Skip to main content
SpringerLink
Log in

Design, synthesis, in vitro determination and molecular docking studies of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine derivatives with terminal sulfonamide derivatives in LPS-induced RAW264.7 macrophage cells

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

In the present work, a new series of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine possessing terminal ethyl or propyl sulfonamides was designed and synthesized. The cytotoxic effect of the final compounds was measured by applying MTT assay in LPS-Induced RAW264.7 macrophage cells. The final target compounds were screened for their anti-inflammatory effect through their ability to inhibit NO and PGE2 production and cytokines production (TNF-α, IL-6, IL-1β) in LPS-induced RAW264.7 macrophage at 10 μM concentration. Compounds 8d, 9d, and 9k showed the highest inhibitory effect on NO production. Compounds 8d and 9k exhibited high PGE2 inhibition with IC50 values of 3.47, 2.54 μM, respectively. Compounds 8d and 9k exhibited high cytokines inhibition ≥60%. The most potent compounds 8d and 9k were tested to determine their effect on iNOS and COX-2 mRNA expression level. Compound 9k activity on iNOS and COX-2 proteins level, pro-inflammatory mediators and cytokines was determined and showed remarkable inhibition for both proteins level. Compounds 8d, 9k showed high binding affinity to COX-2 active site and exhibited similar binding interactions of the native ligand celecoxib.

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
Scheme 1
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 9

Similar content being viewed by others

References

  1. El-Din MMG, El-Gamal MI, Abdel-Maksoud MS, Lee H, Choi J, Kim T-W, et al. Inhibitory effects of triarylpyrazole derivatives on LPS-induced nitric oxide and PGE2 productions in murine RAW 264.7 macrophages. Bioorg Med Chem Lett. 2020;30:126884.

    Article  CAS  Google Scholar 

  2. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xu X, Yin P, Wan C, Chong X, Liu M, Cheng P, et al. Punicalagin inhibits inflammation in LPS-induced RAW264. 7 macrophages via the suppression of TLR4-mediated MAPKs and NF-κB activation. Inflammation 2014;37:956–65.

    Article  CAS  PubMed  Google Scholar 

  4. Takeda K, Akira S. Toll-like receptors in innate immunity. Int Immunol. 2005;17:1–14.

    Article  CAS  PubMed  Google Scholar 

  5. Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature 2000;406:782–7.

    Article  CAS  PubMed  Google Scholar 

  6. Carralot J-P, Kim T-K, Lenseigne B, Boese AS, Sommer P, Genovesio A, et al. Automated high-throughput siRNA transfection in raw 264.7 macrophages: a case study for optimization procedure. J Biomol Screen. 2009;14:151–60.

    Article  CAS  PubMed  Google Scholar 

  7. Shao J, Li Y, Wang Z, Xiao M, Yin P, Lu Y, et al. 7b, a novel naphthalimide derivative, exhibited anti-inflammatory effects via targeted-inhibiting TAK1 following down-regulation of ERK1/2-and p38 MAPK-mediated activation of NF-κB in LPS-stimulated RAW264. 7 macrophages. Int Immunopharmacol. 2013;17:216–28.

    Article  CAS  PubMed  Google Scholar 

  8. Chun J, Choi RJ, Khan S, Lee D-S, Kim Y-C, Nam Y-J, et al. Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-κB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. Int Immunopharmacol. 2012;14:375–83.

    Article  CAS  PubMed  Google Scholar 

  9. Du L, Li J, Zhang X, Wang L, Zhang W. Pomegranate peel polyphenols inhibits inflammation in LPS-induced RAW264. 7 macrophages via the suppression of MAPKs activation. J Funct Foods. 2018;43:62–9.

    Article  CAS  Google Scholar 

  10. Bhardwaj A, Batchu SN, Kaur J, Huang Z, Seubert JM, Knaus EE. Cardiovascular properties of a nitric oxide releasing rofecoxib analogue: beneficial anti‐hypertensive activity and enhanced recovery in an ischemic reperfusion injury model. ChemMedChem 2012;7:1365–8.

    Article  CAS  PubMed  Google Scholar 

  11. Bhardwaj A, Huang Z, Kaur J, Knaus EE. Rofecoxib analogues possessing a nitric oxide donor sulfohydroxamic acid (SO2NHOH) cyclooxygenase‐2 pharmacophore: synthesis, molecular modeling, and biological evaluation as anti‐inflammatory agents. ChemMedChem 2012;7:62–7.

    Article  CAS  PubMed  Google Scholar 

  12. Kaur J, Bhardwaj A, Huang Z, Knaus EE. Aspirin analogues as dual cyclooxygenase‐2/5‐lipoxygenase inhibitors: synthesis, nitric oxide release, molecular modeling, and biological evaluation as anti‐inflammatory agents. ChemMedChem 2012;7:144–50.

