Biopolym. Cell. 2019; 35(6):437-447.
http://dx.doi.org/10.7124/bc.000A17
Bioorganic Chemistry
Synthesis and in vivo evaluation of pyrazoline-thiazolidin-4-one hybrid Les-5581 as a potential non-steroidal anti-inflammatory agent
1, 2, 3Holota S. M., 4Derkach H. O., 1Demchuk I. L., 4Vynnytska R. B., 1Antoniv O. I., 5Furdychko L. O., 2Slyvka N. Yu., 1Nektegayev I. O., 1, 6Lesyk R. B.
  1. Danylo Halytsky Lviv National Medical University
    69, Pekarska Str., Lviv, Ukraine, 79010
  2. Lesya Ukrainka Eastern European National University
    13, Volya Av, Lutsk, Ukraine, 43025
  3. Lviv Medical Institute
    76, V. Polischuk Str., Lviv, Ukraine, 79018
  4. Ivano-Frankivsk National Medical Universitу
    2, Halytska Str., Ivano-Frankivsk, Ukraine, 76018
  5. Bogomolets National Medical University
    13, Shevchenko Blvd., Kyiv, Ukraine, 01601
  6. University of Information Technology and Management in Rzeszow
    2, Sucharskiego Str., Rzeszow, Poland, 35-225

Abstract

Aim. Synthesis and study in vivo of acute toxicity, anti-inflammatory (anti-exudative) activity and evaluation of side effects of pyrazoline-thiazolidin-4-one hybrid Les-5581 under conditions of therapeutic use in experimental animals. Methods. Traditional organic synthesis. The Litchfield - Wilcoxon method. Carrageenin- and formaldehyde-induced inflammatory paw edema models of white rats. Clinical laboratory tests: study of general blood parameters and biochemical profile of liver function (ALT, AST, LF and γ-GGT levels). Evaluation of ulcerogenic action. Results. The target hybrid Les-5581 has been synthesized in convenient and efficient aminolysis of 5-etoxymethylidenerhodanine by 3,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-pyrazole. The LD50 value for Les-5581 was determined with intraperitoneal use and it was 510 mg/kg. The Les-5581 exhibits significant anti-inflammatory activity at a dose of 50 mg/kg (intraperitoneal use) in [the] experiment on carrageenin- and formaldehyde-induced inflammatory models in white rats. At the same time, the use of Les-5581 does not provoke a negative impact on the blood pattern, the liver enzymes function and has no ulcerogenic effect. Conclusions. The pyrazoline-thiazolidine-4-one hybrid Les-5581 is a good molecular platform for the development of new potential low-toxicity anti-inflammatory drugs without ulcerogenic action.
Keywords: pyrazoline, thiazolidin-4-one, NSAIDs, molecular hybrid
Full text: (PDF, in English)

