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1.
Bioorg Chem ; 108: 104563, 2021 03.
Article in English | MEDLINE | ID: mdl-33376014

ABSTRACT

The monoamine oxidase (MAO) enzymes are key metabolic enzymes of neurotransmitter and other bioactive amines, and represent important drug targets for the treatment of neuropsychiatric and neurodegenerative disorders. Inhibitors of MAO are established medications for the treatment of depression and Parkinson's disease, and may have future roles in other disease states such as the therapy of prostate cancer, cardiovascular disease and inflammatory diseases. Based on these considerations, the present study synthesizes a series of 22 pyrazolo[1,5-a]quinoxalin-4-one derivatives and evaluated them as potential inhibitors of human MAO-A and MAO-B. The results show that 8 derivatives inhibit MAO-A, and 3 derivatives inhibit MAO-B with IC50 values in the submicromolar range (<1 µM). The most potent MAO-A inhibitor, N-[5-(acetyloxy)-2-(4-chlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxalin-7-yl]acetamide (7c), exhibit an IC50 value of 0.028 µM and displays 50-fold selectivity for MAO-A over MAO-B. The most potent MAO-B inhibitor, 2-(4-methylphenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carbonitrile (4f), exhibit an IC50 value of 0.617 µM and displays 8-fold selectivity for MAO-B. This is the first report of MAO inhibition by pyrazolo[1,5-a]quinoxalin-4-one derivatives, and this study concludes that these compounds are suitable leads for the future development of MAO inhibitors, particularly of the MAO-A isoform.


Subject(s)
Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Quinoxalines/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Structure-Activity Relationship
2.
Drug Dev Res ; 80(7): 970-980, 2019 11.
Article in English | MEDLINE | ID: mdl-31348537

ABSTRACT

In recent studies, we have investigated the monoamine oxidase (MAO) inhibition properties of pyrrolo[3,4-f]indole-5,7-dione and indole-5,6-dicarbonitrile derivatives. Since numerous high potency MAO inhibitors are present among these chemical classes, the present study synthesizes 44 additional derivatives in an attempt to further derive structure-activity relationships (SARs) and to establish optimal substitution patterns for MAO inhibition. The results show that, with the exception of one compound, all indole-5,6-dicarbonitrile derivatives (10) exhibit submicromolar IC50 values for the inhibition of MAO, with the most potent MAO-A inhibitor exhibiting an IC50 value of 0.006 µM while the most potent MAO-B inhibitor exhibits an IC50 value of 0.058 µM. Interestingly, an N-oxide derivative (4c) also proved to be a potent and nonspecific MAO inhibitor. With the exception of one compound, all of the pyrrolo[3,4-f]indole-5,7-diones (28) also exhibit submicromolar IC50 values for the inhibition of an MAO isoform. The most potent inhibitor exhibit an IC50 value of 0.011 µM for MAO-A. This study proposes that high potency MAO inhibitors such as those investigated here, may act as lead compounds for the development of treatments for neurodegenerative and neuropsychiatric disorders such as Parkinson's disease and depression.


Subject(s)
Indolequinones/pharmacology , Indoles/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Nitriles/pharmacology , Humans , Indolequinones/chemical synthesis , Indoles/chemical synthesis , Inhibitory Concentration 50 , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Nitriles/chemical synthesis , Structure-Activity Relationship
3.
Drug Dev Res ; 79(2): 81-93, 2018 03.
Article in English | MEDLINE | ID: mdl-29570223

ABSTRACT

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 IC50 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 IC50 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.


Subject(s)
Indoles/pharmacology , Models, Molecular , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Pyrroles/pharmacology , Humans , Indoles/chemistry , Monoamine Oxidase Inhibitors/chemistry , Pyrroles/chemistry
4.
Bioorg Med Chem Lett ; 26(9): 2214-9, 2016 May 01.
Article in English | MEDLINE | ID: mdl-27020523

ABSTRACT

In a recent study we have shown that several indole-5,6-dicarbonitrile derivatives are potent inhibitors of human monoamine oxidase (MAO) A and B. To expand on these results and to further determine structure-activity relationships (SARs) for MAO inhibition by this chemical class, the present study investigates the MAO inhibition properties of additional indole-5,6-dicarbonitriles and related indole-5,6-dicarboxylic acid and pyrrolo[3,4-f]indole-5,7-dione derivatives. Among the active compounds two pyrrolo[3,4-f]indole-5,7-dione derivatives inhibited MAO-A (4 g) and MAO-B (4d) with IC50 values of 0.250 and 0.581 µM, respectively. In general indole-5,6-dicarbonitriles, however, exhibit higher MAO inhibition potencies while indole-5,6-dicarboxylic acids are weak MAO inhibitors. Active MAO inhibitors such as 4 g and 4d may be used as leads for the development of drugs for the treatment of disease states such as Parkinson's disease and depression. MAO inhibitors are also under investigation as potential agents for the treatment of prostate cancer, certain types of cardiomyopathies and Alzheimer's disease.


Subject(s)
Monoamine Oxidase Inhibitors/pharmacology , Crystallography, X-Ray , Models, Molecular , Monoamine Oxidase Inhibitors/chemistry , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 25(6): 1206-11, 2015 Mar 15.
Article in English | MEDLINE | ID: mdl-25701250

ABSTRACT

Recent studies have found that phthalonitrile derivatives are remarkably potent inhibitors of human monoamine oxidase (MAO) A and B. In an attempt to further determine the structure-activity relationships (SARs) for MAO inhibition by this class of compounds and to discover novel potent MAO inhibitors, the present study investigated the MAO inhibition properties of a series consisting of indole-5,6-dicarbonitrile derivatives. The results document that 3-chloro-1H-indole-5,6-dicarbonitrile derivatives exhibited potent inhibition of the MAOs. For example, 3-chloro-2-(4-methylphenyl)-1H-indole-5,6-dicarbonitrile inhibited MAO-A and MAO-B with IC50 values of 0.014µM and 0.017µM, respectively. It was further shown that this compound acts as a reversible and competitive inhibitor of both MAO isoforms. An analysis of the SARs for MAO inhibition by 3-chloro-1H-indole-5,6-dicarbonitriles showed that methylation of the indole nitrogen eliminates MAO-B inhibition activity, and replacement of the 2-phenyl ring with the thienyl results in a 9-fold reduction of MAO-B inhibition activity. A series of 3-bromo-1-hydroxy-1H-indole-5,6-dicarbonitriles are, in turn, comparatively weaker MAO inhibitors. It may be concluded that indole-5,6-dicarbonitrile derivatives are suitable leads for the design MAO inhibitors for the treatment of disorders such as Parkinson's disease and depression.


Subject(s)
Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase/chemistry , Crystallography, X-Ray , Humans , Indoles/chemistry , Kinetics , Molecular Conformation , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/metabolism , Nitriles/chemistry , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Structure-Activity Relationship
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