QCS-h

This study presents the rational design, synthesis, and comprehensive evaluation of a novel series of quinoline-sulfonamide-chalcone (QCSa-i) hybrids as potential multi-targeted therapeutic agents. By a hybridization approach, the series was investigated for the antimicrobial, anti-quorum sensing, antibiofilm, and anticancer activities, complemented by extensive in silico analyses including (DFT) calculations and molecular docking simulations against key oncogenic targets (Bcl-2, EGFR, Survivin), alongside ADME profiling. The studied compounds demonstrated promising biological activities, with QCS-h emerging as a lead candidate exhibiting broad-spectrum antimicrobial activity against both B. cereus, P. aeruginosa, and C. glabrata, with considerably lower IC₅₀ values compared to the used standards, tetracycline and nystatin. Furthermore, QCS-h demonstrated superior antibiofilm activity, achieving over 80% inhibition against strong biofilm-forming Escherichia coli at all tested concentrations. Molecular docking studies revealed the QCS-h's remarkable binding affinity for the Epidermal Growth Factor Receptor (EGFR), with a binding energy of -11.25 kcal/mol and a theoretical inhibition constant of 5.68 nM, significantly outperforming the control compound (1.85 μM). DFT calculations provided insights into the electronic properties, facilitating the understanding of the wet experiments. The favorable ADME profiles further support the drug-like potential of these compounds. This integrative approach highlights the therapeutic promise of quinoline-sulfonamide-chalcone hybrids, particularly QCS-h, as multi-targeted agents for combating antimicrobial resistance and gastrointestinal malignancies, providing valuable insights for future rational drug design strategies.