Purpose: This research is devoted to designing the synthesis of sulfanyl-substituted 3,5-dimethylisoxazoles, which contain structural analogues of the SAM drug in the molecule. SAM (S-adenosyl-L-methionine), formed in the biosynthetic process, is used as an effective hepatoprotective drug. Complexation and hepatoprotective properties of the combinatorial series of bis(isoxazolylsulfanyl)ethane have been studied.Methods: Bis(isoxazol-4-ylmethylsulfanyl)alkanes were synthesized using the one-pot method. The structures of compounds were established by one-dimensional (1H,13C) and two-dimensional (COSY, HCQS, HMBC) NMR spectroscopy, mass-spectrometry and X-ray diffraction. The biological activity of the combinatorial series of sulfanyl derivatives of diketones, azoles and their metal complexes has been studied by in vivo method. Simulation of the animal associated processes was carried out in accordance with the principles of bioethics. Screening studies of hepatoprotective activity were carried out in a model of acute CC14 intoxication after a single injection intraperitoneally as a 50% solution in olive oil. The pharmacologically known hepatoprotective drug SAM served as a control.Results: Two-step synthesis of novel α,ω-bis(isoxazol-4-ylmethylsulfanyl)alkanes was carried out via the multicomponent reaction between 2,4-pentandione, CH2O and α,ω-dithiols, then the resulting α,ω-bis(1,3-diketone-2-ylmethylsulfanyl)alkanes were transformed by hydroxyl amine to obtain bis-isoxasole derivatives. Promising precursor 1,2-bis(isoxazol-4-ylmethylsulfanyl)ethane was converted to metal complexes by interaction with PdCl2 or CuCl. The obtained compounds were found to be practically non-toxic compounds (1001 – 3000 mg/kg) according to the classification of K.K. Sidorov, but copper complex refers to low-toxic compounds substances (165 mg/kg). Compounds of sulfanyl ethane series demonstrate hepatoprotective activity.Conclusion: Palladium(II) complex being almost non-toxic possesses hepatoprotective activity comparable to the drug like SAM.

Purpose: In order to investigate mechanisms underlying the hepatoprotective action of S,Spalladaheterocycle, inhibition of cytochromes P450 has been modeled by molecular docking of four palladaheterocycle stereoisomers to the active sites of an enzymatic oxidase system. To obtain a deeper insight into biochemical aspects providing a basis for the therapeutic effects of five-membered palladacycles (as mixture of stereoisomers), a number of preclinical trials has been conducted Methods: 2D and 3D structures of palladaheterocycle stereoisomers were obtained via converting into SDF files by means of software MarvinSketch. Binding of palladaheterocycle at the active sites of cytochromes P450 2E1 and P450 2C9 has been studied by molecular docking using LeadIT 2.3.2. Hepatoprotective activity of palladaheterocycle at 2.5, 25 and 250 mg/kg doses has been studied based on a model of acute intoxication by CCl4 using in vivo methods. Results: By molecular docking it was identify amino acid fragments responsible for binding with palladacyclic isomers. The tested compound is comparable, in terms of its activity to the hepatoprotective drug SAM according to the in vivo and in vitro experiments such as animal survival data, the efficiency of correction of the cytolytic syndrome, the liver excretory function, carbohydrate, protein and lipid metabolism, and the correction efficiency of the liver antitoxic function (the latter has been determined based on the results of a hexobarbital control experiment). Conclusion: Taking into account results obtained in vivo, in vitro and in silico, it can be concluded that the five-membered S,S-palladaheterocycle effectively protect the liver against acute damage caused by CCl4 , via activation of catalase and glucuronyltransferase, as well as via inhibition of the oxidative stress enzymes.

Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.