Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry

Cagide, Fernando; Silva, Tiago; Reis, Joana; Gaspar, Alexandra; Gomes, Lígia R.; Low, John N.

doi:10.1039/c4cc08798d

Cited by 44 publications

(49 citation statements)

References 16 publications

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“…The title quinolone derivative 1 was synthesized by a one-pot reaction between 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 3,4-dimethylaniline in the presence of POCl 3 following a procedure described previously (Cagide et al, 2015). The title compound was obtained in 70% yield and characterized by NMR.…”

Section: Synthesis and Crystallizationmentioning

confidence: 99%

The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide

et al. 2020

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The structure of the title quinoline carboxamide derivative, C26H25N3O, is described. The quinoline moiety is not planar as a result of a slight puckering of the pyridine ring. The secondary amine has a slightly pyramidal geometry, certainly not planar. Both intra- and intermolecular hydrogen bonds are present. Hirshfeld surface analysis and lattice energies were used to investigate the intermolecular interactions.

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Section: Synthesis and Crystallizationmentioning

confidence: 99%

The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide

et al. 2020

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“…Cagide et al discovered two new classes of potent and selective MAO‐BIs based on chromane‐2,4‐dione ( 37a ‐ d ) and chromone‐3‐carboxamide ( 38a ‐ d ) scaffolds (Figure ). The results showed that regardless of functionalization of dihydropyran‐2,4‐dione ( 37a ‐ d ) and pyrone rings ( 38a ‐ d ), majority of compounds displayed potent and selective hMAO‐B inhibitory activity in micromolar to nanomolar range.…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

“…Chromane‐2,4‐diones ( 37a ‐ d ) and chromone‐3‐carboxamides ( 38a ‐ d ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration; SI, selectivity index…”

Section: Discovery and Development Of Mao‐b Inhibitors (2015‐2018)mentioning

confidence: 99%

“…Chromane-2,4-diones (37a-d) and chromone-3-carboxamides (38a-d) 170. hMAO, human monoamine oxidase; IC50 , half maximal inhibitory concentration; SI, selectivity index TRIPATHI AND AYYANNAN |1629 Kallitsakis et al171 investigated purine + coumarin hybrids(39)(40)(41)(42) for the MAO-B inhibitory activity (Figure 31).The hybrids were selective MAO-BIs, the most potent being 40 (IC 50 = 6.8 ± 0.6 μM; SI > 14.7).…”

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

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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“…[3][4][5] Recently, several research groups have reported chromone derivatives substituted at different positions of the chromone ring and their inhibitory effects towards MAO-A and MAO-B. 2,[6][7][8][9][10][11][12] These reports suggested that structural changes induced by the substitutions on the chromone ring can increase the biological activity of the compound.…”

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confidence: 99%

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

Takao

Saito

Chikuda

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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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...

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Discovery of two new classes of potent monoamine oxidase-B inhibitors by tricky chemistry

Cited by 44 publications

References 16 publications

The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide

The synthesis, crystal structure and Hirshfeld analysis of 4-(3,4-dimethylanilino)-N-(3,4-dimethylphenyl)quinoline-3-carboxamide

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

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

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