Liver damage is a common problem around the world, and pharmacocorrection of such disease is carried out by administration of various drugs. Natural and synthetic thio-containing compounds are important in this respect. Most of these, however, have side effects and do not always meet the criteria of evidence-based medicine. Therefore, the search for new drugs with hepatoprotective properties, characterized by high efficiency and low toxicity, is an urgent problem of current pharmacology and biochemistry. The purpose of this study was to assess the acute toxicity of new potentially bioactive S-substituted pteridinones, to select the least toxic substance, to improve the pharmaco-technological characteristics, and to study the hepatoprotective properties in an experimental model of tetrachloromethane hepatitis in rats. Herein, comparison of the hepatoprotective properties of compound 4.1 and the reference drug "Thiotriazoline" is based on biochemical studies. The research results showed that sub-stance 4.1 had a positive effect on biochemical processes by increasing the compensatory mechanisms of antioxidant systems, while reducing the infiltrative, destructive and inflamma-tory process in the liver, evoking decreases in the cytolytic process, restoring the structure of the components of the membrane of hepatocytes, stabilizing and enhancing the functional activity of the liver, restoring the liver’s protein-synthesizing function and increasing the abil-ity to restore metabolic disorders in the liver. As a result of the biochemical study of the hepa-toprotective effect of compound 4.1, it was found that the studied substance is a non-toxic compound with antioxidant properties.

The presented material describes the results of the purposeful search for the novel hepatoprotective agents among synthetic sulfur-containing pteridines. The studied compounds were obtained using previously described synthetic procedures. SwissADME and ProTox-II services, as well as a docking study were used to predict the compounds` pharmacokinetics, drug-likeness and toxicity. The effects of sulfur-containing pteridines on lipid peroxidation in vitro and GSH/GSSG levels in vivo were studied for evaluation of their hepatoprotective potential. In silico procedures allowed us to exclude the compounds with inappropriate ADME parameters and high predicted toxicity. Molecular docking of the obtained compounds towards the active site of CYP-enzyme allowed us to clarify the specifics of ligand-enzyme interactions and predict cytochrome-inhibiting activity of the studied agents. The antioxidant activity of the studied compounds was evaluated in vitro using the linoleic acid peroxidation model. It has been found that sulfur-containing pteridines inhibit the peroxidation of linoleic acid. The structure – antioxidant activity relationships were evaluated and discussed as well. Additionally, it has been estimated that antioxidant properties of the studied pteridines directly correlate with their hydrophilicity and number of functional groups with exchangeable proton in molecules. In vivo studies showed that some of the studied sulfur-containing pteridines reduced severity of the hepatotoxic effects caused by the administration of carbon tetrachloride. (3-(7-Hydroxy-4-oxo-2-thioxo-1,2,3,4-tetrahydropteridin-6-yl)propanoyl)alanine has been identified as the most active hepatoprotective agent. The above mentioned compound significantly increases the content of GSH and decreases the level of GSSG compared with non-treated experimental pathology, which reliably affirms its hepatoprotective activity. The hepatoprotective activity of the studied compounds is likely associated with their ability to increase the level of GSH, inhibit lipid peroxidation and decrease prooxidant compounds levels. The obtained results attest the reasonability of further search for hepatoprotective agents among sulfur-containing pteridine derivatives.

