Computer-aided design, synthesis, and biological evaluation of new indole-2-carboxamide derivatives as PI3Kα/EGFR inhibitors.

ABSTRACT

Structure-based drug design and molecular modeling were employed to identify a new series of indole-2-carboxamides as potential anticancer agents. These compounds were synthesized and characterized with the aid of several spectroscopic techniques, such as FT-IR, NMR, and mass spectrometry as well as by elemental analysis. Molecular docking studies confirmed that the newly synthesized compounds accommodate PI3Kα and EGFR kinase catalytic sites and form H-bonding with the key binding residues. The antitumor activity of these new compounds against an array of cancer cell lines (human colon carcinoma (HCT116), leukemia (K562), and breast cancer (MDA231) was evaluated. Results revealed that these compounds were selective against the kinase domain, and none of them showed any inhibitory activity against K562. In addition, results showed that compound 13 exhibited high potency in HCT116 and MDA231 with IC50 values of 19 and 15µM, respectively. Our findings recommend that further optimization of this series would be beneficial for colon and breast cancer treatment.