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. Since we were dealing with potentially reac- tive compounds, before carrying out the assays, we tested the chemical stability of the different acyl deriv- atives in the assay conditions by 1H NMR spectroscopy. The coumarin-3-carboxylic acids, 2a–e, proved to be reversible and selective inhibitors of the MAO-B iso- form, displaying pIC50 values of particular interest: 2a shows pIC50 7.76 and a selectivity index (pS.I.) 2.94 and 2b shows pIC50 7.72 and a pS.I. of 2.80. The coumarin-3-acyl chlorides 3a–e showed high pIC50 values against both MAO-A and MAO-B isoforms, 3d being the highest against MAO-B with a pIC50 value of 8.00. In order to rationalize the activity/selectivity results, molecular de- scriptors were generated. Further insight about enzyme–inhibitor interaction was obtained by docking experiments with the MAO-B isoform. Among the tested derivatives we selected coumarin-3-carboxylic acids 2a–e as potent anti-MAO agents, derivatives 2a and 2b being highly selective against the MAO-B isoform. Coumarin- 3-acyl chlorides 3a–e showed strong anti-MAO activity against both isoforms, especially compound 3d, which shows the highest activity against MAO-B. Unfor- tunately this compound showed a very low selectivity index. MAO-B docking experiments, examined as the probability of occupancy of the enzyme cleft, are crucial to improve the correlation with pIC50 and provide binding modes partially corresponding to the interactions found with another series of inhibi- tors.17 Availability of the MAO-A crystallographic structure will be necessary to complete the correlation study with selectivity inhibition data. The information from this study is important for the rational drug design of more potent/selective MAO inhibitors based on the coumarin scaffold.