alpha-Tetralone derivatives as inhibitors of monoamine oxidase

作者：Legoabe Lesetja J^*; Petzer Anel; Petzer Jacobus P

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(12): 2758-2763.

DOI：10.1016/j.bmcl.2014.04.021

• Monoamine oxidase (MAO)
• Inhibition
• alpha-Tetralone
• Structure-activity relationship

In the present study, a series of fifteen alpha-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 alpha-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 alpha-tetralones are highly potent MAO-B inhibitors with all compounds exhibiting IC50 values in the nano-molar range (< 78 nM). Although most compounds are selective inhibitors of MAO-B, the alpha-tetralones are also potent MAO-A inhibitors with ten compounds exhibiting IC50 values in the nano-molar 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 alpha-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 alpha-tetralone derivatives are promising leads for design of therapies for Parkinson's disease and depression.

• 出版日期2014-6-15
• 单位西北大学