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

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 dis
played 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.