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

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.

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).

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.

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