Biopolym. Cell. 2021; 37(1):46-61.
Bioorganic Chemistry
The novel pyrazolin-5-one bearing thiazolidin-4-ones: synthesis, characterization and biological evaluation
1, 2, 3Holota S. M., 1Nektegayev I. O., 3Soronovych I. I., 1Chubuchna I. I., 1Kolishetska M. A., 1Sysak S. P., 1Regeda M. S., 1, 4Lesyk R. B.
  1. Danylo Halytsky Lviv National Medical University
    69, Pekarska Str., Lviv, Ukraine, 79010
  2. Lesya Ukrainka Volyn National University
    13, Voli Ave., Lutsk, Ukraine, 43025
  3. Lviv Medical Institute
    76, V. Polischuk Str., Lviv, Ukraine, 79018
  4. University of Information Technology and Management in Rzeszow
    2, Sucharskiego Str., Rzeszow, Poland, 35-225


Aim. Synthesis, structure determination, in vivo study of anti-inflammatory (anti-exudative) and ulcerogenic activity, estimation of an impact of novel pyrazolin-5-one bearing thiazolidin-4-ones on liver function. Methods. Organic synthesis: multicomponent reactions (MCRs), [2+3]-cycloaddition reactions. Spectral methods: IR, LC-MS, 1H NMR. Biological methods: study of anti-cancer activity (NCI NIH, USA) protocol for 3-cell line panel); carrageenin-induced inflammatory paw edema model of white rats, biochemical laboratory tests (ALT, AST, ALP, γ-GGT levels determination); evaluation of ulcerogenic action. Results. The series of novel C-5 and N-3 substituted 2-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) amino/imino]thiazolidin-4-ones had been synthesized using MCR and [2+3]-cycloaddition reactions as potential biologically active compounds. The results of screening anti-exudativeactivity revealed that the tested derivatives possess promising anti-inflammatory effect. The SARs were formed and possible mechanisms of their action were discussed. Conclusions. The results presented in paper suggest that the design and synthesis of new pyrazolin-5-on/thiazolidin-4-one hybrids as potential molecules are an attractive area for the search for novel agents with promising pharmacological properties
Keywords: antipyrine, pyrazolin-5-one, thiazolidin-4-one, hybrids, multicomponent reactions, tautomers/rotamers, anticancer/anti-inflammatory activity Introduction


[1] Brune K. The early history of non-opioid analgesics. Acute Pain. 1997; 1(1):33–40.
[2] Zhao Z, Dai X, Li C, Wang X, Tian J, Feng Y, Xie J, Ma C, Nie Z, Fan P, Qian M, He X, Wu S, Zhang Y, Zheng X. Pyrazolone structural motif in medicinal chemistry: Retrospect and prospect. Eur J Med Chem. 2020;186:111893.
[3] Sahoo J, Sahoo CR, Nandini Sarangi PK, Prusty SK, Padhy RN, Paidesetty SK. Molecules with versatile biological activities bearing antipyrinyl nucleus as pharmacophore. Eur J Med Chem. 2020;186:111911.
[4] Tripathy R, McHugh RJ, Ghose AK, Ott GR, Angeles TS, Albom MS, Huang Z, Aimone LD, Cheng M, Dorsey BD. Pyrazolone-based anaplastic lymphoma kinase (ALK) inhibitors: control of selectivity by a benzyloxy group. Bioorg Med Chem Lett. 2011;21(24):7261-4.
[5] Gu W, Dai Y, Qiang H, Shi W, Liao C, Zhao F, Huang W, Qian H. Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors. Bioorg Chem. 2017;72:116-122.
[6] Norman MH, Liu L, Lee M, Xi N, Fellows I, D'Angelo ND, Dominguez C, Rex K, Bellon SF, Kim TS, Dussault I. Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives. J Med Chem. 2012;55(5):1858-67.
[7] Zhou S, Ren J, Liu M, Ren L, Liu Y, Gong P. Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents. Bioorg Chem. 2014;57:30-42.
[8] Mahajan SS, Scian M, Sripathy S, Posakony J, Lao U, Loe TK, Leko V, Thalhofer A, Schuler AD, Bedalov A, Simon JA. Development of pyrazolone and isoxazol-5-one cambinol analogues as sirtuin inhibitors. J Med Chem. 2014;57(8):3283-94.
[9] Marković V, Erić S, Stanojković T, Gligorijević N, Aranđelović S, Todorović N, Trifunović S, Manojlović N, Jelić R, Joksović MD. Antiproliferative activity and QSAR studies of a series of new 4-aminomethylidene derivatives of some pyrazol-5-ones. Bioorg Med Chem Lett. 2011;21(15):4416-21.
[10] Zhang M, Xie ZF, Zhang RT, Chen DK, Gu M, Cui SC, Zhang YM, Zhang XW, Yu YY, Li J, Nan FJ, Li JY. Novel substituted pyrazolone derivatives as AMP-activated protein kinase activators to inhibit lipid synthesis and reduce lipid accumulation in ob/ob mice. Acta Pharmacol Sin. 2018;39(10):1622-1632.
[11] Eldebss TMA, Farag AM, Abdalla MM, Khedr AA. Synthesis of some new pyrazolone-based heterocycles con-taining sulphone moiety acting as α-glucosidase and α-amylase inhibitors. J Heterocycl Chem. 2019; 56(3):765–80.
[12] Kirsch P, Hartman AM, Hirsch AKH, Empting M. Concepts and Core Principles of Fragment-Based Drug Design. Molecules. 2019;24(23):4309.
