Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors.

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives - prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives -, -, and . Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds -, -, and demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and - (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than - and , indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI = 1.10 µM), compounds , , , , , and were the most effective of the synthesised derivatives, with GI ranging from 0.95 µM to 1.50 µM. Compounds , , , , , and were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.