Synthesis and evaluation of hexahydropyrrolo[3,4-d]isoxazole-4,6-diones as anti-stress agents

A series of 2,3-diphenyl-5-(naphthalen-1-yl)-4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione derivatives were synthesized via 1,3-dipolar cycloaddition of azomethine N-oxides with N-(α-naphthyl)maleimide. The pyrrolo-isoxazole derivatives were assigned cis- and trans- configurations (3-A and 3-B) with respect to proton C3-H on azomethinic carbon on the basis of their 1H NMR. The reaction proceeds through cis- endo addition rule indicating the predominance of cis isomer. The cis- and trans- isomers of a prototype compound 3ai.e., compound 3a-A and compound 3a-B were evaluated for anti-stress activity in immobilization-induced acute stress. Compound 3a-A (5 and 10 mg/kg) and compound 3a-B (10 mg/kg) attenuated immobilization stress-induced behavioral alterations in Swiss albino mice suggesting that pyrrolo-isoxazole may serve as lead molecule for the development of anti-stress agents.

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► Hexahydropyrollo[3,4-d]isoxazole-4,6-dione derivatives were synthesized.
► Compound 3a, as a prototype, evaluated for anti-stress activity in mice.
► Mice displayed significant degree of behavioral alterations.