Background/Objectives: Liver disease is one of the most common medical problems in the world. The pharmacological correction of these pathologies includes the use of drugs with antioxidant and hepatoprotective action, among which there are natural and synthetic sulfur-containing compounds. However, many of these drugs have side effects, and their application does not always correspond to approaches in evidence-based medicine. Therefore, today the urgent problem is the search for new effective substances with high metabolitotropic properties and high safety criteria. The aim of this work was an in-depth study of the hepatoprotective and antioxidant action of a new investigational pteridine-containing “lead-compound” (DCTP) under conditions of experimental tetrachloromethane hepatitis in rats in comparison with the reference drug “Thiotriazoline”. Methods: The hepatoprotective effect of the compound was studied using a model of acute tetrachloromethane (CCl₄) hepatitis in adult male Wistar rats. The levels of biochemical liver damage markers were estimated with spectrophotometric methods. Histological and immunohistochemical methods were used for the determination of hepatocyte damage. The statistical processing of data was performed using the nonparametric Wilcoxon–Mann–Whitney method. Results: The results of the studies showed that DCTP was superior to the reference drug Thiotriazoline in terms of its effect on the levels of AST, DC, Schiff bases, and carbonylated proteins, which are markers of oxidative (Nrf2) and inflammatory (Lipocalin-2) stress, as well as its effect on animal survival. The results were confirmed by histological examination data, which showed regeneration of the hepatocyte membrane structure; a reduction in infiltrative, destructive, and inflammatory process in the liver; a reduction in the cytolytic process; stabilization; and an increase in the functional activity of the liver due to the administration of the study drug. The pharmacological effects of the studied compound (DCTP) are probably associated with its structural similarity to tetrahydrofolic acid, which is an integral component of oxidation–reduction processes and a participant in the biosynthesis of nitrogenous bases of nucleotides and amino acids. The obtained data show the antioxidant and hepatoprotective properties of the studied “lead-compound” from the pteridinethione group (DCTP). Conclusions: It was shown that the studied substance DCTP significantly reduces acute hepatotoxic effects caused by CCl₄, as evidenced by the decrease in the level of lipid peroxidation and prooxidant markers, the normalization of liver biochemical markers, the regeneration of the liver architecture, the limitation of inflammatory effects, the decrease in Nrf2 and Lipocalin-2 markers, and the induction of liver antioxidant enzymes.

Background/Objectives: Liver disease is one of the most common medical problems in the world. Pharmacocorrection of these pathologies includes the use of drugs with anti-oxidant and hepatoprotective action, among which there are natural and synthetic sul-fur-containing compounds. However, many of the drugs have side effects and their ap-plication does not always correspond to the approaches of evidence-based medicine. Therefore, today the urgent problem is the search for new effective substances with high metabolitotropic properties and high safety criteria. The aim of the work was in-depth study of the hepatoprotective and antioxidant action of the new investigational "lead-compound" among pteridine S-substituted (DCTP) under conditions of experi-mental tetrachloromethane hepatitis in rats in comparison with the reference drug "Thio-triazoline". Methods: The hepatoprotective effect of the compound was studied using the model of acute tetrachloromethane (CCl4) hepatitis in adult male Wistar rats. The levels of biochemical liver damage markers were estimated with spectrophotometric methods. Histological and immunohistochemical methods were used for determination of hepato-cytes damage. Statistical processing of data was performed using the nonparametric Wil-cox-on-Mann-Whitney method. Results: The results of the studies showed that DCTP was superior to the reference drug Thiotriazoline in its effect on the level of AST, DC, Schiff bases and carbonylated proteins, markers of oxidative (Nrf2) and inflammatory (Lipocalin-2) stress, as well as on animal survival. The results were confirmed by histological examination data, which showed re-generation of the hepatocyte membrane structure, reduction of the infiltrative, destructive and inflammatory process in the liver, reduction of the cytolytic process, stabilization and increase in the functional activity of the liver due to the administration of the study drug. The pharmacological effects of lead-compound (DCTP) are probably associated with its structural similarity to tetrahydrofolic acid, which is an integral component of oxida-tion-reduction processes and a participant in the biosynthesis of nitrogenous bases of nu-cleotides, amino acids. The obtained data indicate antioxidant and hepatoprotective properties of the studied “lead-compound” from the pteridinethione group (DCTP). Con-clusions: It was shown that the studied substance DCTP significantly reduces acute hepa-totoxic effects caused by CCl4, as evidenced by a decrease in the level of lipid peroxi-da-tion and prooxidant markers, normalization of liver biochemical markers, as well as regeneration of liver architecture, limitation of inflammatory effects, a decrease in Nrf2 and Lipocalin-2 markers, and induction of liver antioxidant enzymes.