Design, synthesis, and antiproliferative activity of new indole/1,2,4‐triazole/chalcone hybrids as EGFR and/or c‐MET inhibitors

Abstract

A novel group of indolyl-1,2,4-triazole-chalcone hybrids was designed, synthesized, and assessed for their anticancer activity. The synthesized compounds exhibited significant antiproliferative activity. Compounds 9a and 9e exhibited significant cancer inhibition with GI₅₀ ranging from 3.69 to 20.40 µM and from 0.29 to >100 µM, respectively. Both compounds displayed a broad spectrum of anticancer activity with selectivity ratios ranging between 0.50-2.78 and 0.25-2.81 at the GI₅₀ level, respectively. The synthesized compounds were also screened for their cytotoxicity by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazol (MTT) assay and for inhibition of epidermal growth factor receptor (EGFR) and c-MET (mesenchymal-epithelial transition factor). Some of the tested compounds exhibited significant inhibition against EGFR and/or c-MET. Compound 9b showed the highest c-MET inhibition (IC₅₀ = 4.70 nM) compared to foretinib (IC₅₀ = 2.5 nM). Compound 9d showed equipotent activity compared with erlotinib against EGFR (IC₅₀ = 0.052 µM) and displayed significant c-MET inhibition with an IC₅₀ value of 4.90 nM.