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 g...

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Huvudupphovsmän:	Dotsenko, V. V., Доценко, В. В., Aksenov, N. A., Аксенов, Н. А., Aksenova, I. V., Аксенова, И. В.
Materialtyp:	Статья
Språk:	English
Publicerad:	2023
Ämnen:	Cyanothioacetamide NMR studies X-ray studies Heterocyclization Hepatoprotectors 2, 3, 4-tetrahydropyridines 1, 4-dihydropyridines
Länkar:	https://dspace.ncfu.ru/handle/20.500.12258/23615
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record_format	dspace
spelling	ir-20.500.12258-236152023-06-09T09:45:09Z Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines Dotsenko, V. V. Доценко, В. В. Aksenov, N. A. Аксенов, Н. А. Aksenova, I. V. Аксенова, И. В. Cyanothioacetamide NMR studies X-ray studies Heterocyclization Hepatoprotectors 2, 3, 4-tetrahydropyridines 1, 4-dihydropyridines 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. 2023-06-09T09:40:08Z 2023-06-09T09:40:08Z 2023 Статья Dotsenko V.V., Krivokolysko B.S., Bibik E.Y., Frolov K.A., Aksenov N.A., Aksenova I.V., Krivokolysko S.G. Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines // Current Bioactive Compounds. - 2023. - 9(5), art. no. e171022210054, pp. 73-88. - DOI: 10.2174/1573407219666221017095803 http://hdl.handle.net/20.500.12258/23615 en Current Bioactive Compounds application/pdf
institution	СКФУ
collection	Репозиторий
language	English
topic	Cyanothioacetamide NMR studies X-ray studies Heterocyclization Hepatoprotectors 2, 3, 4-tetrahydropyridines 1, 4-dihydropyridines
spellingShingle	Cyanothioacetamide NMR studies X-ray studies Heterocyclization Hepatoprotectors 2, 3, 4-tetrahydropyridines 1, 4-dihydropyridines Dotsenko, V. V. Доценко, В. В. Aksenov, N. A. Аксенов, Н. А. Aksenova, I. V. Аксенова, И. В. Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
description	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.
format	Статья
author	Dotsenko, V. V. Доценко, В. В. Aksenov, N. A. Аксенов, Н. А. Aksenova, I. V. Аксенова, И. В.
author_facet	Dotsenko, V. V. Доценко, В. В. Aksenov, N. A. Аксенов, Н. А. Aksenova, I. V. Аксенова, И. В.
author_sort	Dotsenko, V. V.
title	Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
title_short	Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
title_full	Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
title_fullStr	Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
title_full_unstemmed	Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines
title_sort	synthesis and in vivo evaluation of hepatoprotective effects of novel sulfur-containing 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines
publishDate	2023
url	https://dspace.ncfu.ru/handle/20.500.12258/23615
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Synthesis and In vivo Evaluation of Hepatoprotective Effects of Novel Sulfur-Containing 1,4-Dihydropyridines and 1,2,3,4-Tetrahydropyridines

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