Rational design, biological and in-silico evaluation of quinoline-chalcone hybrids: A new series of antimicrobial and...

This study investigates the synthesis, antimicrobial, anticancer, and in silico properties of novel quinoline-chalcone hybrids (nQCa-l), which were synthesized and characterized. Their antimicrobial activity revealed broad-spectrum efficacy, with compound 2QC-h demonstrating superior potency compared to several standard antibiotics and antifungals. The anticancer potential was assessed against gastrointestinal system cancer cell lines (AGS, HepG2, HCT116), where 2QC-h emerged as the most potent antiproliferative agent, often surpassing oxaliplatin in efficacy, particularly in AGS gastric cancer cells. Mechanistic studies have demonstrated that 2QC-h synergistically induces apoptosis and inhibits epithelial-mesenchymal transition (EMT) in AGS cells through the intrinsic mitochondrial pathway, thereby enhancing the anticancer effect of oxaliplatin. Crucially, 2QC-h exhibited selective cytotoxicity towards gastrointestinal system cancer cells (AGS cells: 4.85 ± 0.22 µg/mL and 2.66 ± 0.58 µg/mL, HCT116 cells: 6.61 ± 0.29 µg/mL and 2.39 ± 0.57 µg/mL, and HepG2 cells: 9.14 ± 0.49 µg/mL and 6.15 ± 0.27 µg/mL for 24 h and 48 h, respectively) and minimal morphological effects on healthy HUVEC cells. Computational studies, including DFT analysis, MEP, RDG, ELF, LOL, and ALIE, provided comprehensive insights into the electronic structure, reactivity, and non-covalent interactions, elucidating the structure-activity relationships (SAR). Molecular docking simulations identified VEGFR-2 and EGFR as the preferential targets for these derivatives, with nanomolar binding affinities, which correlated strongly with experimental cytotoxic potencies. ADME highlighted favorable drug-likeness properties while identifying areas for further optimization. Overall, this research establishes quinoline-chalcone hybrids as promising multi-target therapeutic agents with significant potential for developing novel antimicrobial and anticancer drugs.