Synthesis, molecular docking, and protective effect of novel thiohydantoin derivative: (Z)-5-(pyridin-2-ylmethylene)-2-thioxothiazolidin-4-one in a diethynitrosamine model of hepatotoxicity

Abstract

BackgroundDiethyl nitrosamine (DEN) consumption was well documented to cause liver cell damage, compensatory proliferation, and inflammation, so this study aimed to examine the hepatoprotective effects of (Z)-5-(pyridin-2-ylmethylene)-2-thioxothiazolidin-4-one (Z5–2T) on diethyl nitrosamine (DEN) induced liver damage in a rat model. MethodsThirty male wistar rats were divided into three groups, each with ten rats, as the following, Group 1: Vehicle (normal saline), group 2: DEN control, 200 mg/kg single dose injection intraperitonially, group 3: were given 50 mg/kg by oral feeding of (Z5–2T). Five rats from each group were sacrificed in the second week of the experiment, and the other half were sacrificed in the sixth week. Resultsinjection of 200 mg/kg of DEN to rats resulted in elevation of liver function enzymes Total Bilirubin (8.02 ± 0.1 mg/dL), direct Bilirubin (8.22 ± 0.2 mg/dL), indirect Bilirubin (0.03 ± 0.03 mg/dL), aspartate Aminotransferase (303 ± 1.2 U/L), alanine Aminotransferase (287 ± 0.9 U/L) and alkaline Phosphatase (390 ± 0.6 U/L) indicating liver damage, along with elevation in the TNF-α and IL-6. The results of both LFTs and ELISA in the treatment group showed improvements and exhibited decline in the levels of the markers. Histopathological examination showed fibrosis, necrosis, and infiltration of inflammatory cells in DEN group, with less intensity in the treatment group. Immunohistochemistry staining reveled strong positive staining of both HSA and ki-67 antibodies in the DEN group, with much less intensity in the treatment group. The correct absorption and binding between the drug and the receptor were evaluated through computerized molecular docking by using AutoDock program. (Z5–2T) had remarkable interaction with TNF-α (PDB ID:1TNF) and IL-6 (PDB ID: 1IL6), binding site energy -6.5 and -6.0 (kcal/mol), respectively. Conclusionhepatoprotective effect of the (Z5–2T) against DEN-induced hepatocellular damage and cancer in experimental rats was accomplished.