A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed
as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of
the new compounds was studied. 5c, 5d, 5f, 5g, 6e, and 6f have the highest antiproliferative activity with GI50
values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 ¼ 33nM). Compounds 5d,
5f, and 5g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM.
Moreover, compounds 5f and 5g had the most potent inhibitory activity against EGFRT790M with IC50 values of
9.5± 2 and 11.9 ±3nM, respectively, being equivalent to the reference osimertinib (IC50 ¼ 8±2nM).
Compounds 5f and 5g 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 5f and 5g within EGFRWT and EGFRT790M active sites. Finally, in silico
ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds