Design, synthesis, and biological evaluation of novel EGFR inhibitors containing 5-chloro-3-hydroxymethyl-indole-2-carboxamide scaffold with apoptotic antiproliferative activity

[Display omitted] •A series of novel indole-2-carboxmide derivatives 9–23 as EGFR inhibitors has been designed and synthesized.•Compounds 10, 11, 13, 15 and 17–19 were the most active antiproliferative agents.•15, 16, 19 and 20 display potent antiproliferative activity with strong inhibition of EGFR.•Compound 19 induced apoptosis and cell cycle arrest in pre-G1 and G2/M phases.•Docking study revealed that compounds 15, 16, 19, and 20 exhibited higher affinities toward EGFR compared to erlotinib. New EGFR inhibitor series of fifteen 5-chloro-3-hydroxymethyl-indole-2-carboxamide derivatives has been designed, synthesized, and tested for antiproliferative activity against a panel of cancer cell lines. The results showed that p-substituted phenethyl derivatives 10, 11, 13, 15 and 17–19 showed superior antiproliferative activity compared to their m-substituted counterparts 12, 14, 16 and 20. Compounds 15, 16, 19 and 20 displayed promising EGFR inhibitory activity as well as an increase in caspase 3 levels. Compounds 15 and 19 increased caspase-8 and 9 levels, as well as inducing Bax and decreasing Bcl-2 protein levels. Compound 19 demonstrated cell cycle arrest at pre-G1 and G2/M phases. The results of the docking study into the active site of EGFR revealed strong fitting of the new compounds with higher binding affinities compared to erlotinib.