Novel (coumarin-3-yl)carbamates as selective MAO-B inhibitors: Synthesis, in vitro and in vivo assays, theoretical evaluation of ADME properties and docking study

• Published in: European journal of medicinal chemistry 2013-05, Vol.63, p.151-161
• Main Authors: Matos, Maria J., Vilar, Santiago, Gonzalez-Franco, Rosa Mª, Uriarte, Eugenio, Santana, Lourdes, Friedman, Carol, Tatonetti, Nicholas P., Viña, Dolores, Fontenla, Jose A.
• Format: Article
• Language: English
• Subjects: (Coumarin-3-yl)carbamate scaffold; ADME properties; Animals; Biocatalysis - drug effects; Carbamates - chemical synthesis; Carbamates - chemistry; Coumarins - chemistry; Docking studies; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide - metabolism; In vitro assays; In vivo assays; Mice; Models, Molecular; Molecular Structure; Monoamine oxidase (MAO); Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Monoamine Oxidase Inhibitors - pharmacology; Motor Activity - drug effects; Protein Binding; Protein Structure, Tertiary; Selegiline - pharmacology; Substrate Specificity; Tyramine - metabolism
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.02.009

A series of (coumarin-3-yl)carbamates was synthesized and evaluated in vitro as monoamine oxidase (MAO-A and MAO-B) inhibitors. Most of the new compounds selectively inhibited MAO-B isoenzyme with IC50 values in the micro or nanoMolar ranges. Since these compounds must achieve the brain cells, theoretical evaluation of ADME properties were also carried out. Compound 8 (benzyl(coumarin-3-yl)carbamate), which presented the most interesting in vitro MAO-B inhibitory profile (IC50 against MAO-B = 45 nM), was subjected to further studies. This in vitro MAO-B inhibitory activity is comparable with that of the selegiline, the reference compound (IC50 against MAO-B = 20 nM). Taking into account the in vitro results of compound 8, in vivo assays and docking calculations were also carried out for this derivative. [Display omitted] ► Coumarin derivatives as an interesting scaffold. ► Search for new molecules displaying selective monoamine oxidase B inhibitory activity. ► Experimental results corroborated with a docking study. ► ADME properties of a good drug candidate. ► Preliminary SAR study based on the synthesis, in vitro and in vivo activities.