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Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d]pyridazine bearing 3,4,5-trimethoxyphenyl

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Abstract

A new series of 3,4,5-trimethoxyphenyl bearing pyrazole (4a–g) and pyrazolo[3,4-d]pyridazine (5a–g) scaffolds were synthesized in good yield. The newly synthesized compounds were characterized on the basis of elemental and spectroscopic analyses. Their inhibitory activity against the pro-inflammatory inducible nitric oxide synthase and cyclooxygenase-2 proteins expression in lipopolysaccharide-stimulated murine RAW 264.7 macrophages were assessed and showed various potencies. All pyrazolo[3,4-d]pyridazine compounds (5a–g) strongly down regulated lipopolysaccharide inducible nitric oxide synthase expression to the range of 20.3 ± 0.6–51.3 ± 3.5% relative to the bioactive pyrazole derivatives 4b, 4c, 4e and 4g. With the exception of inactive compounds 4c and 4d, all other synthesized compounds inhibited cyclooxygenase-2 expression below 100% in the lipopolysaccharide-stimulated cells, which being declined maximally to 42.8 ± 1.4% by one of the pyrazolo[3,4-d]pyridazine compounds (5d). Moreover, the neuroprotective activity of the less cytotoxic compounds 4b, (4e–g) and (5a–g) were evaluated against 6-hydroxydopamine (6-OHDA)-induced neuroblastoma SH-SY5Y cell death and exhibited significant (p < 0.05) cell protection. The pyrazolo[3,4-d]pyridazine compound (5e) exhibited more than 100% of relative neuroprotection (110.7 ± 4.3%) with an additional advantage of having the highest cell viability index (107.2 ± 2.9%).

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References

  • Abdel-Aziz M, Abuo-Rahma Gel D, Hassan AA (2009) Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur J Med Chem 44(9):3480–3487

    Article  CAS  PubMed  Google Scholar 

  • Ahmed AF, Hsieh YT, Wen ZH, Wu YC, Sheu JH (2006) Polyoxygenated sterols from the formosan soft coral Sinularia gibberosa. J Nat Prod 69(9):1275–1279

    Article  CAS  PubMed  Google Scholar 

  • Alegaon SG, Alagawadi KR, Garg MK, Dushyant K, Vinod D (2014) 1,3,4-Trisubstituted pyrazole analogues as promising anti-inflammatory agents. Bioorg Chem 54:51–59

    Article  CAS  PubMed  Google Scholar 

  • Bohlken A, Cheung BB, Bell JL, Koach J, Smith S, Sekyere E, Thomas W, Norris M, Haber M, Lovejoy DB, Richardson DR, Marshall GM (2009) ATP7A is a novel target of retinoic acid receptor beta2 in neuroblastoma cells. Br J Cancer 100(1):96–105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cairns JA (2007) The coxibs and traditional nonsteroidal anti-inflammatory drugs: a current perspective on cardiovascular risks. Can J Cardiol 23(2):125–131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen WF, Chakraborty C, Sung CS, Feng CW, Jean YH, Lin YY, Hung HC, Huang TY, Huang SY, Su TM, Sung PJ, Sheu JH, Wen ZH (2012) Neuroprotection by marine-derived compound, 11-dehydrosinulariolide, in an in vitro Parkinson’s model: a promising candidate for the treatment of Parkinson’s disease. Naunyn-Schmiedeberg’s Arch Pharmacol 385(3):265–275

    Article  CAS  Google Scholar 

  • Domiati S, El-Mallah A, Ghoneim A, Bekhit A, El Razik HA (2016) Evaluation of anti-inflammatory, analgesic activities, and side effects of some pyrazole derivatives. Inflammopharmacology 24(4):163–172

    Article  CAS  PubMed  Google Scholar 

  • el-Hawash SA, el-Mallah AI (1998) Synthesis of some novel pyrazole derivatives as potential antiinflammatory agents with minimum ulcerogenic activity. Pharmazie 53(6):368–373

    CAS  PubMed  Google Scholar 

  • Garn H, Bahn S, Baune BT, Binder EB, BisgaardH, Chatila TA, Chavakis T, Culmsee C, Dannlowski U, Gay S, Gern J, Haahtela T, Kircher T, Muller-Ladner U, Neurath MF, Preissner KT, Reinhardt C, Rook G, Russell S, Schmeck B, Stappenbeck T, Steinhoff U, van Os J, Weiss S, Zemlin M, Renz H (2016) Current concepts in chronic inflammatory diseases: Interactions between microbes, cellular metabolism, and inflammation. J Allergy Clin Immunol 138(1):47–56

