Monoamine oxidase inhibition properties of 2,1-benzisoxazole derivatives

Abstract

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 (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, 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.

Keywords: 2,1-benzisoxazole; Inhibition; MAO; Monoamine oxidase; Specificity.

Fig. 1

The general structure of the 2,1-benzisoxazole derivatives that were investigated in this study as well as the structures of 3-(2-aminoethoxy)-1,2-benzisoxazole derivative RS-1636, zonisamide and leflunomide

Fig. 2

The synthesis of 2,1-benzisoxazole derivatives 3a–o and the bis-condensation product 5

Fig. 3

The synthesis of 2,1-benzisoxazole derivatives 7a–c

Fig. 4

OLEX2 view of 3c displaying thermal ellipsoids at 50% probably level

Fig. 5

Plots of MAO-B catalytic rate versus inhibitor concentration (log[I]) for 7a (filled circles) and 7c (open circles)

Fig. 6

Lineweaver–Burk plots for the inhibition of MAO-A and MAO-B by 3l (a) and 7a (b), respectively. The following inhibitor concentrations were used: 0 × IC₅₀ (filled squares), ¼ × IC₅₀ (open squares), ½ × IC₅₀ (filled circles), ¾ × IC₅₀ (open circles), 1 × IC₅₀ (triangles) and 1¼ × IC₅₀ (diamonds). The insets are replots of the slopes of the Lineweaver–Burk plots versus inhibitor concentration. The K_i value equals the negative of the x-axis intercept when y = 0

Fig. 7

The predicted binding of 3l (a) and 7a (b) to MAO-A and MAO-B, respectively. The orientations of harmine in MAO-A and zonisamide in MAO-B are shown in magenta lines, while the FAD is shown in green sticks. Hydrogen bonding is indicated by the dashed lines