Anticancer potential of some imidazole and fused imidazole derivatives: exploring the mechanism via epidermal growth factor receptor (EGFR) inhibition

Imidazole-based epidermal growth factor receptor (EGFR) inhibitors were computationally designed and synthesized. All the compounds were assessed for their anti-proliferative activity against five cancer cell lines,viz., MDA-MB-231 (breast), T47D (breast) and MCF-7 (breast), A549 (lung) and HT-29 (colorectal). Compounds2cand2demerged as better anticancer molecules with no toxicity towards normal cells.2cand2dinhibited EGFR enzymatic activityin vitrowith IC(50)values of 617.33 +/- 0.04 nM and 710 +/- 0.05 nM, respectively. In order to further improve the potency, we explored an unoccupied area of the ATP binding domain of EGFR and analysed anin silicointeraction model of2cand2d-EGFR complexes that guided and allowed substitution of the 4-fluorophenyl ring (2cand2d) with 4-(4-methylpiperazinyl)-3-nitrophenyl at the N-9 position, resulting in compound3cwith a better binding score and potent EGFR inhibitory activity (IC50: 236.38 +/- 0.04 nM), which was comparable to the positive control erlotinib (239.91 +/- 0.05 nM).3cexhibited a great improvement in anticancer potency with inhibition of cell growth of all cancer cell lines at very low micromolar concentrations (IC50= 1.98 to 4.07 mu M). Further investigation revealed that3calso induced an increase in ROS levels in cancer cells in a mitochondrial-independent manner and halted the cell cycle at the sub-G(1)phase.