Musatat, Ahmad BadreddinKiliccioglu, IlkerLouaileche, TinhinaneDulger, GorkemMaouche, ChaimaTabti, SalimaKurman, Yener2025-10-112025-10-1120250022-28601872-8014https://doi.org/10.1016/j.molstruc.2025.143401https://hdl.handle.net/20.500.12684/21947Novel carbazole-quinoline-chalcone hybrids (nQCC1-4) were synthesized via Claisen-Schmidt condensation and evaluated against AGS gastric adenocarcinoma cells. The most potent compound, 1QCC-1, exhibited significant antiproliferative activity (IC50 values of 19.11 mu g/mL and 7.91 mu g/mL at 24 h and 48 h). Compounds 1QCC-4, 1QCC-3, and 2QCC-2 demonstrated comparable cytotoxic efficacy against AGS cells. Density functional theory (DFT) calculations revealed substituent-dependent electronic properties, with chloro-quinoline derivatives displaying enhanced electrophilicity (omega = 13.745-14.157 eV) and reduced HOMO-LUMO gaps (Delta E = 3.304-3.347 eV), correlating with improved bioactivity profiles. Molecular docking studies identified robust binding interactions with oncogenic targets, MAPK1 p38 kinase, HER2, and RhoA, with 1QCC-4 exhibiting superior binding affinity for HER2 (Delta G = -12.05 kcal/mol, IC50 = 1.48 nM) through hydrogen bonding with Lys114 and it-alkyl interactions with Leu156. ADMET profiling highlighted favorable drug-likeness parameters despite solubility challenges (LogS = -7.846 to -6.291) and potential CYP450 inhibition. Non-covalent interaction (NCI-RDG) and molecular electrostatic potential (MEP) analyses elucidated key stabilizing interactions and nucleophilic/electrophilic hotspots. These hybrids represent a strategic integration of natural product pharmacophores, leveraging synergistic electronic and steric effects for selective kinase inhibition, positioning them as promising leads for targeted gastric cancer therapy.en10.1016/j.molstruc.2025.143401info:eu-repo/semantics/closedAccessCarbazoleChalconeQuinolineAGS CancerIn silicoArticle13482-s2.0-105011257477WOS:001552072000001Q1Q2