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Experimental chronic heart failure (CHF), caused by administration of L-isoproterenol (2.5 mg/kg twice a day intraperitoneally for 21 days), promotes uncoupling of respiration and oxidative phosphorylation. The rate of mitochondrial oxygen consumption in the metabolic state V3 by Chance in animals with CHF decreased by 53.3% (p<0.05) with malate using (as an oxidation substrate feeding сomplex I of the electron transport chain (ETC)), by 70.6% (p<0.05) with succinate using (сomplex II substrate) and by 63.6% (p<0.05) when malate and succinate were added simultaneously. The respiratory control ratio significantly decreased 2.3 times for сomplex I, 2.5 for сomplex II, and 2.6 times for the simultaneous operation of two respiratory chain complexes in mitochondria of CHF rats compared to intact animals. Mitochondrial dysfunction in experimental CHF is evidently due to the development of oxidative stress. It was revealed that the content of malonic dialdehyde (MDA) in the group of rats with experimental CHF was higher by 54.7% (p<0.05), as compared with intact animals. The activity of superoxide dismutase (SOD) and catalase was lower by 17.5% (p<0.05), and by 18.4%, respectively than in the intact group. The dense extract from herba of Primula veris L. (DEHPV) 30 mg/kg limits the development of mitochondrial dysfunction in rats with experimental CHF, as evidenced by an increase in the role of V3 respiration for the first and second respiratory chain complexes in 1.7 (p<0.05) and 2.0 times (p<0.05), respectively, the ratio of respiratory control (RCR) - 1.7 times (p<0.05) for сomplex I and 2 times (p<0.05) for сomplex II compared with the negative control. The concentration of MDA was by 15.7% (p<0.05), lower and the activity of SOD was by 56.3% (p<0.05) higher.

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.

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