Design, synthesis and biological evaluation of pyrazole derivatives as potential multi-kinase inhibitors in hepatocellular carcinoma

We described the optimization, by molecular modelling, of small pyrazole derivatives, as kinase inhibitors, obtained through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes. The two compounds, selected as potential agents active against hepatocellular carcinoma (HCC) were then evaluated in vitro for their biological activity on HCC-derived cell lines. The compounds show a promising inhibitory growth efficacy (IC50 50–100 μM) in SNU449 cell line, as well as block of cell cycle progression and induction of apoptosis, and can be considered as lead compounds for further SAR developments.

Figure optionsDownload as PowerPoint slideHighlights
► Molecular modelling for optimization of 3,5-substituted pyrazoles as kinase inhibitors in hepatocellular carcinoma.
► Synthesis through a 1,3-dipolar cycloaddition between nitrile imines and functionalized acetylenes.
► Inhibitory growth efficacy in HCC SNU449 cell line, block of cell cycle progression and induction of apoptosis.
► Inhibition of the PI3K/AKT/mTOR pathway in HCC.
► Potential leads for further SAR development.