Synthesis and Biological Evaluation of Polyfluoroalkylated Antipyrines and their Isomeric O-Methylpyrazoles

Author(s): Natalya Agafonova, Evgeny Shchegolkov*, Yanina Burgart, Victor Saloutin, Alexandra Trefilova, Galina Triandafilova, Sergey Solodnikov, Vera Maslova, Olga Krasnykh, Sophia Borisevich, Sergey Khursan

Journal Name: Medicinal Chemistry

Volume 15 , Issue 5 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices.

Objective: Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds.

Methods: In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, “open field” test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2.

Results: We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo.

Conclusion: The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties.

Keywords: Methylation, 1H-pyrazol-5-ols, polyfluoroalkyl-containing antipyrine, analgesic and anti-inflammatory activities, toxicity, permeability, molecular docking, COX-1/2 inhibitor.

Brune, K. The early history of non-opioid Analgesics. Acute Pain, 1997, 1(1), 33-40.
Aronson, J.K. Meyler’s Side Effects of Analgesics and Anti-Inflammatory Drugs; ,Elsevier Science B.V: The Netherland, Amsterdam;. , 2009.
Bruera, E.D.; Portenoy, R.K. Cancer Pain: Assessment and Management; Cambridge University Press: New York, USA, 2009.
Jasiecka, A.; Maślanka, T.; Jaroszewski, J.J. Pharmacological characteristics of Metamizole. Pol. J. Vet. Sci., 2014, 17(1), 207-214.
Kötter, T.; da Costa, B.R.; Fässler, M.; Blozik, E.; Linde, K.; Jüni, P.; Reichenbach, S.; Scherer, M. Metamizole-associated adverse events: A systematic review and meta-analysis. PLoS One, 2015, 10(4)e0122918
Tesfa, D.; Keisu, M.; Palmblad, J. Idiosyncratic drug-induced Agranulocytosis: Possible mechanisms and management. Am. J. Hematol., 2009, 84(7), 428-434.
Watanabe, T.; Tahara, M.; Todo, S. The novel antioxidant Edaravone: From bench to bedside. Cardiovasc. Ther., 2008, 26(2), 101-114.
Kikuchi, K.; Miura, N.; Kawahara, K-I.; Murai, Y.; Morioka, M.; Lapchak, P.A.; Tanaka, E. Edaravone (Radicut), a free radical scavenger, is a potentially useful addition to Thrombolytic therapy in patients with acute ischemic stroke. Biomed. Rep., 2013, 1(1), 7-12.
Sawada, H. Clinical efficacy of Edaravone for the treatment of Amyotrophic Lateral Sclerosis. Expert Opin. Pharmacother., 2017, 18(7), 735-738.
Pierre, S.C.; Schmidt, R.; Brenneis, C.; Michaelis, M.; Geisslinger, G.; Scholich, K. Inhibition of Cyclooxygenases by Dipyrone. Br. J. Pharmacol., 2009, 151(4), 494-503.
Rogosch, T.; Sinning, C.; Podlewski, A.; Watzer, B.; Schlosburg, J.; Lichtman, A.H.; Cascio, M.G.; Bisogno, T.; Di Marzo, V.; Nüsing, R.; Imming, P. Novel bioactive metabolites of Dipyrone (Metamizol). Bioorg. Med. Chem., 2012, 20(1), 101-107.
Nassini, R.; Fusi, C.; Materazzi, S.; Coppi, E.; Tuccinardi, T.; Marone, I.M.; De Logu, F.; Preti, D.; Tonello, R.; Chiarugi, A.; Patacchini, R.; Geppetti, P.; Benemei, S. The TRPA1 channel mediates the analgesic action of Dipyrone and Pyrazolone derivatives. Br. J. Pharmacol., 2015, 172(13), 3397-3411.
