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

Abstract

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, <i>viz.</i>, MDA-MB-231 (breast), T47D (breast) and MCF-7 (breast), A549 (lung) and HT-29 (colorectal). Compounds <b>2c</b> and <b>2d</b> emerged as better anticancer molecules with no toxicity towards normal cells. <b>2c</b> and <b>2d</b> inhibited EGFR enzymatic activity <i>in vitro</i> with IC₅₀ 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 an <i>in silico</i> interaction model of <b>2c</b> and <b>2d</b>-EGFR complexes that guided and allowed substitution of the 4-fluorophenyl ring (<b>2c</b> and <b>2d</b>) with 4-(4-methylpiperazinyl)-3-nitrophenyl at the N-9 position, resulting in compound <b>3c</b> with 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). <b>3c</b> exhibited 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 μM). Further investigation revealed that <b>3c</b> also induced an increase in ROS levels in cancer cells in a mitochondrial-independent manner and halted the cell cycle at the sub-G₁ phase.