    Article  CAS  PubMed  Google Scholar 

  • Gokhan-Kelekci N, Yabanoglu S, Kupeli E, Salgin U, Ozgen O, Ucar G, Yesilada E, Kendi E, Yesilada A, Bilgin AA (2007) A new therapeutic approach in Alzheimer disease: some novel pyrazole derivatives as dual MAO-B inhibitors and antiinflammatory analgesics. Bioorg Med Chem 15(17):5775–5786

    Article  PubMed  Google Scholar 

  • Hall A, Billinton A, Brown SH, Clayton NM, Chowdhury A, Giblin GM, Goldsmith P, Hayhow TG, Hurst DN, Kilford IR, Naylor A, Passingham B, Winyard L (2008) Non-acidic pyrazole EP1 receptor antagonists with in vivo analgesic efficacy. Bioorg Med Chem Lett 18(11):3392–3399

    Article  CAS  PubMed  Google Scholar 

  • Hamdy NA1, El-Senousy WM (2013) Synthesis and antiviral evaluation of some novel pyrazoles and pyrazolo[3,4-d]pyridazines bearing 5,6,7,8-tetrahydronaphthalene. Acta Pol Pharm 70(1):99–110

    CAS  PubMed  Google Scholar 

  • Hewett JA, Roth RA (1993) Hepatic and extrahepatic pathobiology of bacterial lipopolysaccharides. Pharmacol Rev 45(4):382–411

    CAS  PubMed  Google Scholar 

  • Jayaraj RL, Tamilselvam K, Manivasagam T, Elangovan N (2013) Neuroprotective effect of CNB-001, a novel pyrazole derivative of curcumin on biochemical and apoptotic markers against rotenone-induced SK-N-SH cellular model of Parkinson’s disease. J Mol Neurosci 51(3):863–870

    Article  CAS  PubMed  Google Scholar 

  • Jouzeau JY, Terlain B, Abid A, Nedelec E, Netter P (1997) Cyclo-oxygenase isoenzymes. How recent findings affect thinking about nonsteroidal anti-inflammatory drugs. Drugs 53(4):563–582

    Article  CAS  PubMed  Google Scholar 

  • Koistinaho J, Koponen S, Chan PH (1999) Expression of cyclooxygenase-2 mRNA after global ischemia is regulated by AMPA receptors and glucocorticoids. Stroke 30(9):1900–19005

    Article  CAS  PubMed  Google Scholar 

  • Korhonen R, Lahti A, Hamalainen M, Kankaanranta H, Moilanen E (2002) Dexamethasone inhibits inducible nitric-oxide synthase expression and nitric oxide production by destabilizing mRNA in lipopolysaccharide-treated macrophages. Mol pharmacol 62(3):698–704

    Article  CAS  PubMed  Google Scholar 

  • Lee KY, Sung SH, Kim YC (2006) Neuroprotective bibenzyl glycosides of Stemona tuberosa roots. J Nat Prod 69(4):679–681

    Article  CAS  PubMed  Google Scholar 

  • Michaux C, Charlier C (2004) Structural approach for COX-2 inhibition. Mini Rev Med Chem 4(6):603–615

    Article  CAS  PubMed  Google Scholar 

  • Myatt JW, Healy MP, Bravi GS, Billinton A, Johnson CN, Matthews KL, Jandu KS, Meng W, Hersey A, Livermore DG, Douault CB, Witherington J, Bit RA, Rowedder JE, Brown JD, Clayton NM (2010) Pyrazolopyridazine alpha-2-delta-1 ligands for the treatment of neuropathic pain. Bioorg Med Chem Lett 20(15):4683–4688

    Article  CAS  PubMed  Google Scholar 

  • Oh YC, Jeong YH, Cho WK, Ha JH, Gu MJ, Ma JY (2015) Anti-inflammatory and analgesic effects of pyeongwisan on LPS-stimulated murine macrophages and mouse models of acetic acid-induced writhing response and xylene-induced ear edema. Inter J Mol Sci 16(1):1232–1251

    Article  CAS  Google Scholar 

  • Özdemir Z, Kandilci HB, Gümüşel B, Çalış Ü, Bilgin AA (2007) Synthesis and studies on antidepressant and anticonvulsant activities of some 3-(2-furyl)-pyrazoline derivatives. Eur J Med Chem 42(3):373–379

