STUDY OF ACUTE TOXICITY AND POTENTIAL HYPOGLYCEMIC ACTIVITY OF A NEW THIAZOLIDONE (ETHYL ESTER OF 4{(2-ETOXY-2-OXOETHYLIDENE-4-OXO-1-(4-DIFLUORO¬METOXY¬PHENYL-THIAZOLIDINE-2-YLIDENE]HYDRAZONO}-1-METHYLPYRAZOL-3-CARBOXYLIC ACID)

Abstract

Abstract. Prevalence of diabetes mellitus (DM) is one of the most pressing medical and social challenges in the world. In spite of a large quantity of experimental and clinical studies related to the means and methods of prophylaxis and treatment of DM, goal-oriented synthesis of new compounds with potential hypoglycemic activity, improved pharmacodynamics and pharmacokinetics is prospective. Thiazolidinediones are among the known insulin sensitisers, but their use is not, unfortunately, without adverse events. The search for safe antidiabetic agents from the thiazolidinediones group is continuing. A derivative of a less toxic thiazolidone – ethyl ester of 4{(2-etoxy-2-oxoethylidene-4-oxo-1-(4-difluoro­metoxy­phenylthiazolidine-2-ylidene]hydrazono}-1-methylpyrazol-3-carboxylic acid, synthesized in the laboratory of organic synthesis of Higher State Educational Establishment in Ukraine Bukovinian state medical university under the supervision of prof. M.K. Bratenko, became the subject of this research.Objective - to study the acute toxicity and potential hypoglycemic activity of a new thiazolidone derivative.Material and methods. The acute toxicity of a new investigated compound (IC) was assessed using the V.B. Prozorovsky short-term method, on white sexually mature rates of both sexes, weighing 180-220 g, against a background of intragastric administration in 3% starch suspension on an empty stomach. One-day monitoring of glucose levels in the rats blood was studied after intragastric administration of IC in the dose 1/100 and 1/10 of DL50, (12.8 mg/kbw and 128 mg/kbw, respectively). A medical product from the thiazolidinediones group, Glutazone, with a chemical structure similar to the IC, was used as a reference drug; it was administered to the animals in the dose of 20 mg/kbw (1/100 DL50). The blood glucose level was assessed every 2 hours, using rapid analyzer «OneTouch SelectSimple», before and after IC and Glutazone administration.Results. The absence of animal deaths when the dose 1000 mg/kg was administered suggests that this dose is the maximum tolerated dose (DL0). When IC was administered in wider dose range (1260-2000 mg/kg), decrease of motion activity, loss of appetite, and breathing difficulty were observed. Animal death was observed on the 3d-5th day after administration at DL50 1280±90 mg/kg.One day monitoring of animal blood glucose concentration after administration in the dose of 12.8 mg/kbw had shown the most expressed hypoglycemic effect after single IC administration in the dose of 1/100 DL50 by the sixth, eighth hour, and did not significantly differ in expression and duration of hypoglycemic effect from reference drug (when taken in DL50-equivalent dose). When the dose of IC was increased (128 mg/kg), the hypoglycemic effect took place sooner, was more expressed, and lasted longer. Conclusions. By the toxicological classification of K.K. Sidorov by the DL50 index, the studied compound belongs to the IV toxicity class («low-toxic compounds»). Ethyl ester of 4{(2-etoxy-2-oxoethylidene-4-oxo-1-(4-difluorometoxy­phenylthiazolidine-2-ylidene]hydrazono}-1-methylpyrazol-3-carboxylic acid, when administered in the single dose of 12.8 mg/kg (1/100 DL50), causes mild hypoglycemic effect in rats, similar to the effect of reference drug glutazone (when taken in DL50-equivalent dose). Hypoglycemic activity of the compound after single dose administration into the stomach is dose dependent: when the dose is increased 10-fold (128.6 mg/kg, 1/10 DL50), the hypoglycemic effect happens earlier, is more expressed and prolonged.