Design, synthesis, apoptotic, and antiproliferative effects of 5-chloro-3- (2-methoxyvinyl)-indole-2-carboxamides and pyrido[3,4-b]indol-1-ones as potent EGFR WT/ EGFR T790M inhibitors.

A new series of indole-2-carboxamides , and pyrido[3,4-b]indol-1-ones and have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. , , , , , and have the highest antiproliferative activity with GI values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI = 33 nM). Compounds , , and inhibited EGFR with IC values ranging from 68 to 85 nM while the GI of erlotinib is 80 nM. Moreover, compounds and had the most potent inhibitory activity against EGFR with IC values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC = 8 ± 2 nM). Compounds and demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds and within EGFR and EGFR active sites. Finally, ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.