    Article  PubMed  Google Scholar 

  • Park EK, Shin YW, Lee HU, Kim SS, Lee YC, Lee BY, Kim DH (2005) Inhibitory effect of ginsenoside Rb1 and compound K on NO and prostaglandin E2 biosynthesis of RAW264.7 cells induced by lipopolysaccharide. Bio Pharm Bull 28(4):652–656

    Article  CAS  Google Scholar 

  • Patel MV, Bell R, Majest S, Henry R, Kolasa T (2004) Synthesis of 4,5-diaryl-1H-pyrazole-3-ol derivatives as potential COX-2 inhibitors. J Organic Chem 69(21):7058–7065

    Article  CAS  Google Scholar 

  • Ragab FA, Abdel Gawad NM, Georgey HH, Said MF (2013) Synthesis of novel 1,3,4-trisubstituted pyrazoles as anti-inflammatory and analgesic agents. Eur J Med Chem 63:645–654

    Article  CAS  PubMed  Google Scholar 

  • Shaaban MR, Farag AM, Salah TS, Osman FH (2007) Regioselective synthesis of some novel pyrazoles, isoxazoles, pyrazolo[3,4-d]pyridazines and isoxazolo[3,4-d]pyridazines pendant to benzimidazole. J Heterocycl Chem 44(1):177–181

    Article  CAS  Google Scholar 

  • Sharma PK, Kumar S, Kumar P, Kaushik P, Kaushik D, Dhingra Y, Aneja KR (2010) Synthesis and biological evaluation of some pyrazolylpyrazolines as anti-inflammatory-antimicrobial agents. Eur J Med Chem 45(6):2650–2655

    Article  CAS  PubMed  Google Scholar 

  • Skaper SD (2007) The brain as a target for inflammatory processes and neuroprotective strategies. Ann N Y Acad Sci 1122(1):23–34

    Article  CAS  PubMed  Google Scholar 

  • Tewari AK, Dubey R, Mishra A (2011) 2-Substituted-8-methyl-3,6-dihydroimidazo[4,5-c]pyrazolo[3,4-e]pyridazine as an anti-inflammatory agent. Med Chem Res 20(1):125–129

    Article  CAS  Google Scholar 

  • Tewari AK, Mishra A (2001) Synthesis and anti-inflammatory activities of N4, N5-disubstituted-3-methyl-1H-pyrazolo[3,4-c]pyridazines. Bioorg Med Chem 9(3):715–718

    Article  CAS  PubMed  Google Scholar 

  • Tewari AK, Srivastava P, Singh VP, Singh A, Goel RK, Mohan CG (2010) Novel anti-inflammatory agents based on pyrazole based dimeric compounds; design, synthesis, docking and in vivo activity. Chem Pharm Bull 58(5):634–638

    Article  CAS  PubMed  Google Scholar 

  • Villa V, Thellung S, Corsaro A, Novelli F, Tasso B, Colucci-D’Amato L, Gatta E, Tonelli M, Florio T (2016) Celecoxib inhibits prion protein 90-231-mediated pro-inflammatory responses in microglial cells. Mol Neurobiol 53(1):57–72

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for funding this research group no. (RG 1435–006).

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Mashooq A. Bhat & Mohamed A. Al-Omar

  2. Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia

    Atallah F. Ahmed

  3. Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt

    Atallah F. Ahmed

  4. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan

    Zhi-Hong Wen

  5. Applied Organic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt

    Hatem A. Abdel-Aziz

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  1. Mashooq A. Bhat
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  2. Atallah F. Ahmed
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  3. Zhi-Hong Wen
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  4. Mohamed A. Al-Omar
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  5. Hatem A. Abdel-Aziz
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Correspondence to Mashooq A. Bhat, Atallah F. Ahmed or Hatem A. Abdel-Aziz.

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Bhat, M.A., Ahmed, A.F., Wen, ZH. et al. Synthesis, anti-inflammatory and neuroprotective activity of pyrazole and pyrazolo[3,4-d]pyridazine bearing 3,4,5-trimethoxyphenyl. Med Chem Res 26, 1557–1566 (2017). https://doi.org/10.1007/s00044-017-1870-5

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  • DOI: https://doi.org/10.1007/s00044-017-1870-5

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