B isoform, displaying pIC(50) values of particular interest: 2a shows pIC(50) 7.76 and a selectivity index (pS.I.) 2.94 and 2b shows pIC(50) 7.72 and a pS.I. of 2.80. The coumarin-3-acyl chlorides 3a-e showed high pIC(50) values against both MAO-A and MAO-B isoforms, 3d being the highest against MAO-B with a pIC(50) value of 8.00. In order to rationalize the activity/selectivity results, molecular descriptors were generated. Further insight about enzyme-inhibitor interaction was obtained by docking experiments with the MAO-B isoform.
Chimenti
Franco
F
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi di Roma 'La Sapienza', P.le A. Moro 5, 00185 Rome, Italy.
Secci
Daniela
D
Bolasco
Adriana
A
Chimenti
Paola
P
Granese
Arianna
A
Befani
Olivia
O
Turini
Paola
P
Alcaro
Stefano
S
Ortuso
Francesco
F
D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line; D019295:Computational Biology; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008968:Molecular Conformation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D006631:Amine Oxidase (Copper-Containing); C104227:coumarin-3-carboxylic acid