The achievements of modern domestic pharmacy clearly prove the prospects of searching for biologically active molecules among 1,2,4-triazole derivatives. The aim of our work was to predict the safest compound, select it and unambiguously prove the structure of a new promising molecule, to investigate some parameters of its toxicity. Materials and methods. X-ray diffraction analysis was performed in the laboratory of the Institute of Single Crystals of the National Academy of Sciences of Ukraine (Kharkiv). Computer methods were used to build “structure – toxicity” models and predict LD50 using already created models GUSAR, TEST. The degree of toxicity (DL50) and the approximate doses for the subacute experiment were determined by studying the acute toxicity of the test chemical and the injectable solution based on it. Determination of acute toxicity parameters by intragastric administration was performed on white rats, aged 3-4 months, body weight 200-220 g. Results. Due to the study of the toxicity of 1,2,4-triazole derivatives by non-experimental methods using GUSAR and TEST models, it was found that the test compounds could be classified as low-toxic substances. The compound is an organic salt that exists in the crystal as a solvate with one molecule of methanol and two molecules of water. When studying the structure of the crystal, it was found that the crystal is in the pinacoidal triclinic syngony. According to the results of the studies, it was found that after a single intragastric administration of the compound in doses of 1000, 3000 and 5000 mg / kg, all animals remained alive for 14 days. The basis of the biological action of chemical compounds is the violation of several biochemical processes. We found that the studied blood constants, on the background of the use of newly synthesized substance, underwent some changes. Conclusions. According to the assessment of the toxicity of the drug “VPK-434” when administered intragastrically to laboratory rats, it was found that in accordance with SOU 85.2-37-736: 2011 the test substance belongs to the IV class of toxicity (low toxicity). It was found that the average lethal dose of DL50 of the test substance by intramuscular administration to rats is 1666.66 mg / kg body weight. It was studied that some abnormalities in the hematopoietic system (increase in the number of leukocytes, including eosinophils), liver and kidney function (increased activity of transaminases, decreased serum concentrations of total protein, urea and creatinine) and changes in mineral metabolism of experimental animals groups, on the background of receiving 10 multiple doses of the study drug, was short-term, and the restoration of the functional state of the body of rats could be said as early as 4-5 days after discontinuation of the drug into their body

The balance between anti- and prooxidants in animal organisms in general and in each cell in particular is responsible for the regulation of many metabolic processes that provide immunocompetence, growth, development and protection of animals from oxidative stress, related to inflow of cadmium and plumbum. Therefore, the objective of our study was the influence of a liposomal drug based on interferon and milk thistle (Silybum marianum (L.) Gaertn.) on the antioxidative status of the organism of bulls in the conditions of cadmium and plumbum loading. The experiments were performed on six-months-old Black Motley dairy cattle. The fodders in the farm were determined to contain high levels of plumbum and cadmium. The liposomal drug Lipointersyl inhibited the lipid peroxidation processes in the bulls. The drug components promoted the decrease in the level of intermediate and end products of lipid peroxidation, in particular 22% decrease in the level of diene conjugates and 20% decrease in TBA-active products. Intramuscular injection of the liposomal drug to bulls of the experimental group strengthened the antioxidant protection of their organism. On the 30th day of the experiment, blood from experimental group animals was seen to have a 9.8% increase in reduced glutathione. Assay of the enzymatic link of the glutathione system revealed that the activity of glutathione peroxidase and glutathione reductase in the blood of the animals that had been injected the liposomal drug Lipointensyl had increased by 24.0% and 27.7% respectively by the 30th day of the experiment. The experiments conducted on young cattle demonstrated that intermuscularly injected the Lipointensyl liposomal drug – against the background of cadmium and plumbum loading – promoted the activation of the glutathione system of antioxidant protection as a result of increase in the activity of its enzymatic and non-enzymatic links. The study of catalase and superoxide dismutase activities revealed that on the 30th and 40th days of the experiment, the activity of those enzymes varied within the physiological norms. Therefore, the analyzed Silybum marianum-based liposomal drug has antioxidant properties, it is recommended for young cattle in the conditions of contamination with heavy metals in order to prevent the development of oxidative stress.

