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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

Synthetic route to the 2-acetylphenol analogs 2a–o and 3a–b.Note: Reagents and conditions: (a) acetone, K2CO3, reflux.
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f1-dddt-9-3635: Synthetic route to the 2-acetylphenol analogs 2a–o and 3a–b.Note: Reagents and conditions: (a) acetone, K2CO3, reflux.

Mentions: The C5-substituted 2-acetylphenol analogs, 2a–o, were synthesized in low to good yields (39%–93%) by reacting 2′,4′-dihydroxyacetophenone (4) with the appropriate alkyl or arylalkyl bromide (5) in the presence of K2CO3 in acetone (Figure 1). For the synthesis of 3a and 3b, 4′-hydroxyacetophenone (6) and 2′,4′-dihydroxypropiophenone (7), respectively, were reacted with benzyl bromide under the same conditions as earlier. In each instance, the structures and purities of the target compounds were verified by 1H NMR, 13C NMR, and mass spectrometry as cited in the supplementary materials.


2-acetylphenol analogs as potent reversible monoamine oxidase inhibitors.

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

Synthetic route to the 2-acetylphenol analogs 2a–o and 3a–b.Note: Reagents and conditions: (a) acetone, K2CO3, reflux.
© Copyright Policy
Related In: Results  -  Collection

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

f1-dddt-9-3635: Synthetic route to the 2-acetylphenol analogs 2a–o and 3a–b.Note: Reagents and conditions: (a) acetone, K2CO3, reflux.
Mentions: The C5-substituted 2-acetylphenol analogs, 2a–o, were synthesized in low to good yields (39%–93%) by reacting 2′,4′-dihydroxyacetophenone (4) with the appropriate alkyl or arylalkyl bromide (5) in the presence of K2CO3 in acetone (Figure 1). For the synthesis of 3a and 3b, 4′-hydroxyacetophenone (6) and 2′,4′-dihydroxypropiophenone (7), respectively, were reacted with benzyl bromide under the same conditions as earlier. In each instance, the structures and purities of the target compounds were verified by 1H NMR, 13C NMR, and mass spectrometry as cited in the supplementary materials.

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