Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis

Reis, Joana; Manzella, Nicola; Cagide, Fernando; Mialet‐Perez, Jeanne; Uriarte, Eugenio; Parini, Angelo; Borges, Fernanda; Binda, Claudia

doi:10.1021/acs.jmedchem.8b00357

Cited by 67 publications

(38 citation statements)

References 35 publications

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“…To maintain pharmacological efficacy, they are aimed to show a high affinity towards the MAOs and/or tight binding behavior. 9 The design of such reversible and selective inhibitors of MAO A and B became a strongly researched area to identify suitable drug candidates for the treatment of neurological diseases, particularly of PD.…”

Section: Introductionmentioning

confidence: 99%

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

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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Background: Ligands consisting of two aryl moieties connected via a short spacer were shown to be potent inhibitors of monoamine oxidases (MAO) A and B, which are known as suitable targets in treatment of neurological diseases. Based on this general blueprint, we synthesized a series of 66 small aromatic amide derivatives as novel MAO A/B inhibitors. Methods: The compounds were synthesized, purified and structurally confirmed by spectroscopic methods. Fluorimetric enzymological assays were performed to determine MAO A/B inhibition properties. Mode and reversibility of inhibition was determined for the most potent MAO B inhibitor. Docking poses and pharmacophore models were generated to confirm the in vitro results. Results: N-(2,4-Dinitrophenyl)benzo[d][1,3]dioxole-5-carboxamide (55, ST-2043) was found to be a reversible competitive moderately selective MAO B inhibitor (IC 50 = 56 nM, K i = 6.3 nM), while N-(2,4-dinitrophenyl)benzamide (7, ST-2023) showed higher preference for MAO A (IC 50 = 126 nM). Computational analysis confirmed in vitro binding properties, where the anilides examined possessed high surface complementarity to MAO A/B active sites. Conclusion: The small molecule anilides with different substitution patterns were identified as potent MAO A/B inhibitors, which were active in nanomolar concentrations ranges. These small and easily accessible molecules are promising motifs, especially for newly designed multitargeted ligands taking advantage of these fragments.

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Section: Introductionmentioning

confidence: 99%

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

Hagenow¹,

Hagenow²,

Grau³

et al. 2020

DDDT

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“…Recently, Reis et al studied the MAO‐B inhibition mechanism by means of crystallographic and biochemical analysis (Figure ). The crystal structures of hMAO‐B in complex with three chromone analogs N ‐(3′,4′‐dimethylphenyl)‐4‐oxo‐4 H ‐chromene‐3‐carboxamide ( 259 ), N ‐(3′‐chlorophenyl)‐4‐oxo‐4 H ‐chromene‐3‐carboxamide ( 260 ), and N ‐(3′‐fluorophenyl)‐4‐oxo‐4 H ‐chromene‐3‐carboxamide ( 261 ) bearing different substituents on the exocyclic aromatic ring (determined at 1.6‐1.8 Å resolution) showed that they all bind in the active site cavity of the protein with the chromone moiety located in front of the FAD cofactor.…”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

“…Structure and MAO‐B inhibitory profile of chromone analogs ( 259 ‐ 261 ) hMAO, human monoamine oxidase…”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

“…Structure and MAO-B inhibitory profile of chromone analogs(259)(260)(261) 275 hMAO, human monoamine oxidase TRIPATHI AND AYYANNAN | 1693 protein engineering, and in furnishing roadmaps for designing more potent and selective MAO-BIs that can be clinically utilized in treating a variety of neurodegenerative and neuropsychiatric conditions.7 | CONCLUSIONS AND FUTURE PERSPECTIVESLast 3 years have witnessed an exhaustive exploration of MAO-B inhibitory profile of various chemical scaffolds in early stages of development. The summary of highly popular scaffolds with potential MAO-B inhibitory profile with respect to their potency and selectivity is illustrated in Figure 95.…”

mentioning

confidence: 99%

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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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“…Chromone, especially C3‐substituted chromone, is recognized as a privileged template for the design of novel compounds with potential pharmacological interest in the field of neurodegenerative, inflammatory, and infectious diseases as well as diabetes and cancer . For example, 3‐sulfonylchromone derivatives were developed as α‐glucosidase inhibitor due to the noteworthy antioxidant activity .…”

Section: Introductionmentioning

confidence: 99%

Gas phase reaction between chromones and solvent in an electrospray ionization source

et al. 2018

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Chromones were measured by using electrospray ionization mass spectrometry in negative mode. Interestingly, in addition to the deprotonated ion ([M − H]−), unexpected [M + 17]− and [M + 31]− ions were observed in high intensity when water and methanol were used as the solvent. Chromones with different substitutes were tested. Compared with the deprotonated ion, [M + 17]− and [M + 31]− ions were observed with higher abundances when the C‐3 site of chromones was substituted by electron withdrawing groups. Based on high performance liquid chromatography‐mass spectrometry (LC‐MS), deuterium‐labeling and collisional‐induced dissociation experiments, a covalent gas‐phase nucleophilic addition reaction between chromone and water, and the formation of a noncovalent complex between chromone and methanol were proposed as the mechanism for the observed [M + 17]− and [M + 31]− ions, respectively. Understanding and using these unique gas phase reactions can avoid misannotation when analyzing chromones and their metabolites.

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Tight-Binding Inhibition of Human Monoamine Oxidase B by Chromone Analogs: A Kinetic, Crystallographic, and Biological Analysis

Cited by 67 publications

References 35 publications

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

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

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

Gas phase reaction between chromones and solvent in an electrospray ionization source

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