Skip to main content

Synthesis and evaluation of analgesic, anti-inflammatory, and anticancer activities of new pyrazole-3(5)-carboxylic acid derivatives

Abstract

In this article, we synthesized a series of novel 1-benzyl-5(3)-p-tolyl-1H-pyrazole-3(5)-carboxylic acid derivatives and characterized by IR, 1H NMR, and mass spectroscopy. Compounds were evaluated for their in vivo analgesic and anti-inflammatory activity using the p-benzoquinone-induced writhing test and the carrageenan-induced paw edema model, respectively. Out of 14 compounds tested, 7a, 7c, 7e, 7f, 7i, 8ab, and 8fg exhibited potent analgesic and/or anti-inflammatory activity as compared to reference drugs aspirin and indomethacin. Anticancer activity of these compounds was assessed against five cancer cell lines with the MTT assay (HL-60, human promyelocytic leukemia cells; HeLa, human cervical cancer cells; Raji, human B lymphocyte cell line; MCF7, human breast adenocarcinoma cell line; MDA-MB-231, estrogen-independent human breast cancer cell line). Compounds 7a, 8a, and 8b with high anti-inflammatory activity, and also 7d and 7j with mild anti-inflammatory activity exhibited promising anticancer activity against some selected cell lines.

This is a preview of subscription content, access via your institution.

Scheme 1

References

  1. Agrawal A, Fentiman IS (2008) NSAIDs and breast cancer: a possible prevention and treatment strategy. Int J Clin Pract 62(3):444–449. doi:10.1111/j.1742-1241.2007.01668.x

    PubMed  Article  CAS  Google Scholar 

  2. Baker AK, Hoffmann VL, Meert TF (2002) Dextromethorphan and ketamine potentiate the antinociceptive effects of mu- but not delta- or kappa-opioid agonists in a mouse model of acute pain. Pharmacol Biochem Behav 74(1):73–86

    PubMed  Article  CAS  Google Scholar 

  3. Banoglu E, Okcelik B, Kupeli E, Unlu S, Yesilada E, Amat M, Caturla JF, Sahin MF (2003) Amide derivatives of [5-chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic acids as potential analgesic and anti-inflammatory compounds. Arch Pharm (Weinheim) 336(4–5):251–257. doi:10.1002/ardp.200300723

    Article  CAS  Google Scholar 

  4. Banoglu E, Akoglu C, Unlu S, Kupeli E, Yesilada E, Sahin MF (2004) Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compounds. Arch Pharm (Weinheim) 337(1):7–14. doi:10.1002/ardp.200200738

    Article  CAS  Google Scholar 

  5. Banoglu E, Akoglu C, Unlu S, Ergun BC, Kupeli E, Yesilada E, Sahin MF (2005) Synthesis of amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl] acetic acid and their analgesic and anti-inflammatory properties. Arzneimittelforschung 55(9):520–527

    PubMed  CAS  Google Scholar 

  6. Barthel HR, Axford-Gatley RA (2010) Topical nonsteroidal anti-inflammatory drugs for osteoarthritis. Postgrad Med 122(6):98–106. doi:10.3810/pgm.2010.11.2227

    PubMed  Article  Google Scholar 

  7. Bekhit AA, Hymete A, El-Din ABA, Damtew A, Aboul-Enein HY (2010) Pyrazoles as promising scaffold for the synthesis of anti-inflammatory and/or antimicrobial agent: a review. Mini Rev Med Chem 10(11):1014–1033

    PubMed  Article  CAS  Google Scholar 

  8. Bhalke RD, Chavan MJ (2011) Analgesic and CNS depressant activities of extracts of Annona reticulata Linn bark. Phytopharmacology 1(5):160–165

    Google Scholar 

  9. Caliskan B, Luderer S, Ozkan Y, Werz O, Banoglu E (2011) Pyrazol-3-propanoic acid derivatives as novel inhibitors of leukotriene biosynthesis in human neutrophils. Eur J Med Chem 46(10):5021–5033. doi:10.1016/j.ejmech.2011.08.009

    PubMed  Article  CAS  Google Scholar 

  10. Chao SH, Wu AB, Lee CJ, Chen FA, Wang CC (2005) Anti-inflammatory effects of indomethacin’s methyl ester derivative and induction of apoptosis in HL-60 Cells. Biol Pharm Bull 28(12):2206–2210

    PubMed  Article  CAS  Google Scholar 

  11. Charo IF, Taub R (2011) Anti-inflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov 10(5):365–376. doi:10.1038/nrd3444

