Click synthesis of some novel benzo[ <i>d</i> ]thiazole–1,2,3-triazole hybrid compounds with benzamide and/or benzoate tethers as EGFR-dependent signaling inhibitors against breast cancer

The elaboration of anti-breast cancer agents targeting EGFR represents a promising strategy in medicinal chemistry. Consequently, under optimized Cu(i)-catalyzed click synthesis, a new library of 1,4-disubstituted 1,2,3-triazole-based benzo[<i>d</i>]thiazole scaffold carrying benzamide and/or benzoate tethers 5a-t was designed, synthesized, and characterized by appropriate spectral techniques. They were also screened for their <i>in vitro</i> anti-cancer activity against a panel of cancer cell lines, breast (T47D), prostate (PC3), lung (A549), and colon (HCT116) human cancer, along with normal fibroblast cells. Notably, the hybrid triazoles, 5p, 5s, and 5t emerged as the most potent candidates, especially against T47D, with IC₅₀ values of 15, 26, and 28 μM, respectively. Compound 5p significantly induced apoptosis in T47D by 27.3-fold, causing total apoptosis of 19.39% compared to 0.71%, arresting cell proliferation at the G₂/M phase. Regarding EGFR as the molecular target, among the tested compounds, 5p significantly inhibited EGFR by 96.8%, with an IC₅₀ value of 65.6 nM, compared to erlotinib, having an IC₅₀ value of 84.1 nM. Compound 5p showed promising PI3K/AKT/mTOR inhibition as the EGFR-dependent signaling pathway with IC₅₀ values of 4.98 μM, 0.21 μM, and 0.49 nM, respectively, compared to their reference inhibitors. Finally, a molecular docking study highlighted the binding mode disposition and binding interactions with key amino acids as a promising EGFR inhibitor.