In this research, three series of azole-hydrazone derivatives namely, benzimidazole, benzoxazole and benzothiazole were designed and synthesized. Their structures were confirmed by elemental analysis and spectroscopic techniques. Stereochemical configuration of the synthesized compounds (Z/E) was determined. The new derivatives were tested in vitro against both human breast adenocarcinoma (MCF-7) and human hepatic adenocarcinoma (HepG2) cell lines. The most active compounds 3h (IC50 = 0.067 μM against MCF-7) and 3l (IC50 = 0.027 μM against HepG2) were further tested for Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The most active 3h on EGFR was then screened for HER2 and VEGFR enzymes. Caspase-3/9 protein level expression were measured for the two compounds 3h and 3l. Cell cycle analysis showed pre G1 apoptosis and cell cycle arrest at G2/M phase. Up-regulation of Bax and down-regulation of Bcl-2 protein expression level confirmed apoptosis. Molecular docking analysis was performed for all the synthesized compounds inside the active site of EGFR.
Keywords: Benzimidazole; Benzothiazole; Benzoxazole; Caspases; Cell cycle.
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