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

Abstract

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, 5 g, 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 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFR^WT with IC₅₀ values ranging from 68 to 85 nM while the GI₅₀ of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFR^T790M with IC₅₀ values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC₅₀ = 8 ± 2 nM). Compounds 5f and 5 g 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 5 g within EGFR^WT and EGFR^T790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.

Graphical Abstract

Keywords:

• Indole
• antiproliferative
• EGFR
• mutation
• resistance
• apoptosis
• ADME

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was funded by Princess Nourah Bint Abdulrahman University Researchers Supporting Project Number [PNURSP2023R3], Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.