[13] Rao PP, Kabir SN, Mohamed T. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development. Pharmaceuticals (Basel). 2010;3(5):1530-1549.
[14] Zimenkovsky B, Lesyk R, Vladzimirska O, Nektegayev I, Golota S, Chorniy I. The structure - anti-inflammatory activity relationship among thiazolidones: Conclusion from scientific programme. J Pharm Pharmacol. 1999; 51:264.
[15] Lesyk R, Vladzimirska O, Zimenkovsky B, Golota S, Nektgayev I, Cherpak O, Leb'yak M, Kozak O. Synthesis and antiinflammatory activity of novel 3-(2,3-dimethyl-1-phenyl-4-pyrazolon-5-yl)-4-thiazolidones. Boll Chim Farm. 2002;141(3):197-201.
[16] Golota SM, Danylyuk KE, Yushchenko TI, Voloshchuk NI, Bilyk OV, Lesyk RB. The synthesis of 4-thiazolidinone derivatives using 2-(4-R-2-formylphenoxy)-N-(R’-phenyl)acetamides and their anti-inflammatory activity. J Org Pharm Chem. 2015; 3(51):15–20.
[17] Holota SM, Derkach HO, Demchuk IL, Vynnytska RB, Antoniv OI, Furdychko LO, Slyvka N Yu, Nektegayev IO, Lesyk RB. Synthesis and in vivo evaluation of pyrazoline-thiazolidin-4-one hybrid Les-5581 as a potential non-steroidal anti-inflammatory agent. Biopolym Cell. 2019; 35(6):437–47.
[18] 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.
[19] 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.
[20] Cherkas A, Golota S, Guéraud F, Abrahamovych O, Pichler C, Nersesyan A, Krupak V, Bugiichyk V, Yatskevych O, Pliatsko M, Eckl P, Knasmüller S. A Helicobacter pylori-associated insulin resistance in asymptomatic sedentary young men does not correlate with inflammatory markers and urine levels of 8-iso-PGF2-α or 1,4-dihydroxynonane mercapturic acid. Arch Physiol Biochem. 2018;124(3):275-285.
[21] Cherkas A, Abrahamovych O, Golota S, Nersesyan A, Pichler C, Serhiyenko V, Knasmüller S, Zarkovic N, Eckl P. The correlations of glycated hemoglobin and carbohydrate metabolism parameters with heart rate variability in apparently healthy sedentary young male subjects. Redox Biol. 2015;5:301-307.
[22] Cherkas A, Holota S, Mdzinarashvili T, Gabbianelli R, Zarkovic N. Glucose as a Major Antioxidant: When, What for and Why It Fails? Antioxidants (Basel). 2020;9(2):140.
[23] Lal N, Kumar J, Erdahl WE, Pfeiffer DR, Gadd ME, Graff G, Yanni JM. Differential effects of non-steroidal anti-inflammatory drugs on mitochondrial dysfunction during oxidative stress. Arch Biochem Biophys. 2009;490(1):1-8.
[24] Hussain T, Tan B, Yin Y, Blachier F, Tossou MC, Rahu N. Oxidative Stress and Inflammation: What Polyphenols Can Do for Us? Oxid Med Cell Longev. 2016;2016:7432797.
[25] Schadich E, Kryshchyshyn-Dylevych A, Holota S, Polishchuk P, Džubak P, Gurska S, Hajduch M, Lesyk R. Assessing different thiazolidine and thiazole based compounds as antileishmanial scaffolds. Bioorg Med Chem Lett. 2020;30(23):127616.
[26] 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.
[27] Holota SM, Derkach GO, Zasidko VV, Trokhymchuk VV, Furdychko LO, Demchuk IL, Semenciv GM, Soronovych II, Kutsyk RV, Lesyk RB. Features of antimicrobial activity of some 5-aminomethylene-2-thioxo-4-thiazolidinones. Biopolym Cell. 2019;35(5):371–80.
[28] Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 1991;83(11):757-66.
[29] Boyd MR, Paull KD. Some practical considerations and applications of the national cancer institute in vitro anti-cancer drug discovery screen. Drug Dev Res. 1995;34(2):91–109.
[30] Winter CA, Risley EA, Nuss GW. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc Soc Exp Biol Med. 1962;111:544-7.
[31] Stefanov OV. [Doklinichni doslidzhennya likarskyh zasobiv: Metodychni rekomendatsii]. Kyiv: 2001; 528 p.
[32] 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.
[33] Wong RSY. Role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in Cancer Prevention and Cancer Promotion. Adv Pharmacol Sci. 2019;2019:3418975.
[34] Zappavigna S, Cossu AM, Grimaldi A, Bocchetti M, Ferraro GA, Nicoletti GF, Filosa R, Caraglia M. Anti-Inflammatory Drugs as Anticancer Agents. Int J Mol Sci. 2020;21(7):2605.
[35] Elattar KM, Fadda AA. Chemistry of antipyrine. Synth Comm. 2016;46(19): 1567–94.
[36] Liaras K, Fesatidou M, Geronikaki A. Thiazoles and Thiazolidinones as COX/LOX Inhibitors. Molecules. 2018;23(3):685.
[37] Panico A, Maccari R, Cardile V, Avondo S, Crascì L, Ottanà R. Evaluation of the an-ti-inflammatory/chondroprotective activity of aldose reductase inhibitors in human chondrocyte cultures. MedChemComm. 2015;6(5):823–30.
[38] Chatzopoulou M, Pegklidou K, Papastavrou N, Demopoulos VJ. Development of aldose reductase inhibitors for the treatment of inflammatory disorders. Expert Opin Drug Discov. 2013;8(11):1365-80.