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Design, synthesis, and biological evaluation of 1,3,5-trisubstituted pyrazoles as tyrosine kinase inhibitors

  • Sinthiya J. Gawandi
  • Vidya G. DesaiEmail author
  • Sunil G. Shingade
Original Research
  • 62 Downloads

Abstract

We report herein, silica supported molybdic acid mediated oxidative C–N bond formation for the regioselective synthesis of new 1,3,5-trisubstituted pyrazole derivatives. This transformation furnishes a novel synthetic approach with solvent-free neat heat conditions, which was found to be flexible with wide substrate scope and better efficiency towards rapid synthesis of new 1,3,5-trisubstituted pyrazoles. Selected series of the synthesized derivatives were screened for their liability against carcinogenesis. A molecular docking study of the synthesized derivatives was performed in the active site of the tyrosine kinase enzymes. Based on the molecular docking study specific compounds were screened in vitro for their anticancer activity, which showed potent micro molar activity against human MDA-MB-231 breast cancer line and human leukemia cell line K-562 using 3-(4,5-dimethylthiazol-2-yl)–2, 5-diphenyltetrazolium bromide (MTT) assay. Compound 3l possesses higher inhibitory activity with IC50 0.58 ± 0.02 μM against the MDA-MB-231 cell line. Whereas compound 3k showed higher inhibitory activity with IC50 value 0.78 ± 0.03 μM against the K-562 cell line. Fluorescence microscopic studies revealed that the compounds showed late apoptotic mode of cell death. These results can lead to further exploitation of tested pyrazole compounds to the highly active drug molecule.

Keywords

Hydrazones Pyrazoles Solvent-free Tyrosine kinase Apoptosis Anti-proliferative activity 

Notes

Acknowledgements

We are grateful to the Department of Science and Technology of Goa 8-213-2013/STE-DIR/Acct/1265 and 8-213-2013/STE-DIR/Acct/135, and UGC- New Delhi F./2015-16/NFO-2015-17-OBC-GOA-37404/(SA-III/Website) for financial support. We would also like to thank Department of Chemistry, Goa University for providing 1H NMR and 13C NMR data, Department of Chemistry, BITS Pilani Goa campus for XRD data, SAIF Punjab University, Chandigarh for providing NMR and mass spectra. We are also thankful to Maratha Mandal’s NGH Institute of Dental Sciences and Research Center, Belgaum, Karnataka for biological screening facilities.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2018_2282_MOESM1_ESM.docx (3.3 mb)
Supplementary Information

