Abstract
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•Novel azole derivatives were designed, synthesized and screened for their antitumor activity over HepG2 cells.•The cytotoxic screening showed that, triazole 25 exhibited higher activity by 4.75-fold than sorafenib.•Compounds 25 and 29 displayed a dual VEGFR-2 and β-tubulin polymerization inhibition and induced apoptosis by increasing sub-G1 phase.•The pro-apoptotic activity for compounds 25 and 29 were due to up-regulation of P53, Fas/Fas-ligand and BAX/BCL-2 ratio.
Novel azole derivatives 3–30 were designed, synthesized, and screened for their antitumor activity on HepG2 cell line. The cytotoxicity screening demonstrated that imidazolone 8 and triazoles 25 and 29 exhibited more potent cytotoxic activities by 1.21-, 4.75-, and 1.8-fold compared to Sorafenib (SOR). Furthermore, vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme inhibition assay declared that compounds 25 and 29 had inhibitory activity at the nanomolar concentration. Moreover, the tested compounds exhibited good β-tubulin (TUB) polymerization inhibition percentages. In addition, DNA flow cytometry analysis over HepG2 cells indicated that triazoles 25 and 29 demonstrated arrest at G1 and G2/M phase of the cell cycle and induced apoptotic activity by increasing sub-G1 phase. Finally, mechanistic studies of the proapoptotic activities of compounds 8, 10, 11, 25, and 29 indicated that they induced upregulation of P53, Fas/Fas-ligand, and BAX/BCL-2 ratio expression that resulted in increasing the active caspase 3/7 percentages and trigger apoptosis.