| Summary: | Epidermal Growth Factor Receptor (EGFR), its wild type and mutations L858R/T790M, is overexpressed in non-small cell lung cancer (NSCLC) patients and is considered an inevitable oncology target. However, while the potential EGFR inhibitors have been represented in the literature, their cellular activity failed to establish broad potency against EGFR and its mutations. This study identifies a new series of EGFR<sup>L858R/T790M</sup> inhibitors bearing hydantoin acetanilides. Most compounds revealed strong antiproliferative activity in a range of NSCL cancer models (A549, H1975, and PC9), in which <b>5a</b> and <b>5f</b> were the most potent. Compounds <b>5a</b> and <b>5f</b> possessed potent anticancer activity on H1975 cells with IC<sub>50</sub> values of 1.94 and 1.38 µM, respectively, compared to 9.70 µM for erlotinib. Favorably, <b>5a</b> and <b>5f</b> showed low activity on WI-38 normal cells. Western blotting and an EGFR kinase assay test proved the significant EGFR inhibitory activity of <b>5a</b>. Besides, active hydantoin derivative <b>5a</b> strongly arrested the cell cycle at the sub G1 and S phases and triggered apoptosis in A549 cells. These results imply that <b>5a</b> could be considered a promising lead compound for additional development as a potential active agent for anticancer therapy.
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