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2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

Legoabe LJ, Petzer A, Petzer JP - Drug Des Devel Ther (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.

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.

No MeSH data available.


Related in: MedlinePlus

Lineweaver–Burk graphs of human MAO-B activities in the absence (filled squares) and presence of various concentrations of 2e.Notes: The concentrations of 2e used were equal to 1/4× IC50 (open squares), 1/2× IC50 (filled circles), 3/4× IC50 (open circles), 1× IC50 (triangles), 1 1/4× IC50 (diamonds). The insert is a graph of the slopes of the Lineweaver–Burk graphs versus inhibitor concentration.Abbreviation: MAO, monoamine oxidase.
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f3-dddt-9-3635: Lineweaver–Burk graphs of human MAO-B activities in the absence (filled squares) and presence of various concentrations of 2e.Notes: The concentrations of 2e used were equal to 1/4× IC50 (open squares), 1/2× IC50 (filled circles), 3/4× IC50 (open circles), 1× IC50 (triangles), 1 1/4× IC50 (diamonds). The insert is a graph of the slopes of the Lineweaver–Burk graphs versus inhibitor concentration.Abbreviation: MAO, monoamine oxidase.

Mentions: To gain further insight into the mode of MAO-B inhibition by 2-acetylphenols, a set of Lineweaver–Burk graphs were constructed for the inhibition of MAO-B by the representative inhibitor, 2e. The set consisted of six graphs, each constructed by measuring MAO-B catalytic rate at eight different kynuramine concentrations (15–250 µM). The first Lineweaver–Burk graph was constructed in the absence of inhibitor, while the remaining five graphs were constructed in the presence of different concentrations of 2e. As shown in Figure 3 the set of Lineweaver–Burk graphs is indicative of competitive inhibition since the lines are linear and intersect on the y axis. This suggests that 2e is a competitive inhibitor of human MAO-B. From a replot of the slopes of the Lineweaver–Burk plots versus the concentration of 2e, a Ki value of 0.0038 µM is estimated for the inhibition of MAO-B. Global (shared) fitting of the inhibition data directly to the Michaelis–Menten equation yielded a similar Ki value of 0.0039±0.00035 µM (r2=0.99).


2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

Legoabe LJ, Petzer A, Petzer JP - Drug Des Devel Ther (2015)

Lineweaver–Burk graphs of human MAO-B activities in the absence (filled squares) and presence of various concentrations of 2e.Notes: The concentrations of 2e used were equal to 1/4× IC50 (open squares), 1/2× IC50 (filled circles), 3/4× IC50 (open circles), 1× IC50 (triangles), 1 1/4× IC50 (diamonds). The insert is a graph of the slopes of the Lineweaver–Burk graphs versus inhibitor concentration.Abbreviation: MAO, monoamine oxidase.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507791&req=5

f3-dddt-9-3635: Lineweaver–Burk graphs of human MAO-B activities in the absence (filled squares) and presence of various concentrations of 2e.Notes: The concentrations of 2e used were equal to 1/4× IC50 (open squares), 1/2× IC50 (filled circles), 3/4× IC50 (open circles), 1× IC50 (triangles), 1 1/4× IC50 (diamonds). The insert is a graph of the slopes of the Lineweaver–Burk graphs versus inhibitor concentration.Abbreviation: MAO, monoamine oxidase.
Mentions: To gain further insight into the mode of MAO-B inhibition by 2-acetylphenols, a set of Lineweaver–Burk graphs were constructed for the inhibition of MAO-B by the representative inhibitor, 2e. The set consisted of six graphs, each constructed by measuring MAO-B catalytic rate at eight different kynuramine concentrations (15–250 µM). The first Lineweaver–Burk graph was constructed in the absence of inhibitor, while the remaining five graphs were constructed in the presence of different concentrations of 2e. As shown in Figure 3 the set of Lineweaver–Burk graphs is indicative of competitive inhibition since the lines are linear and intersect on the y axis. This suggests that 2e is a competitive inhibitor of human MAO-B. From a replot of the slopes of the Lineweaver–Burk plots versus the concentration of 2e, a Ki value of 0.0038 µM is estimated for the inhibition of MAO-B. Global (shared) fitting of the inhibition data directly to the Michaelis–Menten equation yielded a similar Ki value of 0.0039±0.00035 µM (r2=0.99).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa.

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.

No MeSH data available.


Related in: MedlinePlus