New halogenated 3-phenylcoumarins as potent and selective MAO-B inhibitors.
Bioorganic & medicinal chemistry letters 2010 Jul 8; In press
Matos M MJ, Viña D, Janeiro P, Borges F, Santana L, Uriarte E
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain; CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal.
With the aim to find out the structural features for the MAO inhibitory activity and selectivity, in the present communication we report the synthesis and pharmacological evaluation of a new series of bromo-6-methyl-3-phenylcoumarin derivatives (with bromo atom in both different benzene rings of the skeleton) with and without different number of methoxy substituent at the 3-phenyl ring. The methoxy substituents were introduced, in this new scaffold, in the meta and/or para positions of the 3-phenyl ring. The synthesized compounds 3-7 were evaluated as MAO-A and B inhibitors using R-(-)-deprenyl (selegiline) and iproniazide as reference inhibitors, showing, most of them, MAO-B inhibitory activities in the low nanomolar range. Compounds 4 (IC(50)=11.05nM), 5 (IC(50)=3.23nM) and 6 (IC(50)=7.12nM) show higher activity than selegiline (IC(50)=19.60nM) and higher MAO-B selectivity, with more than 9050-fold, 30,960-fold and 14,045-fold inhibition levels, with respect to the MAO-A isoform.
Keywords: MAO-B