Monoamine oxidase inhibition properties of 2,1‑benzisoxazole derivatives

Abstract

onoamine oxidase (MAO) are favoenzymes that metabolize neurotransmitter, dietary and xenobiotic amines to their corre sponding aldehydes with the production of hydrogen peroxide. Two isoforms, MAO-A and MAO-B, are expressed in humans and mammals, and display diferent substrate and inhibitor specifcities as well as diferent physiological roles. MAO inhibi tors 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 specifcities, 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 specifc inhibitors of MAO-B with the most potent MAO-B inhibition observed for 7a (IC50=0.017 µM) and 7b (IC50=0.098 µM). The most potent MAO-A inhibition was observed for 3l (IC50=5.35 µM) and 5 (IC50=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, lefunomide, have been described as MAO inhibitors. This is however the frst report of MAO inhibition by derivatives of the 2,1-benzisoxazole structural isomer