α-Tetralone derivatives as inhibitors of monoamine oxidase

Abstract

In the present study, a series of fifteen a-tetralone (3,4-dihydro-2H-naphthalen-1-one) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The a-tetralone derivatives examined are structurally related to a series of chromone (1-benzopyran-4-one) derivatives which has previously been shown to act as MAO-B inhibitors. The results document that the a-tetralones are highly potent MAO-B inhibitors with all compounds exhibiting IC50 values in the nanomolar range (<78 nM). Although most compounds are selective inhibitors of MAO-B, the a-tetralones are also potent MAO-A inhibitors with ten compounds exhibiting IC50 values in the nanomolar range (<792 nM). The most potent MAO-B inhibitor, 6-(3-iodobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 4.5 nM with a 287-fold selectivity for MAO-B over the MAO-A isoform, while the most potent MAO-A inhibitor, 6-(3-cyanobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 24 nM with a 3.25-fold selectivity for MAO-A. Analyses of the structure–activity relationships for MAO inhibition show that substitution on the C6 position of the a-tetralone moiety is a requirement for MAO-A and MAO-B inhibition, and that a benzyloxy substituent on this position is more favourable for MAO-A inhibition than phenylethoxy and phenylpropoxy substitution. For MAO-B inhibition, alkyl and halogen substituents on the meta and para positions of the benzyloxy ring enhance inhibitory potency. It may be concluded that a-tetralone derivatives are promising leads for design of therapies for Parkinson’s disease and depression