Abstract
Background: Breast cancer remains one of the leading causes of cancer-related mortality worldwide, necessitating the development of new chemotherapeutic agents with improved efficacy and safety. In this context, molecular hybridization of biologically active heterocycles such as imidazole and dihydropyrimidine offers a promising strategy for anticancer drug discovery. The present study aimed to design, synthesize, characterize, and evaluate a novel series of imidazole-linked 3,4-dihydropyrimidine-2(1H)-thione hybrids as potential anticancer agents against the MCF-7 breast cancer cell line. Methods: The target compounds (4a-4j) were synthesized through an optimized one-pot Biginelli reaction using acetic acid as a green catalyst under mild conditions. Structural elucidation of the synthesized derivatives was carried out using FT-IR, 1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The synthesized compounds were screened for cytotoxic activity against MCF-7 cells using the MTT assay. Molecular docking studies were performed against EGFR tyrosine kinase (PDB ID: 1M17), followed by DFT calculations and in silico ADME/drug-likeness evaluation. Results: Among the synthesized derivatives, compounds 4c and 4g exhibited the most potent cytotoxic activity with IC50 values of 8.3 ± 0.60 µM and 14.8 ± 0.20 µM, respectively. Molecular docking revealed strong binding interactions with EGFR, showing binding affinities of -18.7 kcal/mol for 4c and -16.2 kcal/mol for 4g through hydrogen bonding, π-π stacking, and hydrophobic interactions. DFT analysis indicated favorable electronic properties with low HOMO-LUMO energy gaps, supporting enhanced molecular reactivity. ADME profiling confirmed acceptable drug-likeness, high gastrointestinal absorption, and compliance with Lipinski’s rule of five. Conclusion: The present study demonstrates that imidazole-linked dihydropyrimidine-2(1H)-thione hybrids represent promising anticancer scaffolds. Particularly, compounds 4c and 4g emerged as potential lead molecules for further optimization and preclinical investigation targeting EGFR-mediated breast cancer therapy.