Uramaru, N.; Shigematsu, H.; Toda, A.; Eyanagi, R.; Kitamura, S.; Ohta, S. Design, synthesis, and pharmacological activity of nonallergenic Pyrazolone-type antipyretic analgesics. J. Med. Chem., 2010, 53(24), 8727-8733.
Radwan, M.F.; Dalby, K.N.; Kaoud, T.S. Propyphenazone-based analogues as prodrugs and selective Cyclooxygenase-2 inhibitors. ACS Med. Chem. Lett., 2014, 5(9), 983-988.
Clark, M.P.; Laughlin, S.K.; Laufersweiler, M.J.; Bookland, R.G.; Brugel, T.A.; Golebiowski, A.; Sabat, M.P.; Townes, J.A.; VanRens, J.C.; Djung, J.F.; Natchus, M.G.; De, B.; Hsieh, L.C.; Xu, S.C.; Walter, R.L.; Mekel, M.J.; Heitmeyer, S.A.; Brown, K.K.; Juergens, K.; Taiwo, Y.O.; Janusz, M.J. Development of orally bioavailable bicyclic Pyrazolones as inhibitors of tumor necrosis factor-α production. J. Med. Chem., 2004, 47(11), 2724-2727.
Liu, L.; Siegmund, A.; Xi, N.; Kaplan-Lefko, P.; Rex, K.; Chen, A.; Lin, J.; Moriguchi, J.; Berry, L.; Huang, L.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S.F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.; Norman, M.H.; Harmange, J-C.; Dussault, I.; Kim, T-S. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-Hydroxy-2-Methylpropyl)- N -(5-(7-Methoxyquinolin-4-Yloxy)Pyridin-2-Yl)-5-Methyl-3-Oxo-2-Phenyl-2,3-Dihydro-1 H -Pyrazole-4-Carboxamide (AMG 458). J. Med. Chem., 2008, 51(13), 3688-3691.
Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J.L.; Soloshonok, V.A.; Izawa, K.; Liu, H. Next generation of Fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: New structural trends and therapeutic areas. Chem. Rev., 2016, 116(2), 422-518.
Hiyama, T.; Yamamoto, H. In Organofluorine Compounds; Springer Berlin Heidelberg: Berlin, Heidelberg, Biologically Active Organofluorine Compounds. , 2000, pp. 137-182.
Fluorine in Medicinal Chemistry and Chemical Biology; Ojima, I., Ed.; Wiley-Blackwell: West Sussex, UK, 2009.
Isanbor, C.; O’Hagan, D. Fluorine in medicinal chemistry: A review of anti-cancer agents. J. Fluor. Chem., 2006, 127(3), 303-319.
Bégué, J-P.; Bonnet-Delpon, D. Recent advances (1995-2005) in fluorinated pharmaceuticals based on natural products. J. Fluor. Chem., 2006, 127(8), 992-1012.
Kirk, K.L. Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules. J. Fluor. Chem., 2006, 127(8), 1013-1029.
Hagmann, W.K. The many roles for fluorine in medicinal chemistry. J. Med. Chem., 2008, 51(15), 4359-4369.
O’Hagan, D. Fluorine in health care: Organofluorine containing blockbuster drugs. J. Fluor. Chem., 2010, 131(11), 1071-1081.
Kirsch, P. Modern Fluoroorganic.Chemistry Synthesis, Reactivity, Applications; WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 2004.
Evans, T.A.; Seddon, K.R. Hydrogen bonding in DNA-a return to the status quo. Chem. Commun., 1997, 21, 2023-2024.
Meyer, E.A.; Castellano, R.K.; Diederich, F. Interactions with aromatic rings in chemical and biological recognition. Angew. Chem. Int. Ed., 2003, 42(11), 1210-1250.
