Design, Synthesis, and Biological Evaluation of Novel Quercetin Analogs: Discovery of a Hybrid Molecule with Potent Antitumor Activity in Non-Small Cell Lung Cancer

Quercetin and quinazoline are well-known bioactive scaffolds with anticancer properties. In this study, we designed, synthesized, and evaluated 44 novel hybrid compounds combining quercetin and quinazoline structures to target KRAS-driven non-small cell lung cancer (NSCLC). All compounds were structurally confirmed via NMR and MS. Biological activities were assessed across NSCLC cell lines (H1299, H1975, H441, and A549) using sulforhodamine B (SRB) assays, along with colony formation, migration, and sphere formation assays. Among them, compound 15 exhibited the most potent and consistent activity, with IC₅₀ values in the low micromolar range. Western blot and RNA sequencing analysis revealed that compound 15 selectively downregulated key components of the PI3K/mTOR pathway, without significantly affecting RAF/MAPK signaling. Molecular docking indicated strong binding affinity with KRAS, while molecular dynamics simulations confirmed stable interactions (RMSD < 2.5 Å) and minimal fluctuations at the binding interface (low RMSF). These results suggest that compound 15 is a promising candidate for targeting KRAS-mediated signaling in NSCLC.