Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines

Background: Hepatoprotectors, currently used in clinical practice, often show low efficacy. One of the promising goals in the therapy of liver diseases is the targeted synthesis of smallmolecule drugs with hepatoprotective activity. Some heterocycles, such as 1,4-dihydropyridines, are proven to be good hepatoprotectors. Objective: This study aimed to prepare and investigate the hepatoprotective effects of some dihydro- and tetrahydro pyridines using the experimental rat model of tetrachloromethane (CCl4)- induced acute liver damage. Methods: Several 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines were synthesized by the reaction of cyanothioacetamide with carbonyl compounds and active methylene compounds, such as Meldrum’s acid, ethyl cyanoacetate or β-keto esters, followed by S-alkylation of intermediate pyridine-2-thiolates. In silico prediction studies were performed to explore the possible protein targets. Using virtual bioscreening tools, we selected the six most promising compounds from the library of new partially saturated pyridines. Six novel compounds were characterized by IR, ¹H, ¹³C DEPTQ NMR spectroscopy, 2D NMR experiments (¹H–¹³C HSQC, ¹H–¹³C HMBC), HRMS (ESI), and elemental analysis. The hepatoprotective effects were studied in vivo on eighty white rats with CCl4-induced liver damage. Biochemical studies, including thymol turbidity test and measurements of levels of bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in the blood of rats, were performed. Results: Five of six studied compounds showed a good hepatoprotective effect on a rat model of tetrachloromethane (CCl4)-induced acute hepatitis. The blood of rats in the experimental groups revealed significantly lower levels of total bilirubin, alanine aminotransferases, aspartate aminotransferases, thymol turbidity and alkaline phosphatase compared to the control group of rats with acute toxic tetrachloromethane hepatitis. Conclusion: Our results suggests that compound, (benzyl 4-(4-chlorophenyl)-5-cyano-6-({2-[(3,4- dimethylphenyl)amino]-2-oxoethyl}thio)-2-methyl-1,4-dihydropyridine-3-carboxylate), can be considered as candidate for further preclinical studies. Moreover, as per our knowledge, this is the first report on the hepatoprotective effects of the 1,2,3,4-tetrahydropyridine series.