2-Azolylchromone Derivatives as Potent and Selective Inhibitors of Monoamine Oxidases A and B

Abstract

A series of 2-azolylchromone derivatives were synthesized and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Of the synthesized compounds, compounds 1b, 2b, 4a-c, 5b and 7b showed potent inhibitory activities against MAO-A (IC 50 values, 1b: 0.32 µM; 2b: 0.14 µM; 4a: 0.11 µM; 4b: 0.023 µM; 4c: 0.15 µM; 5b: 0.59 µM; 7b: 0.19 µM) and 4a, c, 5a, c, 6c and 8c for MAO-B (IC 50 values, 4a: 0.028 µM; 4c: 0.019 µM; 5a: 0.73 µM; 5c: 0.28 µM; 6c: 0.28 µM; 8c: 0.27 µM). These data suggest that 6-methoxy substitution favors MAO-A inhibition and 7-methoxy substitution favors MAO-B inhibition. In addition, compound 4b was the most potent inhibitor for MAO-A, and compound 4c for MAO-B. This is the first report identifying 2-azolylchromone derivatives as potent monoamine oxidase inhibitors. These results suggest that the 2-triazolylchromone structure may be a useful scaffold for the design and development of novel monoamine oxidase inhibitors, as evidenced by the activities of 4a-c and 5a-c.Key words 2-azolylchromone; monoamine oxidase A; monoamine oxidase B; inhibitor; structure-activity relationship; 2-triazolylchromone 4H-1-Benzopyran-4-ones (chromones) are an important class of oxygenated heterocyclic compounds that have attracted the attention of organic chemists and biochemists due to their biological activities. The chromone core structure is found in flavones and isoflavones, which are secondary metabolites that are ubiquitous in nature and especially in the plant kingdom, and are present in notable amounts in several species of plants. The chromone scaffold is the pharmacophore of a large number of bioactive molecules of either natural or synthetic origin. The biological effects of these bioactive molecules include anti-inflammatory, anti-tumor and anti-microbial activities, and inhibitory activities towards cyclooxygenases, kinases, phosphatases, aromatases, acetylcholinesterases, and monoamine oxidases. 1,2)The monoamine oxidases A and B (EC 1.4.3.4; MAO-A and MAO-B) are flavoenzymes that play an important role in the oxidative degradation of neurotransmitters such as dopamine, serotonin, and epinephrine. MAOs are found in the outer mitochondrial membrane of various mammalian cell types. MAO-A and MAO-B share approximately 70% sequence identity at the amino acid level and were identified based on their substrate selectivities and inhibitor sensitivities. MAO-A preferentially deaminates serotonin, norepinephrine, and epinephrine and is irreversibly inhibited by clorgyline, whereas MAO-B preferentially deaminates dopamine, β-phenetylamine, and benzylamine and is irreversibly inhibited by R-(−)-deprenyl. MAO inhibitors are important in the treatment of several neurodegenerative diseases. Selective MAO-A inhibitors are used as anti-depressant and anti-anxiety drugs whereas selective MAO-B inhibitors are used to treat Parkinson's disease. [3][4][5] Recently, several research groups have reported chromone derivatives substituted at different positions of the chromone ring and their inhibitory e...

Quantitative Structure–Cytotoxicity Relationship of 2-Azolylchromones

“…Cytotoxicity of a compound is more valuable when it is selective. Although the chemical structures of all 24 compounds used in this study have already been reported (Table I) (4,15), the present study is the first that investigated the relative potency of TS of all…”

“…were synthesized by the conjugated addition reactions of 3-iodochromone derivatives with selected azoles, according to previous methods (4). All compounds were dissolved in DMSO at 40 mM and stored at -20˚C before use.…”

“…Recently we synthesized a series of 2-azolylchromone derivatives that showed potent and selective inhibition of monoamine oxidases A and B (4). The publication of data on the biological activity of azolylchroman derivatives, however, has been limited.…”

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

“…Takao et al evaluated a series of 2‐azolylchromone derivatives ( 46a ‐ b , 47a ‐ b , and 48 ‐ 49 ) for MAO‐B inhibitory activity (Figure ). Compounds 46a ‐ b , 47a ‐ b , 48 , and 49 showed potent inhibitory activities against MAO‐B.…”

“…2‐Azolylchromones ( 46a ‐ b , 47a ‐ b , and 48 ‐ 49 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”