Monoamine oxidase inhibition properties of 2,1-benzisoxazole derivatives

Monoamine oxidase (MAO) are flavoenzymes that metabolize neurotransmitter, dietary and xenobiotic amines to their corresponding aldehydes with the production of hydrogen peroxide. Two isoforms, MAO-A and MAO-B, are expressed in humans and mammals, and display different substrate and inhibitor specif...

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Published in:Molecular diversity 2024-06, Vol.28 (3), p.1009-1021
Main Authors: Shetnev, Anton, Kotov, Alexandr, Kunichkina, Anna, Proskurina, Irina, Baykov, Sergey, Korsakov, Mikhail, Petzer, Anél, Petzer, Jacobus P.
Format: Article
Language:English
Subjects:
Anxiety disorders
Biochemistry
Biomedical and Life Sciences
Dopamine
Enzymes
Humans
Hydrogen peroxide
Isoxazoles - chemistry
Isoxazoles - pharmacology
Life Sciences
Metabolism
Molecular Docking Simulation
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - chemistry
Monoamine Oxidase Inhibitors - pharmacology
Organic Chemistry
Original
Original Article
Pharmacy
Physiology
Polymer Sciences
Prostate cancer
Reagents
Structure-Activity Relationship
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Summary:Monoamine oxidase (MAO) are flavoenzymes that metabolize neurotransmitter, dietary and xenobiotic amines to their corresponding aldehydes with the production of hydrogen peroxide. Two isoforms, MAO-A and MAO-B, are expressed in humans and mammals, and display different substrate and inhibitor specificities as well as different physiological roles. MAO inhibitors are of much therapeutic value and are used for the treatment of neuropsychiatric and neurodegenerative disorders such as depression, anxiety disorders, and Parkinson’s disease. To discover MAO inhibitors with good potencies and interesting isoform specificities, the present study synthesized a series of 2,1-benzisoxazole (anthranil) derivatives and evaluated them as in vitro inhibitors of human MAO. The compounds were in most instances specific inhibitors of MAO-B with the most potent MAO-B inhibition observed for 7a (IC 50  = 0.017 µM) and 7b (IC 50  = 0.098 µM). The most potent MAO-A inhibition was observed for 3l (IC 50  = 5.35 µM) and 5 (IC 50  = 3.29 µM). It is interesting to note that 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, the 1,2-benzisoxazole, zonisamide, as well as the isoxazole compound, leflunomide, have been described as MAO inhibitors. This is however the first report of MAO inhibition by derivatives of the 2,1-benzisoxazole structural isomer. Graphical abstract
ISSN:1381-1991
1573-501X
1573-501X
DOI:10.1007/s11030-023-10628-4