Shchegol’kov, E.V.; Shchur, I.V.; Burgart, Y.V.; Saloutin, V.I.; Trefilova, A.N.; Ljushina, G.A.; Solodnikov, S.Y.; Markova, L.N.; Maslova, V.V.; Krasnykh, O.P.; Borisevich, S.S.; Khursan, S.L. Polyfluorinated Salicylic acid derivatives as analogs of known drugs: Synthesis, molecular docking and biological evaluation. Bioorg. Med. Chem., 2017, 25(1), 91-99.
Djuric, S.W. BaMaung, N.Y.; Basha, A.; Liu, H.; Luly, J.R.; Madar, D.J.; Sciotti, R.J.; Tu, N.P.; Wagenaar, F.L.; Wiedeman, P.E.; Zhou X.; Ballaron S.; Bauch J.; Chen Y.-W.; Chiou X.G.; Fey, T.; Gauvin, D.; Gubbins, E.; Hsieh, G.C.; Marsh, K.C.; Mollison, K.W.; Pong, M.; Shaughnessy, T.K.; Sheets, M.P.; Smith, M.; Trevillyan, J.M.; Warrior, U.; Wegner, C.D.; Carter, G.W. 3,5-Bis(Trifluoromethyl)Pyrazoles: A novel class of NFAT transcription factor regulator. J. Med. Chem., 2000, 43(16), 2975-2981.
Jansson, R.; Bredberg, U.; Ashton, M. Prediction of drug tissue to plasma concentration ratios using a measured volume of distribution in combination with lipophilicity. J. Pharm. Sci., 2008, 97(6), 2324-2339.
Cox, S.R.; Lesman, S.P.; Boucher, J.F.; Krautmann, M.J.; Hummel, B.D.; Savides, M.; Marsh, S.; Fielder, A.; Stegemann, M.R. The pharmacokinetics of Mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs. J. Vet. Pharmacol. Ther., 2010, 33(5), 461-470.
Sheldrick, G.M. Programs for Crystal Structure Solution and Refinement. SHELXS 97 and SHELXL 97; University of Göttingen: Germany, 1997.
Vogel, H.G. Drug Discovery and Evaluation: Pharmacological Assays; Springer-Verlag: Berlin, Heidelberg, New York, 2008.
Mironov, A.N. Guidelines for Pre-Clinical Study of Medicinal Products. Part One.(in Russian); Grif&Ko: Moscow, 2012.
Kallina, C. Tail-flick test I: Impact of a suprathreshold exposure to radiant heat on pain reactivity in rats. Physiol. Behav., 1995, 58(1), 161-168.
Gainok, J.; Daniels, R.; Golembiowski, D.; Kindred, P.; Post, L.; Strickland, R.; Garrett, N. Investigation of the anti-inflammatory, antinociceptive effect of Ellagic acid as measured by digital paw pressure via the Randall-Selitto meter in male Sprague-Dawley rats. AANA J., 2011, 79(4), S28-S34.
Puig, C.; Crespo, M.I.; Godessart, N.; Feixas, J.; Ibarzo, J.; Jiménez, J-M.; Soca, L.; Cardelús, I.; Heredia, A.; Miralpeix, M.; Puig, J.; Beleta, J.; Huerta, J.M.; López, M.; Segarra, V.; Ryder, H.; Palacios, J.M. Synthesis and biological evaluation of 3,4-Diaryloxazolones: A new class of orally active Cyclooxygenase-2 inhibitors. J. Med. Chem., 2000, 43(2), 214-223.
Pasin, J.S.M.; Ferreira, A.P.O.; Saraiva, A.L.L.; Ratzlaff, V.; Andrighetto, R.; Machado, P.; Marchesan, S.; Zanette, R.A.; Bonacorso, H.G.; Zanatta, N.; Martins, M.A.P.; Ferreira, J.; Mello, C.F. Antipyretic and antioxidant activities of 5-Trifluoromethyl-4,5-Dihydro-1H-Pyrazoles in rats. Braz. J. Med. Biol. Res., 2010, 43(12), 1193-1202.
Hall, C.S. Emotional behavior in the rat. III. The relationship between emotionality and ambulatory activity. J. Comp. Psychol., 1936, 22(3), 345-352.
Gould, T.D.; Dao, D.T.; Kovacsics, C.E. The Open Field Test.In:Mood and Anxiety Related Phenotypes in Mice. Neuromethods; Gould, T., Ed.; Humana Press: Totowa, NJ, 2009, Vol. 42, pp. 1-20.