References

  1. Abd El-Karim S, Anwar M, Mohamed N, Nasr T, Elseginy S (2015) Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran–pyrazole derivatives as anticancer agents. Bioorg Chem 63:1–12CrossRefGoogle Scholar
  2. Abdel-Aziz M, El-Din A, Abuo-Rahma G, Hassan A (2009) Synthesis of novel pyrazole derivatives and evaluation of their antidepressant and anticonvulsant activities. Eur J Med Chem 44:3480–3487CrossRefGoogle Scholar
  3. Ahlstrom M, Ridderstrom M, Zamora I, Luthman K (2007) CYP2C9 structure− metabolism relationships: Optimizing the metabolic stability of COX-2 inhibitors. J Med Chem 50:4444–4452CrossRefGoogle Scholar
  4. Ahmed N, Siddiqui Z (2015) Silica molybdic acid catalysed eco-friendly three component synthesis of functionalised tetrazole derivatives under microwave irradiation in water. RSC Adv 5:16707–16717CrossRefGoogle Scholar
  5. Alam M, Alam O, Khan S, Naim M, Islamuddin M, Deora G (2016) Synthesis, anti-inflammatory, analgesic, COX1/2-inhibitory activity, and molecular docking studies of hybrid pyrazole analogues. Drug Des Dev Ther 10:3529–3543CrossRefGoogle Scholar
  6. Ayati A, Esmaeili R, Moghimi S, Bakhshaiesh T, Eslami Z, Majidzadeh K, Safavi M, Emami S, Foroumodi A (2018) Synthesis and biological evaluation of 4-amino-5-cinnamoylthiazoles as chalcone like anticancer agents. Eur J Med Chem 145:404–412CrossRefGoogle Scholar
  7. Bole S, Nargund R, Nargund L, Devaraju K, Vedamurthy A, Shruti S (2011) Synthesis and biological evaluation of novel pyrazole derivatives as urease inhibitors. Der Pharma Chem 3:73–80Google Scholar
  8. Desai V, Desai S, Gaonkar SN, Palyekar U, Joshi SD, Dixit SK (2017) Novel quinoxalinyl chalcone hybrid scaffolds as enoyl ACP reductase inhibitors: Synthesis, molecular docking & biological evaluation. Bioorg Med Chem Lett 27:2174–2180CrossRefGoogle Scholar
  9. Desai V, Gawandi S (2016) Synthesis of new 2, 4 - dinitro phenyl hydrazone derivatives of chalcones and its biological evaluation. Indo Am J Pharm Res 6:4779–4786Google Scholar
  10. Deng X, Mani N (2008) Regioselective synthesis of 1,3,5-tri-and 1,3,4,5-tetrasubstituted pyrazoles from N-arylhydrazones and nitroolefins. J Org Chem 73:2412–2415CrossRefGoogle Scholar
  11. Desai V, Naik S (2013) Use of Solid-Supported Reagents towards Synthesis of 2-Arylbenzoxazole, 3,5-Diarylisoxazole and 1,3,5-Triarylpyrazole. Green & Sustain Chem 3:1–7Google Scholar
  12. Desai V, Satardekar P, Dhumaskar K, Polo S (2012) Regioselective synthesis of 1,3,5-trisubstituted pyrazoles. Syn Comm 42:836–842CrossRefGoogle Scholar
  13. Han Y, Kim K, Choi G, An H, Son D, Kim H, Ha H, Son J, Chung S, Park H, Lee J, Suh Y (2014) Pyrazole-5-carboxamides, novel inhibitors of receptor for advanced glycation end products (RAGE). Eur J Med Chem 79:128–142CrossRefGoogle Scholar
  14. Hafez H, El-Gazzar A (2016) Synthesis and biological evaluation of N- pyrazolyl derivatives and pyrazolopyrimidine bearing a biologically active sulfonamide moiety as potential antimicrobial agent. Molecules 21:1156–1171CrossRefGoogle Scholar
  15. Holliday D, Speirs V (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13:215–221CrossRefGoogle Scholar
  16. Keche P, Hatnapure G, Tale R, Rodge A, Kamble V (2012) 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 22:6611–6615CrossRefGoogle Scholar
  17. Kheder N, Mabkhot Y, Zahian F, Mohamed S (2014) Regioselective synthesis of some pyrazole scaffolds attached to benzothiazole and benzimidazole moieties. J Chem 2014:1–5CrossRefGoogle Scholar
  18. Kumar V, Kaur K, Gupta G, Sharma A (2013) Pyrazole containing natural products: synthetic preview and biological significance. Eur J Med Chem 69:735–753CrossRefGoogle Scholar
  19. Kumar H, Saini D, Jain S, Jain N (2013) Pyrazole scaffold: a remarkable tool in the development of anticancer agents. Eur J Med Chem 70:248–258CrossRefGoogle Scholar
