Synthesis and Biological Assessment of 3',4',5'-Trimethoxychalcone Derivatives against A549 and Molecular Insight Through Molecular Docking and Dynamics Studies.

Abstract

Background: In our previous work, 3',4',5'-Trimethoxychalcone with 3,4-disubstituent (OCH3, OH) on the B ring exhibited high inhibitory activity against A549. Thus, this study aims to further study by replacing functional groups on the B ring with alkyl and halogen groups supported by molecular docking and dynamics studies targeting EGFR-TK to investigate the binding interaction and its stability.

Methods: 3',4',5'-Trimethoxychalcone derivatives were prepared from 3',4',5'- trimethoxyacetophenone and substituted benzaldehyde using Claisen-Schmidt condensation under base condition. The pure products were characterized by 1H, 13C NMR spectroscopy, and mass spectrometry. Cytotoxic activity was performed using the MTT assay method. Moreover, molecular docking and dynamics simulation were conducted using the YASARA package (v21.6.17) targeting EGFR-TK (PDB ID: 1M17).

Results: New compound (2) and sixteen known compounds (1, 3-17) were obtained. Compounds 6 and 7 were two of the best active compounds with IC50 values of 0.43 and 5.47 μM. Molecular docking revealed that compounds 6, 7, and 14 exhibited similar binding interactions, including hydrogen bonding, van der Waals (vdW) forces, π-π stacking, and π-anions. Additionally, molecular dynamics analysis demonstrated that the complexation between the inhibitors (6, 7, 14, and erlotinib) and EGFR-TK was highly stable.

Conclusion: The potential of 3',4',5'-trimethoxychalcone derivatives as anticancer agents for targeting A549 cancer cell lines warrants further investigation.