Skip to main content

Advertisement

SpringerLink
Log in

Elucidation of the molecular mechanism underlying the anti-inflammatory activity of an effective and safe bipyrazole-based compound

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Introduction

Since the synthesis of acetylsalicylic acid by Hoffmann in 1897, new classes of NSAIDs have been introduced; however, their side effects have limited their clinical applications. Consequently, our team has recently synthesized a novel bipyrazole compound that showed a satisfactory efficacy and safety profile. The aim of the current study was to elucidate the molecular mechanism of this bipyrazole compound.

Method

The anti-inflammatory efficacy of the compound was assessed using formalin-induced paw edema test. Computer-assisted simulation docking experiments were carried out. Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), tumor necrosis factor-alpha (TNFα), interleukin-1 (IL1) and interleukin-10 (IL10) gene expression were quantified with real-time polymerase chain reaction (RT-PCR) using SYBR Green technology. The samples were taken from the plantar paw of mice after formalin local injection.

Results

The efficacy of the bipyrazole compound was similar to that of indomethacin, diclofenac, and celecoxib, as proven by the formalin-induced paw edema. Docking study indicated a superior binding score for the studied compound relative to celecoxib, indomethacin, and diclofenac. RT-PCR assessment revealed a significant decrease in iNOS, COX-2, and TNFα gene expression in the bipyrazole-treated group. Moreover, a reduction in IL1 and nNOS gene expression levels and an increase in IL10 level were detected despite being insignificant compared to the control group.

Conclusion

These findings revealed the superiority of the newly synthesized bipyrazole compound not only on the binding site, but also by inhibiting most of the inflammatory mediators including TNF-α.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Brune K, Hinz B. The discovery and development of anti-inflammatory drugs. Arthritis Rheum. 2004;50:2391–9.

    Article  CAS  PubMed  Google Scholar 

  2. Jones R. Nonsteroidal anti-inflammatory drug prescribing: past, present, and future. Am J Med. 2001;110:4S–7S.

    Article  CAS  PubMed  Google Scholar 

  3. Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104(Suppl 3A):2S–8S.

    Article  CAS  PubMed  Google Scholar 

  4. Ambranson SB, Weissmann G. The mechanisms of action of nonsteroidal anti-inflammatory drugs. Arthritis Rheum. 1989;32(1):1–9.

    Article  Google Scholar 

  5. Praveen Rao PN, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci 2008;11(2):81s–110s.

    Article  CAS  PubMed  Google Scholar 

  6. Davies NM, Good RL, Roupe KA, Yanez JA. Cyclooxygenase-3: axiom, dogma, anomaly, enigma or splice error? Not as easy as 1, 2, 3. J Pharm Pharm Sci. 2004;7:217–26.

    CAS  PubMed  Google Scholar 

  7. Mizushima T. Molecular mechanism for various pharmacological activities of NSAIDs. Pharmaceuticals. 2010;3:1614–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hilario MOE, Terreri MT, Len CA. (2006). Nonsteroidal anti-inflammatory drugs: cyclooxygenase 2 inhibitors. J Pediatr 82(5): s206-212.

    Article  Google Scholar 

  9. Lavigne P, Shi Q, Joliccoeur FC, Pelletier JP, Martel-Pelletier J, Fernandes JC. Modulation of IL-1 beta, IL-6, TNF-alpha and PGE(2) by pharmacological agents in explants of membranes from failed total hip replacement. Osteoarthr Cartil. 2002;10(11):898–904.

    Article  CAS  PubMed  Google Scholar 

  10. Deb PK, Mailabaram RP, Al-Jaidi B, Saadh M. Molecular basis of binding interactions of NSAIDs and computer-aided drug design approaches in the pursuit of the development of cyclooxygenase-2 (COX-2) selective inhibitors. Nonsteroidal Anti Inflamm Drugs. 2017;6:101–21.

    Google Scholar 

  11. Mohy El-Din MM, Senbel AM, Bistawroos AA, El-Mallah A, Nour El-Din NA, Bekhit NA, El Razik HAA. A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory and analgesic drug. Basic Clin Pharmacol Toxicol. 2010;108:263–273.

