Design, Synthesis, and Biological Evaluation of Novel 3-Thione Derivatives as Anticancer Agents

This study involved designing and synthesis of 3-substituted-5-(3,4-dimethoxy-phenyl)-3H-[1,3,4]oxadiazole-2-thione derivatives for interaction with EGFR (receptor tyrosine kinase), which plays a role in cancer cell growth. Molecular docking was performed on EGFR receptors using crystal structures with PDB IDs 4WD5 and 2J6M. The combination of hydrogen bonding, hydrophobic, and ionic interactions confirmed the robust nature of the ligand-protein binding. Docking scores for compounds ranged from 6.6 to 8.0 kcal/mol. The compound PODA-21 in this series had the best docking scores of 7.9 and 8.0 kcal/mol, which are greater than the reference drug gefitinib (7.0 and 6.0 kcal/mol) for PDB IDs 4WD5 and 2J6M respectively. The PreADMET study results confirmed good pharmacokinetic and toxicity profile. Ligand interaction with amino acid residues LYS A:745 and MET A:793, shared by reference standard and designed ligands, is vital for the binding affinity and for EGFR inhibition. The synthesized compounds were evaluated (MTT assay and Cell Apoptosis assay) against MCF-7 cell lines, including those resistant to EGFR inhibitors. The MTT assay and cell apoptosis assay showed that samples PODA-21 ("IC50" 50.51 +/- 1.64 mu g/mL) and AODA-13 ("IC50" 43.00 +/- 1.02 mu g/mL) exhibited moderate activity when compared to reference standard and molecular docking study came aligned with the biological results. The synthesized compounds displayed optimum biological activity; therefore, these can be treated as lead nuclei for further structural modification.