Discovery of New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors

Reis, Joana; Cagide, Fernando; Chavarria, Daniel; Silva, Tiago; Fernandes, Carlos; Gaspar, Alexandra; Uriarte, Eugenio; Remião, Fernando; Alcaro, Stefano; Ortuso, Francesco

doi:10.1021/acs.jmedchem.6b00527

Cited by 90 publications

(99 citation statements)

References 34 publications

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“…On the other hand, substitution with fluorine produced a less potent MAO‐B inhibitor than chlorine and bromine substituents in both series of chalcones. Properties such as atomic radius and/or electronegativity may therefore play a significant role in the ligand–enzyme interaction …”

Section: Figurementioning

confidence: 99%

“…Properties such as atomicr adius and/ or electronegativity may therefore play as ignificantr ole in the ligand-enzymei nteraction. [38] Electron-donating substituents such as ethyl and methoxy groups in chlorine-containingc halcones have as ignificant influence on hMAO-B inhibition;f or example, compounds P16 and P13 were found to be better in terms of potency and selectivity than the corresponding compounds P1 and P11 without these substituents. In particular,m ethoxy-substituted compound P13 showedaK i value of 0.22 AE 0.01 mm with SI = 37.55; this SI is much highert han that of the standard selegiline.…”

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confidence: 99%

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Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Mathew

Uçar

Mathew³

et al. 2016

ChemMedChem

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Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A. The most potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (P16), showed a K value of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO-A and B. The ability of the compounds to cross the blood-brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO-B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.

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Section: Figurementioning

confidence: 99%

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confidence: 99%

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Mathew

Uçar

Mathew³

et al. 2016

ChemMedChem

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“…Reis et al reported screening of new library of chromone derivatives toward inhibition of hMAO‐B (Figure ). The compounds were found to potent inhibitors in nanomolar to picomolar concentration range and were highly selective for MAO‐B.…”

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

confidence: 99%

“…Chromones ( 54a ‐ b ) . 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%

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 New Chemical Entities for Old Targets: Insights on the Lead Optimization of Chromone-Based Monoamine Oxidase B (MAO-B) Inhibitors

Cited by 90 publications

References 34 publications

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives

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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