Design, synthesis, and in silico evaluation of phenothiazine-based pyridine and thiazolidine-2,4-dione hybrids as promising EGFR inhibitors through a combined DFT docking and molecular dynamics (MD) simulation approach

A series of phenothiazine-based pyridine and thiazolidine-2,4-dione hybrids ( PHO-1–PHO-5 ) were designed, synthesized, and evaluated as potential EGFR-targeted anticancer agents. The hybrids were characterized by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) spectroscopy, UV-visible (UV-Vis) spectroscopy, and elemental analyses. Photophysical studies revealed strong π–π* and intramolecular charge-transfer transitions with red-shifted absorption for the most conjugated derivatives. Density functional theory (DFT) calculations supported the experimental data, indicating decreased highest occupied molecular orbitals-lowest unoccupied molecular orbitals (HOMO-LUMO) gaps (2.01–2.25 eV) and enhanced charge delocalization in PHO-4 and PHO-5 . Molecular docking against EGFR (PDB ID: 4HJO) showed high affinity, particularly for PHO-4 (-9.02 kcal/mol), forming key hydrogen bonds and π–π interactions with Met769, Asp831, and Thr766. Molecular dynamics (MD) simulations over 100 ns confirmed the complex stability (RMSD 2.0-2.8 Å). Cytotoxic evaluation against MCF-7 cells revealed potent activity for PHO-4 and PHO-5 with IC₅₀ values close to doxorubicin. These findings demonstrate that integrating DFT, molecular docking, and MD simulations can effectively guide the design of novel phenothiazine-based pyridine and thiazolidine-2,4-dione derivatives as promising EGFR inhibitors for anticancer therapy.