    Article  CAS  PubMed  Google Scholar 

  13. Yun H-Y, Dawson VL, Dawson TM. Neurobiology of nitric oxide. Crit Rev Neurobiol. 1996;10:291–316.

    Article  CAS  PubMed  Google Scholar 

  14. Carter PH, Scherle PA, Muckelbauer JA, Voss ME, Liu R-Q, Thompson LA, et al. Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-α. Proc Natl Acad Sci USA. 2001;98:11879–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kollias G, Douni E, Kassiotis G, Kontoyiannis D. On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease. Immunol Rev. 1999;169:175–94.

    Article  CAS  PubMed  Google Scholar 

  16. Bandgar BP, Gawande SS, Bodade RG, Gawande NM, Khobragade CN. Synthesis and biological evaluation of a novel series of pyrazole chalcones as anti-inflammatory, antioxidant and antimicrobial agents. Bioorg Med Chem. 2009;17:8168–73.

    Article  CAS  PubMed  Google Scholar 

  17. Raj DS. Role of interleukin-6 in the anemia of chronic disease. Semin Arthritis Rheum. 2009;38:382–8.

    Article  CAS  PubMed  Google Scholar 

  18. Shishoo C, Ravikumar T, Jain K, Rathod I, Gandhi T, Satia M. Synthesis of novel 1, 2-(un) substituted-3-amino-5-aryl-6-arylaminopyrazolo [3, 4-d] pyrimidin-4 (5H)-ones and their biological activities. IJC-B. 1999;38B:1075–1085.

    CAS  Google Scholar 

  19. Nakamura T, Sato M, Kakinuma H, Miyata N, Taniguchi K, Bando K, et al. Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5, 8, 11, 14-eicosatetraenoic acid synthase inhibitors. J Med Chem. 2003;46:5416–27.

    Article  CAS  PubMed  Google Scholar 

  20. Cheng H, DeMello KML, Li J, Sakya SM, Ando K, Kawamura K, et al. Synthesis and SAR of heteroaryl-phenyl-substituted pyrazole derivatives as highly selective and potent canine COX-2 inhibitors. Bioorg Med Chem Lett. 2006;16:2076–80.

    Article  CAS  PubMed  Google Scholar 

  21. Bekhit AA, Ashour HM, Ghany YSA, Bekhit AE-DA, Baraka A. Synthesis and biological evaluation of some thiazolyl and thiadiazolyl derivatives of 1H-pyrazole as anti-inflammatory antimicrobial agents. Eur J Med Chem. 2008;43:456–63.

    Article  CAS  PubMed  Google Scholar 

  22. Ahlström MM, Ridderström M, Zamora I, Luthman K. CYP2C9 structure− metabolism relationships: optimizing the metabolic stability of COX-2 inhibitors. J Med Chem. 2007;50:4444–52.

    Article  PubMed  CAS  Google Scholar 

  23. Upadhyay K, Bavishi A, Thakrar S, Radadiya A, Vala H, Parekh S, et al. Synthesis and biological evaluation of 4-styrylcoumarin derivatives as inhibitors of TNF-α and IL-6 with anti-tubercular activity. Bioorg Med Chem Lett. 2011;21:2547–9.

    Article  CAS  PubMed  Google Scholar 

  24. Manvar A, Bochiya P, Virsodia V, Khunt R, Shah A. Microwave-assisted and Zn [l-proline] 2 catalyzed tandem cyclization under solvent free conditions: Rapid synthesis of chromeno [4, 3-c] pyrazol-4-ones. J Mol Catal A. 2007;275:148–52.

    Article  CAS  Google Scholar 

  25. Prakash O, Kumar R, Parkash V. Synthesis and antifungal activity of some new 3-hydroxy-2-(1-phenyl-3-aryl-4-pyrazolyl) chromones. Eur J Med Chem. 2008;43:435–40.

    Article  CAS  PubMed  Google Scholar 

  26. Brough PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, et al. 4, 5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer. J Med Chem. 2008;51:196–218.

    Article  CAS  PubMed  Google Scholar 

  27. Vera-DiVaio MA, Freitas AC, Castro HC, de Albuquerque S, Cabral LM, Rodrigues CR, et al. Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series. Bioorg Med Chem. 2009;17:295–302.

    Article  CAS  PubMed  Google Scholar 

  28. Bandgar BP, Chavan HV, Adsul LK, Thakare VN, Shringare SN, Shaikh R, et al. Design, synthesis, characterization and biological evaluation of novel pyrazole integrated benzophenones. Bioorg Med Chem Lett. 2013;23:912–6.