In this study, we’ve performed computable studies of previously synthesized 1,2,4-triazole derivatives by virtual screening due to antioxidant activity. Six enzymes responsible for regulating oxidative stress were selected as key targets. One hundred and twelve compounds were subjected to semi-flexible molecular docking, which resulted in the selection of 23 substances based on binding energy for further ADME analysis. In addition, molecular dynamics studies of complexes with the best docking scores, reference complexes and apo-proteins were described in detail here. The results of 100 ns modeling (RMSD, RMSF, SASA, Rg, PCA) indicate great stability during the formation of complexes with our two potential compounds, as well as favorable binding energy, which was determined theoretically by means of the MM/PBSA method, thereby increase the likelihood of their acting as promising inhibitors of selected enzymes.

The results of the literature analysis indicate a wide spectrum of biological activity of 1,2,4-triazole derivatives. Low toxicity, reactivity, and high biological activity of 1,2,4-triazole derivatives make this class of compounds very attractive. The obtained data determine the relevance of further studies of 1,2,4-triazole derivatives to find new highly effective biologically active substances that can become the basis for new medicines. Our further work aimed to study some toxicity parameters of 3-(3-fluorophenyl)-6-(4-methoxyphenyl)-7H-[1,2,4]-triazolo-[3,4-b][1,3,4] thiadiazine when administered subcutaneously to guinea pigs, which is a necessary condition for further implementation in practice of this compound. In this work, we observed an absence of toxic effects after a single subcutaneous injection to guinea pigs at a dose of 40 mg/kg experimental drug. The results of macro- and microscopic examinations of internal organs 14 days after a single subcutaneous injection of the studied compound at a dose of 20, 40 mg/kg showed the absence of any anatomical and morphological disorders in the tissue structures of guinea pigs. The calculated value indicates a high degree of safety of 3-(3-fluorophenyl)-6-(4-methoxyphenyl)-7H-[1,2,4]-triazolo-[3,4-b][1,3,4] thiadiazine and its prospects for use in veterinary practice as an effective and safe tuberculocidal agent.

The aim of our work is to synthesize new S-derivatives in the series of ((1,2,4-triazol-3(2H)-yl)methyl)thiopyrimidines and to study their antioxidant activity, to identify the most promising compound using molecular docking and kinetic parameters. Materials and methods. The 1H and 13C NMR spectra were recorded on a Bruker AC-500 spectrometer. LC-MS was recorded on an Agilent 1260 Infinity HPLC system equipped with a diode-array detector and proton ionization. Elemental analysis (C, H, N, S) was performed on an ELEMENTAR vario EL cube. Molecular docking was performed using the AutoDock 4.2.6 program. Free radical absorption was measured using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical assay. Results. A series of S-acyl derivatives of 4-methyl-5-((pyrimidin-2-ylthio)methyl)-4H-1,2,4-triazole-3-thiols were synthesized through alkylation and subsequent cyclization. The structure of the obtained compounds was confirmed by ¹H and ¹³C NMR spectroscopy. Antiradical activity was evaluated using the DPPH test, with compound (6) exhibiting the highest activity, surpassing ascorbic acid. Molecular docking with cytochrome c peroxidase (PDB: 2X08) confirmed strong binding interactions, highlighting the potential of these derivatives as antioxidants. Conclusions. Three compounds (1, 6, 8) exhibited higher activity than the reference drug, the natural antioxidant ascorbic acid. This high activity may be associated with the presence of pharmacophore fragments, particularly the pyrimidine skeleton and the sulfur atom linked to the 1,2,4-triazole. The IC50 for the most active compound was calculated as 4.458±1 µM, which is 27 times more effective than ascorbic acid. Molecular docking results showed that compounds 4 and 6 had the lowest binding energies, making them the most effective compounds in terms of antioxidant activity

Derivatives of 1,2,4-triazole are actively researched by scientists and synthetic pharmacologists. The last studies have shown that potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate with low toxicity series exhibits antioxidant and hepatoprotective properties. Therefore, the purpose of this work was to develop a method for determining the API in the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate substance using the method of high-performance liquid chromatography with diode array detection (HPLC-DAD). As a result of this work, it is shown that the developed method is specific and meets the requirements of linearity, accuracy and precision. The results of determining the contents of the API in real samples indicate that the method can be proposed to control the quality of the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio)acetate substance.