HEPATOPROTECTIVE PROPERTIES OF CYANOTHIOACETAMIDE DERIVATIVES WITH ANALGESIC ACTIVITY IN ACUTE PARACETAMOL-INDUCED HEPATITIS

Abstract

Objective: To investigate the effects of novel cyanothioacetamide derivatives with analgesic activity on blood biochemical parameters in rats with acute paracetamol-induced hepatitis (APH). Methods: The experiments were performed on 80 adult male outbred albino rats weighing 250-300 g. The animals were divided into eight groups of 10 rats each: an intact group, a control group, a reference group receiving thiotriazolin at a dose of 10 mg/kg, and five experimental groups receiving original α-cyanothioacetamide derivatives coded Mar-014, Mar-037, Mar-075, d02-123, and TD-0331 at a dose of 5 mg/kg in a preventive/therapeutic regimen. APH was experimentally induced by administering paracetamol at 1,500 mg/kg during the first two days, one hour after administration of the test compounds. On day 5, the animals were euthanized, and blood biochemical parameters were determined. Results: Compared with corresponding values in intact rats, total bilirubin in the control group was 2.8-fold higher, and direct bilirubin was 2.5 - fold higher. Alanine aminotransferase (ALT) activity increased by 59.3%, aspartate aminotransferase (AST) activity by 63.6%, and alkaline phosphatase (ALP) activity by 91.5%. In the reference group and all experimental groups, total and direct bilirubin levels remained comparable to those of intact animals. Experiments in albino rats with experimentally induced APH demonstrated pronounced hepatoprotective properties of the de novo synthesized heterocyclic compounds that had previously been shown to possess analgesic and anti-inflammatory activity. Biochemical blood parameters in rats with APH indicate that the novel heterocyclic compounds coded d02-123, Mar-014, Mar-075, and TD-0331 prevented acute paracetamol-induced liver injury without significant alterations in biochemical markers of liver function, indirectly indicating preservation of hepatocyte integrity. Given our previous studies showing that these compounds have analgesic and anti-inflammatory activity exceeding that of metamizole, ibuprofen, indomethacin, and meloxicam by several-fold to tens-fold, the hepatoprotective properties identified in the present study support further preclinical investigation. Conclusion: Among the novel heterocyclic compounds belonging to the cyano-thioacetamide derivative series, compounds coded d02-123, Mar-014, Mar-075, and TD-0331 demonstrated hepatoprotective activity. Keywords: Liver, hepatotoxicity, hepatoprotective agents, cyanothioacetamide, paracetamol-induced hepatitis