title: α-Tetralone derivatives as inhibitors of monoamine oxidase.
abstract: In the present study, a series of fifteen α-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 α-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 α-tetralones are highly potent MAO-B inhibitors with all compounds exhibiting IC50 values in the nanomolar range (<78nM). Although most compounds are selective inhibitors of MAO-B, the α-tetralones are also potent MAO-A inhibitors with ten compounds exhibiting IC50 values in the nanomolar range (<792nM). The most potent MAO-B inhibitor, 6-(3-iodobenzyloxy)-3,4-dihydro-2H-naphthalen-1-one, exhibits an IC50 value of 4.5nM 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 24nM 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 α-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 α-tetralone derivatives are promising leads for design of therapies for Parkinson's disease and depression.
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: lesetja.legoabe@nwu.ac.za.
authors.forename: Lesetja J
authors.initials: LJ
authors.lastname: Legoabe
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D044024:Tetralones
keywords: Inhibition; Monoamine oxidase (MAO); Structure–activity relationship; α-Tetralone