Synthesis of mono-and bis-derivatives of spiro-2-oxindole[3,3']pyrrole and their antioxidant and anti-inflammatory activities investigation

Abstract

Aim. To synthesize range of mono- and bis-derivatives of spiro-2-oxindole[3,3']pyrrole and to study antioxidant and antiinflammatory activity of the obtained compounds.

Materials and methods. Methods of organic synthesis and instrumental methods for the structure of organic compounds determination were used; the antioxidant properties of synthesized compounds was studied in vitro on the model of spontaneous lipid peroxidation oxidation; model of acute aseptic inflammation (carrageenan edema) was used for determination of antiinflammatory (anti-exudative) activity.

Results and discussion. Series of novel spiro-2-oxindole[3,3']pyrrole derivatives was synthesized by means of three-component cascade interaction of isatin, α-amino acids and dipolarophils based on bis-maleimids. In order to broaden the obtained range of compounds nitroso derivatives of ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-methyl-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 4 and hexamethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-5'-benzyl-2a',5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 5 were synthesized. The structure of the obtained compounds was reliably confirmed by instrumental methods (¹H NMR, IR spectroscopy and chromatographic mass spectrometry). Screening studies of anti-inflammatory properties were produced, which included in vitro exploration of antioxidant action of synthesized compounds. Three of the tested substances revealed the highest antioxidant properties and were subsequently selected for further investigation of their anti-inflammatory activity. The data of the biological experiments showed their pronounced anti-inflammatory properties on the carrageenan edema model.

Conclusions. Current research proved that the preparatory method, namely, the three-component cascade transformation of isatin, α-amino acids and dipolarophils based on bis-maleimides is effective for synthesis of spiro-2-oxindole[3,3']pyrrole mono- and bis-derivatives. Series of hexamethylene- and ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) symmetric derivatives were obtained. The structure of the obtained compounds was confirmed. Investigation of the antioxidant properties of the synthesized compounds revealed the most active substances: 1'-(hexamethylene-N-maleimido)-5'-benzyl-2a',5a'-dihydro-1'H-spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-2,2',6'(1H,3'H,5'H)-trione 1; ethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-5'-methyl-2a,5a'-dihydro-2,2',6'(1H,1'H,5'H)-trione) 6; hexamethylene-N,N'-bis(spiroindole-3,3'-pyrrolo[3,4-c]pyrrole-4'-nitroso-5'-benzyl-2a,5a'-dihydro-2,2',6(1H,1'H,5'H)-trione) 7. Compound 6 also showed anti-inflammatory properties on the reference drug level.