Inhibition of monoamine oxidase by C5-substituted phthalimide analogues

Manley-King, Clarina I.; Bergh, Jacobus J.; Petzer, Jacobus P.

doi:10.1016/j.bmc.2011.06.070

Cited by 39 publications

(21 citation statements)

References 44 publications

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“…Based on the established roles and potential future applications of MAO inhibitors in various disease states, the discovery of novel compounds that inhibit the MAOs is the objective of several research groups (Carradori & Petzer, 2015;Carradori, Secci, Bolasco, Chimenti, & D'Ascenzio, 2012). It was recently shown that phthalimide and nitrile compounds are highly potent and specific MAO-B inhibitors, with for example compounds 1 and 2 exhibiting IC 50 values for the inhibition of human MAO-B of 0.0069 and 0.0048 mM, respectively (Figure 1) (Manley-King, Bergh, & Petzer, 2011. In subsequent studies it was shown that series of pyrrolo [3,4-f]indole-5,7-dione and indole-5,6dicarbonitrile derivatives act as good potency in vitro inhibitors of the MAO enzymes (Chirkova et al, 2015a(Chirkova et al, ,2016.…”

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confidence: 99%

An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives

Chirkova

Kabanova

Filimonov

et al. 2018

Drug Development Research

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Hit, Lead & Candidate Discovery In recent studies, we have shown that pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives act as good potency in vitro inhibitors of the monoamine oxidase (MAO) enzymes. To expand on these series and to further derive structure-activity relationships (SARs) for MAO inhibition, in the present study we synthesized additional homologs and related analogs of these chemical classes. Analyzes of the MAO inhibition properties of the synthesized compounds show that among the pyrrolo[3,4-f]indole-5,7-dione derivatives good potency MAO inhibitors exist as exemplified by 10, which possesses IC values for the inhibition of MAO-A and MAO-B of 0.023 and 0.178 µM, respectively. Among thirteen pyrrolo[3,4-f]indole-5,7-diones, nine compounds exhibit IC values for the inhibition of an MAO isoform in the submicromolar range. It may be concluded that active MAO inhibitors, such as 10 represent suitable leads for the development of drugs for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression. MAO inhibitors are also of interest for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.

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confidence: 99%

An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives

Chirkova

Kabanova

Filimonov

et al. 2018

Drug Development Research

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“…After synthesis it was found that these were indeed poor inhibitors of MAO A [260]. A few of many examples where docking of a compound to MAO A and MAO B are compared can be found in [261][262][263][264][265][266][267]. The best pose from docking programmes, however, does not give the full picture of the dynamic interaction with the active site.…”

Section: Docking and Molecular Dynamics For Maoimentioning

confidence: 99%

Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

Ramsay

2012

Current Topics in Medicinal Chemistry

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Monoamine oxidase (MAO, EC.1.4.3.4) has been a drug target for 60 years, with the primary rationale of developing drugs to treat neuropsychiatric disorders. The biological importance of MAO is to regulate amine levels is the brain and to metabolize amines and drugs in the periphery. This review of the biochemistry of MAO A and MAO B describes the functional properties of the two enzymes integrated with knowledge of the structures of the many MAOinhibitor complexes published in the last 10 years. The analysis of activity, and the chemical and kinetic mechanisms are discussed. Inhibition studies on human MAO in vitro are now facilitated by assays using readily available materials but the kinetics of MAO involving alternative oxidative pathways and sensitivity to the oxygen concentration mean that careful analysis of the data is required as well as the good practice of determining mechanism of inhibition and kinetic constants. Kinetic constants can then be compared with thermodynamic calculations. Inhibitors bind to both the oxidized and reduced forms of MAO present during turnover so both forms should be considered when using molecular dynamics to facilitate drug design. Interaction of inhibitors with the active site can be detected as changes in the visible spectrum and these changes can provide clues about the flavin adduct formed for irreversible inhibitors or about the proximity to the flavin for reversible inhibitors. Developing areas (knock-out mice for behavior, the imidazoline binding site, and imaging to monitor the activity and the inhibition of MAO in the patient) are mentioned.

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“…In fact, the interaction of styryl side chain with the amino acid residues located at the entrance cavity allows a more productive binding with the enzyme compared to isatin [96]. Manley-King et al [97] have synthesized C-5 and C-6 substituted isatin derivatives (R 1 and R 2 , respectively) and have evaluated their inhibitory activities towards human MAO-A and MAO-B ( Table 5). In general the data allow to conclude that all the isatin derivatives behave as reversible and competitive inhibitors of both MAO isoforms.…”

Section: Isatinsmentioning

confidence: 99%

“…Since additional interactions of the C-5 and C-6 substituents of isatins, with the entrance cavity of the enzyme, could enhance the binding affinity, thus showing higher inhibitory potency, a series of phthalimide (an isomer of isatin) derivatives were synthesized and evaluated as inhibitors of recombinant human MAO-A and MAO-B (compounds 82-90) [96,97,99]. The results demonstrate that these analogues are extremely potent and reversible MAO-B inhibitors displaying, in general, IC 50 values in nM range ( Table 6).…”

Section: Phthalimidesmentioning

confidence: 99%

Parkinson's Disease Management. Part II- Discovery of MAO-B Inhibitors Based on Nitrogen Heterocycles and Analogues

Reis¹,

Encarnacao²,

Gaspar³

et al. 2012

Current Topics in Medicinal Chemistry

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Parkinson's disease (PD) is a neurodegenerative disorder mainly characterized by a progressive neurodegeneration of the dopaminergic neurons. The available pharmacological therapy for PD aims to stop the progress of symptoms, reduce disability, slowing the neurodegenerative process and/or preventing long-term complications along the therapy. The main strategic developments that have led to progress in the medical management of PD have focused on improvements in dopaminergic therapies. Despite all the recent research, there are only a few classes of drugs approved for the treatment of motor related symptoms of PD which primarily act on the dopaminergic neurons system: L-dopa, dopamine agonists, monoamine oxidase-B (MAO-B) and catechol-O-methyl transferase (COMT) inhibitors. Anticholinergic drugs and glutamate antagonists are also available but are not commonly used in routine practice. As no effective therapeutic strategy has yet been attended, other solutions must be investigated. Privileged structures, such as indoles, arylpiperazines, biphenyls and benzopyranes are currently ascribed as helpful approaches. Different families of nitrogen and oxygen heterocycles, such as pyrazoles, hydrazinylthiazoles, xanthones, coumarins or chromones have also been extensively used as scaffolds in medicinal chemistry programs for searching novel MAO-B inhibitors. Nitrogen derivatives play a key role in this subject with several studies pointing out hydrazines, thiazoles or indoles as important scaffolds for the development of novel MAO-B inhibitors. This review comprises an overview of the state of the art on the actual pharmacological therapy for PD followed by a specific focus on the discovery and development of nitrogen-based heterocyclic compounds analogues as promising MAO-B inhibitors.

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Inhibition of monoamine oxidase by C5-substituted phthalimide analogues

Cited by 39 publications

References 44 publications

An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives

An investigation of the monoamine oxidase inhibition properties of pyrrolo[3,4‐f]indole‐5,7‐dione and indole‐5,6‐dicarbonitrile derivatives

Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

Parkinson's Disease Management. Part II- Discovery of MAO-B Inhibitors Based on Nitrogen Heterocycles and Analogues

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