New quinazoline-[1,2,4]triazolo[3,4- <i>b</i> ][1,3,4]thiadiazines as inhibitors of EGFR: synthesis, anti-breast cancer evaluation and <i>in silico</i> 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-<i>b</i>][1,3,4]thiadiazines were designed and synthesized using a pharmacophore hybridization technique that combined biologically active scaffolds. <i>In vitro</i> 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) <i>in vitro</i>, 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 <i>in silico</i> molecular docking investigations using the Discovery Studio 2021 methodology.