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.

<p>Reversible Small Molecule Inhibitors of MAO A and MAO B with Anilide Motifs</p>

“…Multiple publications identified two aromatic moieties linked by a short bridging element as mutual MAO scaffold. 8,[12][13][14][15][16] Due to their high stability under physiological conditions, amides were used as linkers in our series. Aromatic moieties bearing different substituents were chosen to elucidate electronic and steric effects on the binding affinities towards both MAO isoforms.…”

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…Based on these results, the same group (2015) synthesized a series of fifteen C5‐substituted 2‐acetylphenol analogs ( 2a‐o ) and examined them for rhMAO‐B inhibitory properties (Figure ) . The 2‐acetylphenol analogs were substituted on C4 position with benzyloxy, phenylethoxy, and phenylpropoxy moieties ( 2a ‐ c ).…”

“…2‐Acetylphenol analogs ( 2a ‐ o and 3a ‐ b ) and 2,4‐dihydroxyacetophenone derivative ( 4 ) . IC 50 , half maximal inhibitory concentration; rhMAO, recombinant human monoamine oxidase; SI, selectivity index…”

“…Based on these results, the same group (2015) synthesized a series of fifteen C5-substituted 2-acetylphenol analogs (2a-o) and examined them for rhMAO-B inhibitory properties ( Figure 13). 150 The 2-acetylphenol analogs were substituted on C4 position with benzyloxy, phenylethoxy, and phenylpropoxy moieties (2a-c). The study disclosed that substitution with benzyloxy moiety (2a) yielded more potent MAO-BIs than substitution with phenylethoxy (2b) and phenylpropoxy (2c) moieties suggesting that, among these three substituents, the benzyloxy moiety is more suitable for MAO-B inhibition.…”

Synthesis of some novel 2-substituted benzothiazole derivatives containing benzylamine moiety as monoamine oxidase inhibitory agents

“…By means of their regulatory effect on the metabolism of neurotransmitters, MAOs are increasingly becoming an important area in medicinal chemistry. MAO-A inhibitors are clinically used mostly as antidepressants 11,12 , whereas MAO-B inhibitors are generally used in dealing with symptoms associated with Parkinson's and Alzheimer's diseases 13,14 . Iproniazid is the first drug used in the therapy of depressive disorder during 1950s 15 .…”