    Article  CAS  PubMed  Google Scholar 

  12. Thore SN, Gupta SV, Baheti KG. Novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates: synthesis and pharmacological activity. J Saudi Chem Soc. 2012;06:(011).

    Google Scholar 

  13. Maddila S, Sampath SGCH, Lavanya P. Synthesis and anti-inflammatory activity of some new 1,3,4-thiadiazoles containing pyrazole and pyrrole nucleus. J Saudi Chem Soc. 2012;11:007.

    Google Scholar 

  14. Paprocka R, Wiese M, Eljaszewicz A, Helmin-Basa A, Gzella A, Modzelewska-Banachiewicz B, Michalkiewicz J. Synthesis and anti-inflammatory activity of new 1,2,4-triazole derivatives. Bioorg Med Chem Lett. 2015;25(13):2664–7.

    Article  CAS  PubMed  Google Scholar 

  15. Domiati S, Mehanna M, Ragab H, Nakkash-Chmaisse H, El Mallah A. Investigation of chronic efficacy and safety profile of two potential anti-inflammatory bipyrazole-based compounds in experimental animals. J Inflamm Res. 2018;11:143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Vogel HG. Drug discovery and evaluation: pharmacologic assays, 3rd ed. Berlin: Springer; 2008.

    Book  Google Scholar 

  17. Wang JL, Limburg D, Graneto MJ, Springer J, Hamper JR, Liao S, Pawlitz JL, Kurumbail RG, Maziasz T, Talley JJ, Kiefer JR, Carter J. Structure of celecoxib bound at the COX-2 active site. Bioorg Med Chem Lett. 2010;20:7159–63.

    Article  CAS  PubMed  Google Scholar 

  18. Chemical Computing Group Inc. (2009) Molecular operating environment (MOE) 2009.10. Montreal, Canada. http://www.chemcomp.com. Accessed 31 March 2018.

  19. Brunton LL, Chabner BA, Knollmann BC. Anti-inflammatory, antipyretic & analgesic agents; pharmacotherapy of gout. In: Goodman, Gilman’s, editors. The pharmacological basis of therapeutics. 12th ed, California, Chap. 34, 2011.

  20. Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci. 1997;2:12–26.

    Google Scholar 

  21. Choy EH, Kingsley GH, Panayi GS. Monoclonal antibody therapy in rheumatoid arthritis. Rheumatology. 1998;37(5):484–90.

    Article  CAS  Google Scholar 

  22. Cattell V, Jansen A. Inducible nitric oxide synthase in inflammation. Histochem J. 1995;27(10):777–84.

    Article  CAS  PubMed  Google Scholar 

  23. Sharma JN, Al Omran A, Parvathy SS. Role of nitric oxide in inflammatory diseases. Inflammopharmacology. 2007;17:252–9.

    Article  Google Scholar 

  24. Korhonen R, Lahti A, Kankaanranta H, Moilanem E. Nitric oxide production and signaling in inflammation. Curr Drug Targets Inflamm Allergy. 2005;4:471–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut Campus, Tarik El Jadida, 5020 Riad El Solh, P.O. Box 11, 11072809, Beirut, Lebanon

    S. Domiati & H. Nakkash-Chmaisse

  2. Department of Pharmaceutical Technology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon

    M. Mehanna

  3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    H. Ragab

  4. Department of Pharmaceutical Sciences, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon

    K. H. Abd El Galil

  5. Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt

    A. El Mallah

Authors
  1. S. Domiati
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Mehanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H. Ragab
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. H. Abd El Galil
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Nakkash-Chmaisse
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. El Mallah
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S. Domiati.

Additional information

Responsible Editor: John Di Battista.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Domiati, S., Mehanna, M., Ragab, H. et al. Elucidation of the molecular mechanism underlying the anti-inflammatory activity of an effective and safe bipyrazole-based compound. Inflamm. Res. 68, 379–386 (2019). https://doi.org/10.1007/s00011-019-01225-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-019-01225-z

Keywords

Search

Navigation