The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase
Chemical Biology and Drug Design
Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom, South Africa; Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom, South Africa
Based on a previous report that α-tetralone (3,4-dihydro-2H-naphthalen-1-one) is a promising scaffold for the design of highly potent inhibitors of the enzyme, monoamine oxidase, the present study investigates the monoamine oxidase inhibitory properties of a synthetic series of fifteen C7-substituted α-tetralone derivatives. Arylalkyloxy substitution on C7 of the α-tetralone moiety yielded compounds with high inhibition potencies toward the human monoamine oxidase-B isoform with all compounds possessing IC<inf>50</inf> values in the submicromolar range (0.00089-0.047 μm). The C7-substituted α-tetralones also were highly potent monoamine oxidase-A inhibitors with thirteen (of fifteen) compounds possessing IC<inf>50</inf> values in the submicromolar range (0.010-0.741 μm). The α-tetralones were, however, in each instance selective for monoamine oxidase-B over the monoamine oxidase-A isoform. Dialyses of enzyme-inhibitor mixtures show that, while a representative inhibitor acts as a reversible monoamine oxidase-A inhibitor, inhibition of monoamine oxidase-B is not readily reversed by dialysis. Using a molecular modeling approach, possible binding orientations and interactions of selected α-tetralones with the active sites of the monoamine oxidases are also proposed. This study suggests that C7-substituted α-tetralones are promising monoamine oxidase inhibitors and may represent lead compounds for the development of therapies for Parkinson's disease and depression. C7-Substituted α-tetralones act as high potency reversible inhibitors of human MAO-A and MAO-B. This class of compounds represent promising leads for the development of therapies for Parkinson's disease and depression. © 2015 John Wiley & Sons A/S.
1 tetralone derivative; amine oxidase (flavin containing) isoenzyme A; amine oxidase (flavin containing) isoenzyme B; lazabemide; monoamine oxidase A inhibitor; monoamine oxidase B inhibitor; monoamine oxidase inhibitor; antidepressant activity; Article; competitive inhibition; crystallization; drug potency; drug safety; drug screening; drug synthesis; enzyme activity; enzyme substrate; hydrogen bond; IC50; molecular docking; molecular dynamics; molecular model; Parkinson disease; priority journal; structure activity relation; therapy effect