Rational design, synthesis, structure–activity relationship, computational investigation, and biological evaluation of novel chalcone derivatives against non-small cell lung cancer

This study aimed to explore the therapeutic potential of new chalcone derivatives for non-small cell lung cancer (NSCLC) in depth via multiple methods, including design, synthesis, in silico, and in vitro studies. Three chalcone derivatives, (2E)-1-(3,4-dichlorophenyl)-3-(thiophen-2-yl)prop-2-en-1-one,(2E)-1-(3,4-dichlorophenyl)-3-(3-methylthiophen-2-yl)prop-2-en-1-one, and (2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one, were synthesized via Claisen-Schmidt condensation and characterized via Fourier transform infrared (FT-IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and thermal analysis. Molecular docking studies were subsequently carried out against the vascular endothelial growth factor receptor 2 (VEGFR2) kinase domain (PDB ID: 4ASD), which has favorable docking scores: the ligand with the best docking score of −8.6 kcal/mol was (2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one. Molecular dynamics simulation of this complex (4ASD-(2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one) revealed that it remained stable for a period of 200 ns. Qualitative structure–activity relationship (SAR) investigation discovered that donor–acceptor substitution configurations in -(2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one) boost the biological activities, which is validated by kinase inhibitor prediction based on PASS prediction. The MTT assay revealed that (2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one selectively induced toxicity in the A549 lung cancer cell line (IC ₅₀  = 29.03 µg/ml) compared with normal fibroblasts (IC ₅₀  = 67.54 µg/ml). Flow cytometry-based apoptosis and cell cycle studies confirmed its ability to induce apoptosis (29.6%) and cell cycle arrest at the sub-G1 phase. These promising results from computational and experimental studies underscore the potential of chalcone derivative (2E)-1-(23,4-trichlorophenyl)-3-(24,5-trimethoxyphenyl)prop-2-en-1-one to serve as an excellent therapeutic agent in Non-Small Lung Cancer Cells (NSCLC) therapy.