  20. Kumar A, Jain S, Parle M, Jain N, Kumar P (2013) 3-Aryl-1-phenyl-1H-pyrazole derivatives as new multitarget directed ligands for the treatment of Alzheimer's disease, with acetylcholinesterase and monoamine oxidase inhibitory properties. EXCLI J 12:1030–1042PubMedPubMedCentralGoogle Scholar
  21. Malvar D, Ferreira R, Castro R, Castro L, Freitas A, Costa E, Florentino I, Mafra J, De Souza G, Vanderlinde F (2014) Antinociceptive, anti-inflammatory and antipyretic effects of 1.5-diphenyl-1H-Pyrazole-3-carbohydrazide, a new heterocyclic pyrazole derivative. Life Sci 95:81–88CrossRefGoogle Scholar
  22. Mojzych M, Karczmarzyk Z, Wysocki W, Ceruso M, Supuran C, Krystof V, Lipkowska Z, Kalicki P (2015) New approaches to the synthesis of sildenafil analogues and their enzyme inhibitory activity. Bioorg Med Chem 23:1421–1429CrossRefGoogle Scholar
  23. Mottamal M, Zheng S, huang T, Wang G (2015) Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules 20:3898–3941CrossRefGoogle Scholar
  24. Olender D, Zwawiak J, Zaprutko L (2018) Multidirectional efficacy of biologically active nitro compounds included in medicines. Pharmaceuticals 11:54CrossRefGoogle Scholar
  25. Palkar M, Singhai A, Ronad P, Vishwanathswamy P, Boreddy T, Veerapur V, Shaikh M, Rane R, Karpoormath R (2014) Synthesis, pharmacological screening and in silico studies of new class of diclofenac analogues as a promising anti-inflammatory agents. Bioorg Med Chem 22:2855–2866CrossRefGoogle Scholar
  26. Penning T, Talley J, Bertenshaw S, Carter J, Collins P, Docter S, Graneto M, Lee L, Malecha J, Miyashiro J, Rogers R, Rogier D, Yu S, Anderson G, Burton E, Cogburn J, Gregory S, Koboldt C, Perkins W, Seibert K, Veenhuizen A, Zhang Y, Isakon P (1997) Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J Med Chem 40:1347–1365CrossRefGoogle Scholar
  27. Piwowar K, Milacic V, Chen D, Yang H, Zhao Y, Chan T, Yan B, Dou Q (2006) The proteasome as a potential target for novel anticancer drugs and chemosensitizers. Drug Resist Updtaes 9:263–273CrossRefGoogle Scholar
  28. Renuka N, Kumar K (2013) Synthesis and biological evaluation of novel formyl-pyrazoles bearing coumarin moiety as potent antimicrobial and antioxidant agents. Bioorg Med Chem Lett 23:6406–6409CrossRefGoogle Scholar
  29. Soudy R,H, Etayash H, Bahadorani K, Lavasanifar A, Kaur K (2017) Breast cancer targeting peptide binds Keratin-1 : A new molecular marker for targeted drug delivery to breast cancer. Mol Pharm 14:593–604CrossRefGoogle Scholar
  30. Tantawy A, Nasr M, El-Sayed M, Tawfik S (2012) Synthesis and antiviral activity of new 3-methyl-1, 5-diphenyl-1H-pyrazole derivatives. Med Chem Res 21:4139–4149CrossRefGoogle Scholar
  31. Topcu Z (2001) DNA topoisomerases as targets for anticancer drugs. J Clin Pharm Ther 26:405–416CrossRefGoogle Scholar
  32. Trejo-soto P, Hernandez-campos A, Romo-Mancillar A, Medina-Franco J, Castillo R (2018) In search of AKT Kinase inhibitors as anticancer agents: Structure based design, docking and molecular dynamics studies of 2,4,6-trisubstituted pyridine. J Biomol Struct Dyn 36(2):423–442CrossRefGoogle Scholar
  33. Xia Y, Dong Z, Zhao B, Ge X, Meng N, Shin D, Miao J (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 15:6893–6899CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sinthiya J. Gawandi
    • 1
    • 2
  • Vidya G. Desai
    • 1
    • 2
    Email author
  • Sunil G. Shingade
    • 3
  1. 1.Department of ChemistryDnyanprassarak Mandal’s College & Research CentreBardezIndia
  2. 2.Goa UniversityPanajiIndia
  3. 3.Department of Pharmaceutical ChemistryPES’s Rajaram and Tarabai Bandekar College of Pharmacy, FarmagudiPondaIndia

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