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

TL;DR

This study explores H-thiazine compounds as potential treatments for breast cancer by evaluating their ability to inhibit EGFR, a key cancer driver.

Contribution

The study introduces new H-thiazine derivatives with better binding and stability than existing drugs, though safety concerns remain.

Findings

Methyl- and bromine-substituted H-thiazine derivatives showed higher binding affinity and stability than Olmutinib.

In silico toxicity screening revealed potential mutagenicity and hERG-II inhibition risks for the compounds.

H-thiazine derivatives are promising EGFR-targeted anti-cancer scaffolds requiring further experimental validation.

Abstract

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.

The online version contains supplementary material available at 10.1007/s40203-025-00542-y.

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