Abstract
Breast cancer remains a leading cause of mortality worldwide, making it necessary
to develop more effective therapeutic agents. This study focuses on the
computational design and evaluation of a novel series of 4-phenyl-2H-
[1,3]thiazino[3,2-a]benzimidazol-2-imine (H-thiazine) derivatives as potential
epidermal growth factor receptor (EGFR) inhibitors. Using density functional theory
(DFT) at the M06-2X/aug-cc-pVTZ level, the compounds were optimized and
analyzed for electronic properties, stability, and reactivity. Compound Nitro was
found to be the most reactive and least stable, while compound H was found to be
more stable and the least reactive. Spectroscopic data (NMR, IR) were calculated
and validated against experimental values. Pharmacological potential was
assessed through molecular docking, ADMET predictions, molecular dynamics
(MD) simulations, and MM-GBSA calculations. Several compounds, particularly
Methyl and Bromine-substituted derivatives, demonstrated enhanced binding
affinity, favorable pharmacokinetic profiles, and dynamic stability compared to the
reference drug, Olmutinib. These findings suggest that rationally designed thiazine
derivatives could serve as promising scaffolds for future EGFR-targeted anticancer
therapy.