Synthesis and in vivo evaluation of hepatoprotective effects of novel sulfur-containing 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines
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.
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