Molecular insights into the bioactivity of H-thiazine compounds against breast cancer cells: a computational study

Breast cancer, a leading cause of global mortality, necessitates novel therapies targeting key drivers like the epidermal growth factor receptor (EGFR). This computational study evaluates nine 4-phenyl-2H-[1,3]thiazino[3,2-a]benzimidazol-2-imine (H-thiazine) derivatives as potential EGFR inhibitors. Using molecular docking, ADMET profiling, molecular dynamics simulations, and binding energy calculations, we identified methyl- and bromine-substituted derivatives as probable candidates that outperform the reference drug Olmutinib in terms of binding affinity, pharmacokinetics, and stability. Although these compounds showed promising bioactivity, in silico toxicity screening indicated potential AMES mutagenicity and hERG-II inhibition, highlighting important safety liabilities. Overall, thiazine derivatives represent viable scaffolds for EGFR-targeted anti-cancer development; however, further optimization and experimental validation, including biochemical assays and genotoxicity testing, are required to confirm their therapeutic potential. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-025-00542-y.