    Article  CAS  PubMed  Google Scholar 

  29. Keche AP, Hatnapure GD, Tale RH, Rodge AH, Kamble VM. Synthesis, anti-inflammatory and antimicrobial evaluation of novel 1-acetyl-3, 5-diaryl-4, 5-dihydro (1H) pyrazole derivatives bearing urea, thiourea and sulfonamide moieties. Bioorg Med Chem Lett. 2012;22:6611–5.

    Article  CAS  PubMed  Google Scholar 

  30. Naim MJ, Alam O, Farah Nawaz M, Alam J, Alam P. Current status of pyrazole and its biological activities. J Pharm Bioallied Sci. 2016;8:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. El-Gamal MI, Khan MA, Tarazi H, Abdel-Maksoud MS, Gamal El-Din MM, Yoo KH, et al. Design and synthesis of new RAF kinase-inhibiting antiproliferative quinoline derivatives. Part 2: Diarylurea derivatives. Eur J Med Chem. 2017;127:413–23.

    Article  CAS  PubMed  Google Scholar 

  32. Abdel-Maksoud MS, El-Gamal MI, Gamal El-Din MM, Kwak S-S, Kim H-I, Oh C-H. Broad-spectrum antiproliferative activity of a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives. Med Chem Res. 2016;25:824–33.

    Article  CAS  Google Scholar 

  33. Abdel-Maksoud MS, Ammar UM, El-Gamal MI, Gamal El-Din MM, Mersal KI, Ali EMH, et al. Design, synthesis, and anticancer activity of imidazo[2,1-b]oxazole-based RAF kinase inhibitors. Bioorg Chem. 2019;93:art. no. 103349.

    Article  CAS  Google Scholar 

  34. Ali EMH, El-Telbany RFA, Abdel-Maksoud MS, Ammar UM, Mersal KI, Zaraei S-O, et al. Design, synthesis, biological evaluation, and docking studies of novel (imidazol-5-yl)pyrimidine-based derivatives as dual BRAFV600E/p38α inhibitors. Eur J Med Chem. 2021;215:art. no. 113277.

    Article  CAS  Google Scholar 

  35. Abdel-Maksoud MS, El-Gamal MI, Lee BS, Gamal El-Din MM, Jeon HR, Kwon D, et al. Discovery of new imidazo[2,1- b]thiazole derivatives as potent pan-RAF inhibitors with promising in vitro and in vivo anti-melanoma activity. J Med Chem. 2021;64:6877–901.

    Article  CAS  PubMed  Google Scholar 

  36. El-Gamal MI, Abdel-Maksoud MS, Gamal El-Din MM, Shin J-S, Lee K-T, Yoo KH, et al. Synthesis, in vitro antiproliferative and antiinflammatory activities, and kinase inhibitory effects of new 1,3,4-triarylpyrazole derivatives. Anti Cancer Agents Med Chem. 2017;17:75–84.

    Article  CAS  Google Scholar 

  37. Abdel-Maksoud MS, El-Gamal MI, Gamal El-Din MM, Oh CH. Design, synthesis, in vitro anticancer evaluation, kinase inhibitory effects, and pharmacokinetic profile of new 1,3,4-triarylpyrazole derivatives possessing terminal sulfonamide moiety. J Enzym Inhib Med Chem. 2019;34:97–109.

    Article  CAS  Google Scholar 

  38. Abdel-Maksoud MS, El-Gamal MI, Gamal El-Din MM, Choi Y, Choi J, Shin J-S, et al. Synthesis of new triarylpyrazole derivatives possessing terminal sulfonamide moiety and their inhibitory effects on PGE2 and nitric oxide productions in lipopolysaccharide-induced RAW 264.7 macrophages. Molecules. 2018;23:art. no. 2556.

    Article  CAS  Google Scholar 

  39. Lipman AG. MARTINDALE:‘Martindale—the extra pharmacopoeia’, edited by JEF Reynolds. Int J Pharm Pract. 1993;2:124.

  40. Amir M, Kumar S. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of 3, 5-dimethyl pyrazoles, 3-methyl pyrazol-5-ones and 3, 5-disubstituted pyrazolines. IJC-B. 2005;44B:2532–2537.

    CAS  Google Scholar 

  41. Gürsoy A, Demirayak Ş, Çapan G, Erol K, Vural K. Synthesis and preliminary evaluation of new 5-pyrazolinone derivatives as analgesic agents. Eur J Med Chem. 2000;35:359–64.

    Article  PubMed  Google Scholar 

  42. Kumar A, Sharma S, Bajaj K, Bansal D, Sharma S, Saxena AK. et al. Synthesis and anti-inflammatory, analgesic, ulcerogenic and cyclooxygenase activities of novel quinazolinyl-Δ 2-pyrazolines. IJC-B. 2003;42B:1979–1984.

