Search for Potential Antidiabetic Agents among New Derivatives of Dicarboxylic Acids

The experimental search for new highly effective organic compounds with hypoglycemic activity is an acute issue in modern pharmacology. The purpose of this work was a pharmacological study of the effect of new substituted oxamic acids on carbohydrate metabolism in rabbits. Material and methods. 22 new chemical compounds which are derivatives of arensulfonamides of 1-adamantyloxamic acids (comp. 1-8) and N-R1 - amides of 4- (NR-oxamido) –benzenesulfonyloxamic acids (comp. 9-22) were first synthesized at the Department of Pharmaceutical Chemistry of the National University of Pharmacy, Ukraine. The structure of the synthesized substances was confirmed using modern physicochemical methods of elemental analysis, UV, IR, PMR and mass spectrometry, counter synthesis. The purity of these compounds was monitored by thin layer chromatography. The studied compounds are white crystalline substances of the main character, odorless, with a clear melting point, soluble in polar organic solvents, solutions of caustic bases, mineral acids. The study of the hypoglycemic activity of new chemical compounds was carried out according to the standard technique on rabbits of the Chinchilla breed weighing 2.2-3.5 kg using the Eksan-G apparatus. The studied compounds were administered to laboratory animals intragastrically at a dose of 0.01 LD50. The control group of animals did not receive test substances. A blood test was taken from the ear vein of rabbits 2, 4, 8, and 24 hours after a single injection of the studied compounds. The glucose level in the blood of the control group animals was determined at the same time intervals as in the experimental animals. Comparative drugs were the standard hypoglycemic drugs “Butamid” and “Bukarban” in doses of 50 mg / kg. There were 3 series of experiments where each substance was studied on 5 animals. Results and discussion. Analysis of the obtained data on the study of the effect of new substituted oxamic acids on carbohydrate metabolism in rabbits showed that most of the new substances had a sufficient sugar-lowering effect. High hypoglycemic activity was detected by 1-adamantyloxamic acid arensulfonamides (comp. 1-8), which decreased the blood sugar in the experiment by 14.3-38.1%. Most N- R1 - amides of 4- (N-R-oxamido) -benzenesulfonyloxamic acids (comp. 9-22) also have a pronounced hypoglycemic effect. Sufficiently high glucose lowering activity was found in amides containing in the structure of their molecules two sawn (comp. 9), two isopropyl (comp. 1), two butyl (comp. 11), hydroxyethyl and hydroxyl (comp. 13) radicals. Compound 21 at a dose of 54.3 mg / kg showed a pronounced hypoglycemic effect among the substances of this group: after the administration of this compound, the level of glucose in the blood of animals decreased after 2 hours by 14.2%, after 4 hours it lowered by 28.5%, after 6 hours it decreased by 28.6%, and after 8 hours it decreased by 27.0%. This substance contains in its structure the hydroxyl radical at the benzene ring in the 4th position, and propyl radical in the side chain. The most active among all the studied substances was compound 7, which contains a chlorine atom in the 4th position, which at a dose of 30.7 mg / kg, lowers the level of sugar in the blood after 4 hours by 31.7%, after 6 hours it decreases sugar by 38.2%, and after 8 hours it lowers the blood sugar level by 37.4%. The effectiveness of this substance exceeded the standard comparison drugs "Butamid" and "Bukarban". Conclusions. Oxamic acid derivatives are a promising group of organic compounds for further study, targeted synthesis and pharmacological screening in order to create new drugs with hypoglycemic properties on their basis.