Design, synthesis, and biological evaluation of 1,3,5-trisubstituted pyrazoles as tyrosine kinase inhibitors
- 62 Downloads
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.
KeywordsHydrazones Pyrazoles Solvent-free Tyrosine kinase Apoptosis Anti-proliferative activity
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.
- 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
- 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
- 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
- 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
- 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