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

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.

Keywords: Depression; Inhibition; Monoamine oxidase; Parkinson’s disease; Pyrazolo[1,5-a]quinoxalin-4-one; Selectivity.