References

[1] Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012;32(6):1491-502.
[2] Meek IL, Van de Laar MA, E Vonkeman H. Non-Steroidal Anti-Inflammatory Drugs: An Overview of Cardiovascular Risks. Pharmaceuticals (Basel). 2010;3(7):2146-2162.
[3] Nasuti C, Gabbianelli R, Falcioni G, Cantalamessa F. Antioxidative and gastroprotective activities of an-ti-inflammatory formulations derived from chestnut honey in rats. Nut Res. 2006; 26(3):130-7.
[4] Boelsterli UA. Mechanisms of NSAID-induced hepatotoxicity: focus on nimesulide. Drug Saf. 2002;25(9):633-48.
[5] Pandit A, Sachdeva T, Bafna P. Drug-induced hepatotoxicity: a review. J Appl Pharm Sci. 2012; 2(5):233-43.
[6] Gaba M, Gaba P, Uppal D, Dhingra N, Bahia MS, Silakari O, Mohan C. Benzimidazole derivatives: search for GI-friendly anti-inflammatory analgesic agents. Acta Pharm Sin B, 2015; 5(4):337-42.
[7] Rao PP, Kabir SN, Mohamed T. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development. Pharmaceuticals (Basel). 2010;3(5):1530-1549.
[8] Bosquesi PL, Melo TR, Vizioli EO, Santos JL, Chung MC. Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach. Pharmaceuticals (Basel). 2011;4(11):1450-1474.
[9] Sawraj S, Bhardawaj TR, Sharma PD. Design, synthesis, and evaluation of novel indomethacin–antioxidant codrugs as gastrosparing NSAIDs. Med Chem Res, 2012; 21(6):834-43.
[10] Kaminskyy D, Kryshchyshyn A, Lesyk R. 5-Ene-4-thiazolidinones - An efficient tool in medicinal chemistry. Eur J Med Chem. 2017;140:542-594.
[11] Geronikaki AA, Lagunin AA, Hadjipavlou-Litina DI, Eleftheriou PT, Filimonov DA, Poroikov VV, Alam I, Saxena AK. Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/lipoxygenase inhibition. J Med Chem. 2008;51(6):1601-9.
[12] Marella A, Ali MR, Alam MT, Saha R, Tanwar O, Akhter M, Shaquiquzzaman M, Alam MM. Pyrazolines: a biological review. Mini Rev Med Chem. 2013;13(6):921-31.
[13] Saso L, Firuzi O. Pharmacological applications of antioxidants: lights and shadows. Curr Drug Targets. 2014;15(13):1177-99.
[14] Golbidi S, Laher I. Antioxidant therapy in human endocrine disorders. Med Sci Monit. 2010;16(1):RA9-24. Review.
[15] Lu X, Murphy TC, Nanes MS, Hart CM. PPAR{gamma} regulates hypoxia-induced Nox4 expression in human pulmonary artery smooth muscle cells through NF-{kappa}B. Am J Physiol Lung Cell Mol Physiol. 2010;299(4):L559-66.
[16] Kumar A, Varadaraj BG, Singla RK. Synthesis and evaluation of antioxidant activity of novel 3, 5-disubstituted-2-pyrazolines. Bull Fac Pharm Cairo Univ, 2013; 51(2):167-73.
[17] Jagadish PC, Soni N, Verma A. Design, synthesis, and in vitro antioxidant activity of 1, 3, 5-trisubstituted-2-pyrazolines derivatives. J Chem, 2013: ID 765768.
[18] Havrylyuk D, Roman O, Lesyk R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline-thiazolidine-based hybrids. Eur J Med Chem. 2016;113:145-66.
[19] Havrylyuk D, Zimenkovsky B, Karpenko O, Grellier P, Lesyk R. Synthesis of pyrazoline-thiazolidinone hybrids with trypanocidal activity. Eur J Med Chem. 2014;85:245-54.
[20] Golota S, Sydorenko I, Surma R, Karpenko O, Gzella A, Lesyk R. Facile one-pot synthesis of 5-aryl/heterylidene-2-(2-hydroxyethyl-and 3-hydroxypropylamino)-thiazol-4-ones via catalytic aminolysis. Synth Comm, 2017; 47(11):1071-6.
[21] Cherkas A, Golota S. An intermittent exhaustion of the pool of glycogen in the human organism as a simple universal health promoting mechanism. Med Hypotheses. 2014;82(3):387-9.
[22] Cherkas A, Eckl P, Gueraud F, Abrahamovych O, Serhiyenko V, Yatskevych O, Pliatsko M, Golota S. Helicobacter pylori in sedentary men is linked to higher heart rate, sympathetic activity, and insulin resistance but not inflammation or oxidative stress. Croat Med J. 2016;57(2):141-9.
[23] Holota S, Shylych Ya, Derkach H, Karpenko O, Gzella A, Lesyk R. Synthesis of 4-(2H-[1,2,4]-Triazol-5-ylsulfanyl)-1,2-dihydropyrazol-3-one via Ring-Switching Hydrazinolysis of 5-Ethoxymethylidenethiazolo[3,2-b][1,2,4]triazol-6-one. Molbank, 2018; 2018(4):M1022.
[24] Lo CP, Croxall WJ. 5-Alkoxymethylenerhodanines and their Reactions with Rhodanines. JACS, 1954; 76(16):4166-9.
[25] Litchfield JJ, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharm Exp Therap, 1949; 96(2):99-113.
[26] Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflamma-tory drugs. Proc Soc Exp Biol Med, 1962; 111:544-7.
[27] Trinus FP, Mochort NA, Klebanov BM. Nesteroidnyje protivospalitelnyje sredstva (Non-steroidal an-ti-inflammatory drugs), Kyiv: Zdorov’ya, 1975; 238 p
[28] Lee G, Goosens KA. Sampling blood from the lateral tail vein of the rat. J Vis Exp. 2015;(99):e52766.
[29] Stefanov OV. Doklinichni doslidzhennya likarskyh zasobiv: Metodychni rekomendatsii (Preclinical studies of drugs. Guidelines), Kyiv. 2001; 528 p.