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

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 IC sub(50) 0.58 plus-minus 0.02 micrometre against the MDA-MB-231 cell line. Whereas compound 3k showed higher inhibitory activity with IC sub(50) value 0.78 plus-minus 0.03 micrometre 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.