    CAS  Google Scholar 

  43. Chavan HV, Adsul LK, Kotmale AS, Dhakane VD, Thakare VN, Bandgar BP. Design, synthesis, characterization and in vitro and in vivo anti-inflammatory evaluation of novel pyrazole-based chalcones. J Enzym Inhib Med Chem. 2015;30:22–31.

    Article  CAS  Google Scholar 

  44. Havrylyuk D, Roman O, Lesyk R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline–thiazolidine-based hybrids. Eur J Med Chem. 2016;113:145–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kim T-W, Shin J-S, Chung K-S, Lee Y-G, Baek N-I, Lee K-T. Anti-Inflammatory mechanisms of Koreanaside A, a lignan isolated from the flower of Forsythia koreana, against LPS-induced macrophage activation and DSS-induced colitis mice: the crucial role of AP-1, NF-κB, and JAK/STAT signaling. Cells 2019;8:1163.

    Article  CAS  PubMed Central  Google Scholar 

  46. Reddy AR, Sampath A, Goverdhan G, Yakambaram B, Mukkanti K, Reddy PP. An improved and scalable processfor celecoxib: a selective cyclooxygenase-2 inhibitor. Org. Process Res. Dev. 2009;13:98–101.

    Article  CAS  Google Scholar 

  47. Won JH, Im HT, Kim YH, Yun KJ, Park HJ, Choi JW, et al. Anti‐inflammatory effect of buddlejasaponin IV through the inhibition of iNOS and COX‐2 expression in RAW 264.7 macrophages via the NF‐κB inactivation. Br J Pharmacol. 2006;148:216–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lee H-H, Jang E, Kang S-Y, Shin J-S, Han H-S, Kim T-W, et al. Anti-inflammatory potential of Patrineolignan B isolated from Patrinia scabra in LPS-stimulated macrophages via inhibition of NF-κB, AP-1, and JAK/STAT pathways. Int Immunopharmacol. 2020;86:106726.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Support of this work was offered by Korea Institute of Science and Technology (KIST), and KIST project (2E30341& 2E31130).

Author information

Authors and Affiliations

  1. Center of Biomaterials, Korea Institute of Science & Technology (KIST School), Seongbuk-gu, Seoul, 02792, Republic of Korea

    Karim I. Mersal, Eslam M. H. Ali, Seyed-Omar Zaraei & Chang-Hyun Oh

  2. University of Science & Technology (UST), Yuseong-gu, Daejeon, 34113, Republic of Korea

    Karim I. Mersal, Eslam M. H. Ali, Seyed-Omar Zaraei & Chang-Hyun Oh

  3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo, 12055, Egypt

    Karim I. Mersal & Eslam M. H. Ali

  4. Medicinal & Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre NRC (ID: 60014618)), Dokki, Giza, 12622, Egypt

    Mohammed S. Abdel-Maksoud

  5. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0NR, Scotland, United Kingdom

    Usama M. Ammar

  6. Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea

    Jae-Min Kim & Su-Yeon Kim

  7. Department of Biomedical and Pharmaceutical Sciences, College of Pharmarcy, Kyung Hee University, Seoul, 02447, Republic of Korea

    Jae-Min Kim

  8. Department of Life and Nanopharmaceutical Sciences, College of Pharmarcy, Kyung Hee University, Seoul, 02447, Republic of Korea

    Su-Yeon Kim

  9. Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul, 130-701, Republic of Korea

    Kyung-Tae Lee

  10. Center for Biomaterials, Korea Institute of Science & Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea

    Kwan Hyi Lee

  11. KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea

    Kwan Hyi Lee

  12. Department of Beauty Science, Hanseo University, Seosan, 31962, Republic of Korea

    Si-Won Kim

  13. Advanced Analysis Center, Korea Institute of Science & Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea

    Hyun-Mee Park & Mi-Jung Ji

Authors
  1. Karim I. Mersal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammed S. Abdel-Maksoud
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eslam M. H. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Usama M. Ammar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seyed-Omar Zaraei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jae-Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Su-Yeon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kyung-Tae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kwan Hyi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Si-Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hyun-Mee Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mi-Jung Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chang-Hyun Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Chang-Hyun Oh.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mersal, K.I., Abdel-Maksoud, M.S., Ali, E.M.H. et al. Design, synthesis, in vitro determination and molecular docking studies of 4-(1-(tert-butyl)-3-phenyl-1H-pyrazol-4-yl) pyridine derivatives with terminal sulfonamide derivatives in LPS-induced RAW264.7 macrophage cells. Med Chem Res 30, 1925–1942 (2021). https://doi.org/10.1007/s00044-021-02784-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02784-9

Keywords

Search

Navigation