    PubMed  Article  CAS  Google Scholar 

  12. Claria J, Romano M (2005) Pharmacological intervention of cyclooxygenase-2 and 5-lipoxygenase pathways. Impact on inflammation and cancer. Curr Pharm Des 11(26):3431–3447

    PubMed  Article  CAS  Google Scholar 

  13. Ding XL, Zhang HY, Qi L, Zhao BX, Lian S, Lv HS, Miao JY (2009) Synthesis of novel pyrazole carboxamide derivatives and discovery of modulators for apoptosis or autophagy in A549 lung cancer cells. Bioorg Med Chem Lett 19(18):5325–5328. doi:10.1016/j.bmcl.2009.07.131

    PubMed  Article  CAS  Google Scholar 

  14. Ergun BC, Nunez MT, Labeaga L, Ledo F, Darlington J, Bain G, Cakir B, Banoglu E (2010) Synthesis of 1,5-diarylpyrazol-3-propanoic acids towards inhibition of cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4 formation. Arzneimittelforschung 60(8):497–505

    PubMed  CAS  Google Scholar 

  15. Farag AM, Ali KA, El-Debss TM, Mayhoub AS, Amr AG, Abdel-Hafez NA, Abdulla MM (2010) Design, synthesis and structure-activity relationship study of novel pyrazole-based heterocycles as potential antitumor agents. Eur J Med Chem 45(12):5887–5898. doi:10.1016/j.ejmech.2010.09.054

    PubMed  Article  CAS  Google Scholar 

  16. Fischer SM, Hawk ET, Lubet RA (2011) Coxibs and other nonsteroidal anti-inflammatory drugs in animal models of cancer chemoprevention. Cancer Prev Res (Phila) 4(11):1728–1735. doi:10.1158/1940-6207.CAPR-11-0166

    Article  CAS  Google Scholar 

  17. Ghosh J, Myers CE (1997) Arachidonic acid stimulates prostate cancer cell growth: critical role of 5-lipoxygenase. Biochem Biophys Res Commun 235(2):418–423. doi:10.1006/bbrc.1997.6799

    PubMed  Article  CAS  Google Scholar 

  18. Ghosh J, Myers CE (1998) Inhibition of arachidonate 5-lipoxygenase triggers massive apoptosis in human prostate cancer cells. Proc Natl Acad Sci USA 95(22):13182–13187

    PubMed  Article  CAS  Google Scholar 

  19. Greenhough A, Smartt HJ, Moore AE, Roberts HR, Williams AC, Paraskeva C, Kaidi A (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis 30(3):377–386. doi:10.1093/carcin/bgp014

    PubMed  Article  CAS  Google Scholar 

  20. Grossman EM, Longo WE, Panesar N, Mazuski JE, Kaminski DL (2000) The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells. Carcinogenesis 21(7):1403–1409

    PubMed  Article  CAS  Google Scholar 

  21. Gupta LK, Bansal U, Chandra S (2007) Spectroscopic and physicochemical studies on nickel(II) complexes of isatin-3,2′-quinolyl-hydrazones and their adducts. Spectrochim Acta A 66:972–975

    Article  Google Scholar 

  22. Heneka MT, Kummer MP, Weggen S, Bulic B, Multhaup G, Munter L, Hull M, Pflanzner T, Pietrzik CU (2011) Molecular mechanisms and therapeutic application of NSAIDs and derived compounds in Alzheimer’s disease. Curr Alzheimer Res 8(2):115–131

    PubMed  Article  CAS  Google Scholar 

  23. Kasahara Y, Hikino H, Tsurufuji S, Watanabe M, Ohuchi K (1985) Antiinflammatory actions of ephedrines in acute inflammations1. Planta Med 51(4):325–331. doi:10.1055/s-2007-969503

    PubMed  Article  CAS  Google Scholar 

  24. Keter FK, Darkwa J (2011) Perspective: the potential of pyrazole-based compounds in medicine. Biometals. doi:10.1007/s10534-011-9496-4

  25. Kupeli E, Tatli II, Akdemir ZS, Yesilada E (2007) Estimation of antinociceptive and anti-inflammatory activity on Geranium pratense subsp. finitimum and its phenolic compounds. J Ethnopharmacol 114(2):234–240

    PubMed  Article  Google Scholar 

  26. Lian S, Su H, Zhao BX, Liu WY, Zheng LW, Miao JY (2009) Synthesis and discovery of pyrazole-5-carbohydrazide N-glycosides as inducer of autophagy in A549 lung cancer cells. Bioorg Med Chem 17(20):7085–7092. doi:10.1016/j.bmc.2009.09.004

