Adv Pharm Bull. 2018;8(2):267-275.
doi: 10.15171/apb.2018.031
  Abstract View: 115
  PDF Download: 211

Research Article

Synthesis of Bis(Isoxazol-4-Ylmethylsulfanyl)Alkanes and Some Metal Complexes as a Hepatoprotective Agents

Vnira Rakhimovna Akhmetova 1 * , Rozalia Akramovna Galimova 2, Nail Salavatovich Akhmadiev 1, Albina Midkhatovna Galimova 2, Ravil Akhmetzyanovich Khisamutdinov 3, Galiya Maratovna Nurtdinova 1, Eduard Feliksovich Agletdinov 2, Valery Alekseevich Kataev 2

1 Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, 450075 Ufa, Russia.
2 Bashkir State Medical University, 3 Lenin Str., 450008 Ufa, Russia.
3 Ufa Institute of Chemistry, Russian Academy of Sciences, 71 Prospekt Oktyabrya, 450054 Ufa, Russia.

Abstract

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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Submitted: 31 Aug 2017
Revised: 27 Mar 2018
Accepted: 09 Apr 2018
First published online: 19 Jun 2018
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