OECD Guideline 423: Acute Oral Toxicity. Paris: OECD 1996.
Saloutin, V.I.; Fomin, A.N.; Pashkevich, K.I. Reaction of fluorinecontaining B-ketoesters with bifunctional N-nucleophiles. Bull. Acad. Sci. USSR. Div. Chem. Sci., 1985, 34(1), 135-141.
Al-Mutairi, A.A.; El-Baih, F.E.M.; Al-Hazimi, H.M. Microwave versus ultrasound assisted synthesis of some new heterocycles based on Pyrazolone Moiety. J. Saudi Chem. Soc., 2010, 14(3), 287-299.
Hamper, B.C.; Kurtzweil, M.L.; Beck, J.P. Cyclocondensation of alkylhydrazines and beta-substituted acetylenic esters: Synthesis of 3-Hydroxypyrazoles. J. Org. Chem., 1992, 57(21), 5680-5686.
Chen, Z-P.; Chen, M-W.; Shi, L.; Yu, C-B.; Zhou, Y-G. Pd-catalyzed asymmetric hydrogenation of fluorinated aromatic Pyrazol-5-Ols via capture of active tautomers. Chem. Sci., 2015, 6(6), 3415-3419.
Nemytova, N.A.; Shchegol’kov, E.V.; Burgart, Y.V.; Slepukhin, P.A.; Borisevich, S.S.; Khursan, S.L.; Saloutin, V.I. Regiocontrolled N-,O- and C-Methylation of 1-Phenyl-3-Polyfluoroalkyl-1H-Pyrazol-5-ols. J. Fluor. Chem., 2018, 206, 72-81.
Grillot, G.; Aftergut, S.; Botteron, D. Notes - Trifluoroantipyrene. J. Org. Chem., 1958, 23(1), 119-120.
Amrein, K.; Hunziker, D.; Kuhn, B.; Mayweg, A.; Neidhart, W. New pyrazolones as 11b-HSD1 inhibitors for diabetes. Patent US Patent 2,007,049,574, March 01 2007.
Volz, M.; Kellner, H. Kinetics and metabolism of Pyrazolones (propyphenazone, aminopyrine and dipyrone). Br. J. Clin. Pharmacol., 1980, 10(S2), 299S-308S.
Ariza, A.; García-Martín, E.; Salas, M.; Montañez, M.I.; Mayorga, C.; Blanca-Lopez, N.; Andreu, I.; Perkins, J.; Blanca, M.; Agúndez, J.A.G.; Torres, M.J. Pyrazolones metabolites are relevant for identifying selective Anaphylaxis to Metamizole. Sci. Rep., 2016, 6(1), 23845.
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
Mirza, A.; Desai, R.; Reynisson, J. Known drug space as a metric in exploring the boundaries of drug-like chemical space. Eur. J. Med. Chem., 2009, 44(12), 5006-5011.
Small-Molecule Drug Discovery Suite 2017-4, Schrödinger, LLC, New York, NY. 2017.
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 1997, 23(1-3), 3-25.
Congreve, M.; Carr, R.; Murray, C.; Jhoti, H.A. ‘Rule of Three’ for fragment-based lead discovery? Drug Discov. Today, 2003, 8(19), 876-877.
Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: Parallel artificial membrane permeation assay in the description of passive absorption processes. J. Med. Chem., 1998, 41(7), 1007-1010.
Ruell, J.A.; Avdeef, A. Absorption Screening Using the PAMPA Approach.In Optimization in Drug Discovery; Yan, Z.; Caldwell, G.W., Eds.; Humana Press: Totowa, NJ, 2004, pp. 37-64.
Barnes-Seeman, D.; Beck, J.; Springer, C. Fluorinated compounds in medicinal chemistry: Recent applications, synthetic advances and matched-pair analyses. Curr. Top. Med. Chem., 2014, 14(7), 855-864.
Gein, V.L.; Popov, A.V.; Kolla, V.E.; Popova, N.A.; Potemkin, K.D. Synthesis and biological activity of 1,5-Diaryl-3-Arylamino-4-Carboxymethyl-2,5-Dihydro-2-Pyrrolones and 1,5-Diaryl-4-Carboxymethyltetrahydropyrrole-2,3-Diones. Pharm. Chem. J., 1993, 27(5), 343-346.
