Novel Quinoline-4-ester Derivatives as Antifungal Agent: Synthesis, and In Silico Study

A novel series of 2,3-dimethyl-8-fluoro-6-tert-butylquinoline-4-ester derivatives ( 5a–5p ) were designed and synthesized based on a quinoline scaffold. Their structures were confirmed by 1 H NMR, 1 3 C NMR, IR, and HRMS, and compound 5g was further characterized by single-crystal x-ray diffraction. The in vitro antifungal activities of the target compounds were evaluated against ten phytopathogenic fungi, with tebufloquin as the positive control. Several derivatives showed selective activity against Magnaporthe oryzae , among which compounds 5j , 5l , and 5o exhibited 88.9% inhibition at 50 ppm. Preliminary structure–activity relationship analysis suggested that electron-withdrawing substituents on the benzoyl moiety were favorable for activity. Hirshfeld surface analysis, DFT calculations, ADMET prediction, and molecular docking were further performed to investigate the structural features, electronic properties, and possible binding mode of the representative active compound. These results provide useful guidance for the further optimization of fluorinated quinoline-4-ester derivatives as candidate fungicides. Graphical A series of fluorinated quinoline-4-ester derivatives is designed and synthesized based on the tebufloquin scaffold. Several compounds exhibit excellent selective inhibition (88.9%) against Magnaporthe oryzae . Structure–activity relationship analysis reveals that electron-withdrawing substituents on the benzoyl moiety favor activity. DFT calculations, ADMET prediction, and molecular docking provide insights into electronic properties and binding modes.