2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

Abstract

Based on a previous report that substituted 2-acetylphenols may be promising leads for the design of novel monoamine oxidase (MAO) inhibitors, a series of C5-substituted 2-acetylphenol analogs (15) and related compounds (two) were synthesized and evaluated as inhibitors of human MAO-A and MAO-B. Generally, the study compounds exhibited inhibitory activities against both MAO-A and MAO-B, with selectivity for the B isoform. Among the compounds evaluated, seven compounds exhibited IC50 values <0.01 µM for MAO-B inhibition, with the most selective compound being 17,000-fold selective for MAO-B over the MAO-A isoform. Analyses of the structure-activity relationships for MAO inhibition show that substitution on the C5 position of the 2-acetylphenol moiety is a requirement for MAO-B inhibition, and the benzyloxy substituent is particularly favorable in this regard. This study concludes that C5-substituted 2-acetylphenol analogs are potent and selective MAO-B inhibitors, appropriate for the design of therapies for neurodegenerative disorders such as Parkinson's disease.

• Authors: Lesetja J Legoabe, Anél Petzer, Jacobus P Petzer
• Journal: Drug design, development and therapy (Drug Des Devel Ther) Vol. 9 Pg. 3635-44 ( 2015) ISSN: 1177-8881 [Electronic] New Zealand
• PMID: 26203229 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetophenones
• Monoamine Oxidase Inhibitors
• Recombinant Proteins
• Monoamine Oxidase
• monoamine oxidase A, human

Topics

• Acetophenones (chemical synthesis, metabolism, pharmacology)
• Binding, Competitive
• Catalysis
• Drug Design
• Humans
• Kinetics
• Models, Biological
• Molecular Structure
• Monoamine Oxidase (chemical synthesis, chemistry, metabolism, pharmacology)
• Monoamine Oxidase Inhibitors (chemical synthesis, metabolism, pharmacology)
• Protein Binding
• Recombinant Proteins
• Structure-Activity Relationship