New quinazoline-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines as inhibitors of EGFR: synthesis, anti-breast cancer evaluation and in silico studies†

Breast cancer is the most frequently diagnosed malignancy in women. Invasive breast cancer will be diagnosed in approximately one in every eight women during their lifetime. Quinazoline-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed and synthesized using a pharmacophore hybridization technique that combined biologically active scaffolds. In vitro assays of the synthesized compounds' cancer activity against three breast cancer cell lines: MCF-7, MDA-MB-231, and MDA-MB-468, compounds 6i, 6k, and 6l exhibited significant activity. Compounds 6j and 6m exhibited equivalent efficacy relative to the standard drug against the MDA-MB-231 cell line, but compound 6i showed significant activity against the MDA-MB-468 cell line. Moreover, compound 6i (IC₅₀ = 0.37 ± 0.03 μM) demonstrated superior efficacy compared to the standard erlotinib (IC₅₀ = 0.42 ± 0.01 μM) in vitro, based on EGFR inhibitory assays and compound 6k (IC₅₀ = 0.51 ± 0.04 μM) showed good EGFR inhibitory activity. To validate the activity data and the drug-likeness of the compounds, six potent compounds were subjected to in silico molecular docking investigations using the Discovery Studio 2021 methodology.