    PubMed  Article  CAS  Google Scholar 

  27. Liu XH, Rose DP (1996) Differential expression and regulation of cyclooxygenase-1 and -2 in two human breast cancer cell lines. Cancer Res 56(22):5125–5127

    PubMed  CAS  Google Scholar 

  28. Liu W, Zhou J, Bensdorf K, Zhang H, Liu H, Wang Y, Qian H, Zhang Y, Wellner A, Rubner G, Huang W, Guo C, Gust R (2011) Investigations on cytotoxicity and anti-inflammatory potency of licofelone derivatives. Eur J Med Chem 46(3):907–913. doi:10.1016/j.ejmech.2011.01.002

    PubMed  Article  CAS  Google Scholar 

  29. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454(7203):436–444. doi:10.1038/nature07205

    PubMed  Article  CAS  Google Scholar 

  30. Maurin C, Bailly F, Cotelle P (2004) Improved preparation and structural investigation of 4-aryl-4-oxo-2-hydroxy-2-butenoic acids and methyl esters. Tetrahedron 60(31):6479–6486

    Article  CAS  Google Scholar 

  31. Muller-Decker K, Kopp-Schneider A, Marks F, Seibert K, Furstenberger G (1998) Localization of prostaglandin H synthase isoenzymes in murine epidermal tumors: suppression of skin tumor promotion by inhibition of prostaglandin H synthase-2. Mol Carcinog 23(1):36–44. doi:10.1002/(SICI)1098-2744(199809)23:1<36:AID-MC5>3.0.CO;2-F

    PubMed  Article  CAS  Google Scholar 

  32. Nagarapu L, Mateti J, Gaikwad HK, Bantu R, Sheeba Rani M, Prameela Subhashini NJ (2011) Synthesis and anti-inflammatory activity of some novel 3-phenyl-N-[3-(4-phenylpiperazin-1yl)propyl]-1H-pyrazole-5-carboxamide derivatives. Bioorg Med Chem Lett 21(14):4138–4140. doi:10.1016/j.bmcl.2011.05.105

    PubMed  Article  CAS  Google Scholar 

  33. Nakanishi M, Gokhale V, Meuillet EJ, Rosenberg DW (2010) mPGES-1 as a target for cancer suppression: a comprehensive invited review “Phospholipase A2 and lipid mediators”. Biochimie 92(6):660–664. doi:10.1016/j.biochi.2010.02.006

    PubMed  Article  CAS  Google Scholar 

  34. Nitulescu GM, Draghici C, Missir AV (2010) Synthesis of new pyrazole derivatives and their anticancer evaluation. Eur J Med Chem 45(11):4914–4919. doi:10.1016/j.ejmech.2010.07.064

    PubMed  Article  CAS  Google Scholar 

  35. Okun R, Liddon SC, Lasagna L (1963) The effects of aggregation, electric shock, and adrenergic blocking drugs on inhibition of the “writhing syndrome”. J Pharmacol Exp Ther 139:107–109

    PubMed  CAS  Google Scholar 

  36. Pavao-de-Souza GF, Zarpelon AC, Tedeschi GC, Mizokami SS, Sanson JS, Cunha TM, Ferreira SH, Cunha FQ, Casagrande R, Verri WA Jr (2012) Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI(3)K and microglia in mice. Pharmacol Biochem Behav 101(3):320–328. doi:10.1016/j.pbb.2012.01.018

    PubMed  Article  CAS  Google Scholar 

  37. Pereg D, Lishner M (2005) Non-steroidal anti-inflammatory drugs for the prevention and treatment of cancer. J Intern Med 258(2):115–123. doi:10.1111/j.1365-2796.2005.01519.x

    PubMed  Article  CAS  Google Scholar 

  38. Radmark O, Samuelsson B (2010) Microsomal prostaglandin E synthase-1 and 5-lipoxygenase: potential drug targets in cancer. J Intern Med 268(1):5–14. doi:10.1111/j.1365-2796.2010.02246.x

    PubMed  CAS  Google Scholar 

  39. Romano M, Claria J (2003) Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 17(14):1986–1995. doi:10.1096/fj.03-0053rev

    PubMed  Article  CAS  Google Scholar 

  40. Sheng H, Shao J, Kirkland SC, Isakson P, Coffey RJ, Morrow J, Beauchamp RD, DuBois RN (1997) Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2. J Clin Invest 99(9):2254–2259. doi:10.1172/JCI119400

    PubMed  Article  CAS  Google Scholar 

  41. Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M (2010) The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 2010:215158. doi:10.1155/2010/215158

