Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole , , -, and , pyrazolo[4',3':5,6]pyrano[2,3-d]pyrimidine , pyrazolo[3,4-d]pyrimidine and , and pyrazolo[3,4-c]pyrazole derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds , , , , , , and showed nearly 10 fold higher activity than erlotinib (10.6 μM) with IC ranging from 0.31 to 0.71 μM. EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound as the most potent EGFR inhibitor (IC = 0.06 μM) and compound as the most potent VEGFR-2 inhibitor (IC = 0.22 μM). Moreover, compounds and revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.