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Investigation of pyrazolo[1,5-a]quinoxalin-4-ones as novel monoamine oxidase inhibitors.

Authors :
Panova VA
Filimonov SI
Chirkova ZV
Kabanova MV
Shetnev AA
Korsakov MK
Petzer A
Petzer JP
Suponitsky KY
Source :
Bioorganic chemistry [Bioorg Chem] 2021 Mar; Vol. 108, pp. 104563. Date of Electronic Publication: 2020 Dec 15.
Publication Year :
2021

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 IC <subscript>50</subscript> 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 IC <subscript>50</subscript> 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 IC <subscript>50</subscript> 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.<br /> (Copyright © 2020 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1090-2120
Volume :
108
Database :
MEDLINE
Journal :
Bioorganic chemistry
Publication Type :
Academic Journal
Accession number :
33376014
Full Text :
https://doi.org/10.1016/j.bioorg.2020.104563