    PubMed  Google Scholar 

  42. Totzke G, Schulze-Osthoff K, Janicke RU (2003) Cyclooxygenase-2 (COX-2) inhibitors sensitize tumor cells specifically to death receptor-induced apoptosis independently of COX-2 inhibition. Oncogene 22(39):8021–8030. doi:10.1038/sj.onc.1206837

    PubMed  Article  Google Scholar 

  43. Verri WA Jr, Cunha TM, Magro DA, Domingues AC, Vieira SM, Souza GR, Liew FY, Ferreira SH, Cunha FQ (2008) Role of IL-18 in overt pain-like behaviour in mice. Eur J Pharmacol 588(2–3):207–212. doi:10.1016/j.ejphar.2008.04.010

    PubMed  Article  CAS  Google Scholar 

  44. Vinegar R, Schreiber W, Hugo R (1969) Biphasic development of carrageenin edema in rats. J Pharmacol Exp Ther 166(1):96–103

    PubMed  CAS  Google Scholar 

  45. Wang D, Dubois RN (2010) Eicosanoids and cancer. Nat Rev Cancer 10(3):181–193. doi:10.1038/nrc2809

    PubMed  Article  CAS  Google Scholar 

  46. Wei F, Zhao BX, Huang B, Zhang L, Sun CH, Dong WL, Shin DS, Miao JY (2006) Design, synthesis, and preliminary biological evaluation of novel ethyl 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate. Bioorg Med Chem Lett 16(24):6342–6347. doi:10.1016/j.bmcl.2006.09.008

    PubMed  Article  CAS  Google Scholar 

  47. Werz O, Schneider N, Brungs M, Sailer ER, Safayhi H, Ammon HP, Steinhilber D (1997) A test system for leukotriene synthesis inhibitors based on the in vitro differentiation of the human leukemic cell lines HL-60 and Mono Mac 6. Naunyn Schmiedebergs Arch Pharmacol 356(4):441–445

    PubMed  Article  CAS  Google Scholar 

  48. Wun T, McKnight H, Tuscano JM (2004) Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma. Leuk Res 28(2):179–190

    PubMed  Article  CAS  Google Scholar 

  49. Xia Y, Dong ZW, Zhao BX, Ge X, Meng N, Shin DS, Miao JY (2007) Synthesis and structure-activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives as potential agents against A549 lung cancer cells. Bioorg Med Chem 15(22):6893–6899. doi:10.1016/j.bmc.2007.08.021

    PubMed  Article  CAS  Google Scholar 

  50. Xia Y, Fan CD, Zhao BX, Zhao J, Shin DS, Miao JY (2008) Synthesis and structure-activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide hydrazone derivatives as potential agents against A549 lung cancer cells. Eur J Med Chem 43(11):2347–2353. doi:10.1016/j.ejmech.2008.01.021

    PubMed  Article  CAS  Google Scholar 

  51. Xie YS, Pan XH, Zhao BX, Liu JT, Shin DS, Zhang JH, Zheng LW, Zhao J, Miao JY (2008) Synthesis, structure characterization and preliminary biological evaluation of novel 5-alkyl-2-ferrocenyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives. J Organomet Chem 693(7):1367–1374

    Article  CAS  Google Scholar 

  52. Zheng LW, Wu LL, Zhao BX, Dong WL, Miao JY (2009) Synthesis of novel substituted pyrazole-5-carbohydrazide hydrazone derivatives and discovery of a potent apoptosis inducer in A549 lung cancer cells. Bioorg Med Chem 17(5):1957–1962. doi:10.1016/j.bmc.2009.01.037

    PubMed  Article  CAS  Google Scholar 

  53. Zheng LW, Li Y, Ge D, Zhao BX, Liu YR, Lv HS, Ding J, Miao JY (2010) Synthesis of novel oxime-containing pyrazole derivatives and discovery of regulators for apoptosis and autophagy in A549 lung cancer cells. Bioorg Med Chem Lett 20(16):4766–4770. doi:10.1016/j.bmcl.2010.06.121

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

This investigation was supported by a Scientific Research Grant 02/2010-20 awarded by Gazi University BAP. The authors greatly acknowledge D. A. Alkan (Department of Pharmacology) for her assistance for performing in vivo biological experiments. The authors report no conflicts of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Erden Banoglu.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Çalışkan, B., Yılmaz, A., Evren, İ. et al. Synthesis and evaluation of analgesic, anti-inflammatory, and anticancer activities of new pyrazole-3(5)-carboxylic acid derivatives. Med Chem Res 22, 782–793 (2013). https://doi.org/10.1007/s00044-012-0072-4

Download citation

Keywords

  • Carrageenan
  • Hind paw edema
  • Benzoquinone
  • Writhings
  • Cell lines