The synthesis of spiro-2-oxindole-derivative imides of pyrrolidine-3,4-dicarboxylic acid with biogenous sulfur amino acid residues and their antihypoxic activity

Abstract

Modification of the spiro-2-oxindole skeleton due to introduction of pharmacophores of the known biologically active substances is a productive way for searching and creating new biologically active molecules with the non-planar structure.Aim. To synthesize spiro-2-oxindole derivatives of pyrrolidine-3,4-dicarboxylic acid imides with residues of biogenic sulfur-containing α-amino acids and study their anti-hypoxic activity.Results and discussion. Using a three-component one-pot reaction of isatin with sulfur-containing α-amino acids and maleimides a number of new spiro-imides, including 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole-3,2(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones 6a-s, was synthesized with the yields of 55-92 %. The structure and the composition of the compounds synthesized are consistent with the results of X-Ray, elemental analysis, mass and NMR-spectra. It was found that only two of the eight possible enantiomers of spiro-imides were formed. Spiro-imide with a methionine residue in the dose of 10 mg/kg was the most active, and increased the life expectancy in rats with respect to the control group by 33.7 % on average. Against the background of acute asphyxia the preventive administration of piro-imide with a methionine residue in the dose of 5 mg/kg was the most effective; it increased the duration of the bioelectric activity of the heart by 12.1 %.Experimental part. The synthesis of compounds was performed using a three-component condensation in the alcoholic-aqueous medium. The methods of X-Ray, 1H, 13C NMR-spectroscopy, and mass spectrometry were used. The study of the antihypoxic activity was carried out on models of acute normobaric hypoxic hypoxia with hypercapnia and acute asphyxia in male rats of the Wistar line. The antihypoxic effect was assessed by the bioelectric activity of the heart.Conclusions. An effective approach to the synthesis of 4’-R4-5’-alkylthio-S-R3-spiro[1-R1-5-R5-3H-indole- 3,2’(1’H)-pyrrolo[3,4-c]pyrrole]-2,3’,5’(1H,2’aH,4’H)-triones has been developed; among them a compound with a moderate antihypoxic activity has been found.