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Background: Hepatoprotectors, which are currently used in the clinical practice, are often show low efficacy. One of the promising goals in the therapy of liver diseases is the targeted synthesis of small molecule drugs with hepatoprotective activity. Some heterocycles such as 1,4-dihydropyridines were proven to be good hepatoprotector s. Objective: In this study, it is aimed to prepare and investigate the hepatoprotective effects of some dihydro- and tetrahydropyridines using the experimental rat model of tetrachloromethane (CCl4)-induced acute liver damage Methods: The 350+ library of 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines was synthesized by 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 six most promising compounds from the library of new partially saturated pyridines. Six novel compounds were characterized in details 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 80 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 rat blood 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 one 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. Also, there is the very first report on the hepatoprotective effects in the 1,2,3,4-tetrahydropyridine series.

Sequential reaction of 2-chlorobenzaldehyde, cyanothioacetamide, and malononitrile dimer in the presence of an excess of N-methylmorpholine resulted in the formation of N-methylmorphlinium salt of 2-amino-4-(2-chlorophenyl)-6-(dicyanomethyl)-1,4-dihydropyridine-3,5-dicarbonitrile. The resulting salt reacts under Mannich conditions with primary amines and an excess of formaldehyde to form substituted 2-alkylamino-4-(dicyanomethylene)-3,7-diazabicyclo[3.3.1]non-2-ene-1,5-dicarbonitriles. Structure of the key compound was confirmed by single crystal X-ray diffraction analysis.

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Aim. In this research, we studied the parameters of blood biochemical analysis in rats with combined paracetamol-alcoholic liver injury after its pharmacological correction by newly synthesized partially hydrogenated pyridines (cyanothioacetamide derivatives).Materials and methods. 50 samples of new derivatives of partially hydrogenated pyridines synthesized on the basis of the “Chemex” Research Laboratory of the Vladimir Dal’ Lugansk National University underwent virtual bioscreening, which allowed the selection of 4 compounds, the biological activity of which may be associated with the effect on the protein synthesis and detoxifi cation function of the liver. The experiment was conducted on 48 white outbred male rats. For 14 days, the rats of the control and experimental groups were intragastrically injected with 1 ml of 40% ethanol and paracetamol at a dose of 500 mg/kg once a day. Pharmacocorrection with a thiotriazoline reference drug (50 mg/kg) and pyridine derivatives at a dose of 5 mg/kg was performed from the fourth day. On the 15th day, blood was sampled to determine the level of total bilirubin, alanine aminotransferase, aspartate aminotransferase and thymol turbidity test.Results. The value of total bilirubin in the blood of the rats treated with CV046 compounds was 34.88% lower than that in the control group. The animals of the test groups receiving CV047 also showed signifi cant differences with the control group in terms of bilirubin level (a decrease of 31.78%). The AST values in the blood of rats in the test groups had no signifi cant differences as compared with intact animals. Following 10 days of pharmacological correction of combined paracetamol-alcoholic liver injury with CV146, the total bilirubin level in the blood decreased by 26.36% in comparison with the control group, with the activity of ALT and AST demonstrating the levels of intact values.Conclusions. The conducted screening studies of four partially hydrogenated pyridines — cyanothioacetamide derivatives — using the model of combined paracetamol-alcoholic liver injury when used at a dose of 5 mg/kg during ten days have shown a high hepatoprotective and detoxifying activity of the following three compounds: СV046 (2-[(9-tert-butyl-1,5-dicyano4-oxo-3-azaspiro[5,5]undec-1-en-2-yl)thio]-N-(2-ethylphenyl)acetamide — IUPAC), СV047 (2-[(9-tert-butyl-1,5-dicyano-4-oxo-3-azaspiro[5,5]undec-1-en-2-yl)thio]-N-(4-fl uorophenyl) acetamide) and СV146 (benzyl 4-(4-chlorophenyl)-5-cyano-6-({2-[(3,4-dimethylphenyl)amino]-2-oxoethyl}thio)-2-methyl-1,4-dihydropyridine-3-carboxylate).