The Synthesis and Evaluation of C7-Substituted α-Tetralone Derivatives as Inhibitors of Monoamine Oxidase.

Abstract

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 IC50 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 IC50 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.

• Authors: Lesetja J Legoabe, Anél Petzer, Jacobus P Petzer
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 86 Issue 4 Pg. 895-904 (Oct 2015) ISSN: 1747-0285 [Electronic] England
• PMID: 25581511 (Publication Type: Letter, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 John Wiley & Sons A/S.

Chemical References

• Monoamine Oxidase Inhibitors
• Tetralones
• Monoamine Oxidase

Topics

• Humans
• Models, Molecular
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tetralones (chemical synthesis, chemistry, pharmacology)