Endel’man, E.S.; Fadeicheva, A.G.; Fialkov, Y.A.; Danilenko, V.S.; Trinus, F.P.; Chernoshtan, K.A.; Yagupol’skii, L.M. Synthesis and study of the biological properties of fluorinated derivatives of 1-Phenyl-3-Methylpyrazol-5-One. Antipyrine analogs with heteroatomic fluorine-containing substituents. Khim. Farm. Zh., 1976, 10(12), 27.
Piskarev, A.V.; Nesterenko, V.S.; Suminov, S.I. Effect of Pyrazolone and Hydrazine derivatives on the resistance of mice to hypoxia. Farmakol. Toksikol., 1973, 36(1), 48-54.
On Circulation of Medicines. Federal Law of 12.04.2010.№61-FZ RF. [
Lu, Z.; Xiong, X.; Zhang, B.; Lin, G.; Shi, Y.; Liu, Z.; Meng, J.; Zhou, Y.; Mei, Q. Evaluation of 2 Celecoxib derivatives: Analgesic effect and selectivity to cyclooxygenase-2/11. Acta Pharmacol. Sin., 2005, 26(12), 1505-1511.
Romer, D. Pharmacological evaluation of mild analgesics. Br. J. Clin. Pharmacol., 1980, 10(S2), 247S-251S.
Buccafusco, J.J. Methods of Behavior Analysis in Neuroscience, 2nd Edition; CRC Press, Taylor & Francis: Boca Rato, FL, 2009.
Campos, C.; de Gregorio, R.; García-Nieto, R.; Gago, F.; Ortiz, P.; Alemany, S. Regulation of Cyclooxygenase activity by Metamizol. Eur. J. Pharmacol., 1999, 378(3), 339-347.
Nishiyama, T.; Ogawa, M. Intrathecal Edaravone, a free radical scavenger, is effective on inflammatory-induced pain in rats. Acta Anaesthesiol. Scand., 2005, 49(2), 147-151.
Mao, Y-F.; Yan, N.; Xu, H.; Sun, J-H.; Xiong, Y-C.; Deng, X-M. Edaravone, a free radical scavenger, is effective on neuropathic pain in rats. Brain Res., 2009, 1248, 68-75.
Nantel, F.; Denis, D.; Gordon, R.; Northey, A.; Cirino, M.; Metters, K.M.; Chan, C.C. Distribution and regulation of Cyclooxygenase-2 in Carrageenan-induced inflammation. Br. J. Pharmacol., 1999, 128(4), 853-859.
Guay, J.; Bateman, K.; Gordon, R.; Mancini, J.; Riendeau, D. Carrageenan-induced paw edema in rat elicits a predominant prostaglandin E 2 (PGE 2) response in the central nervous system associated with the induction of microsomal PGE 2 synthase-1. J. Biol. Chem., 2004, 279(23), 24866-24872.
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28(1), 235-242.
Sidhu, R.S.; Lee, J.Y.; Yuan, C.; Smith, W.L. Comparison of Cyclooxygenase-1 crystal structures: Cross-talk between monomers comprising Cyclooxygenase-1 homodimers. Biochemistry, 2010, 49(33), 7069-7079.
Wang, J.L.; Limburg, D.; Graneto, M.J.; Springer, J.; Hamper, J.R.B.; Liao, S.; Pawlitz, J.L.; Kurumbail, R.G.; Maziasz, T.; Talley, J.J.; Kiefer, J.R.; Carter, J. The novel benzopyran class of selective Cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life. Bioorg. Med. Chem. Lett., 2010, 20(23), 7159-7163.
Smith, C.J.; Zhang, Y.; Koboldt, C.M.; Muhammad, J.; Zweifel, B.S.; Shaffer, A.; Talley, J.J.; Masferrer, J.L.; Seibert, K.; Isakson, P.C. Pharmacological analysis of Cyclooxygenase-1 in inflammation. Proc. Natl. Acad. Sci., 1998, 95(22), 13313-13318.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [521 - 536]
Pages: 16
DOI: 10.2174/1573406414666181106145435
Price: $65

Article Metrics

PDF: 31