Synthesis, Crystallographic Study, Hirshfeld Surface Analysis, Energy Frameworks, and DFT Calculation of Quinoline-4-Ester Derivatives as Antifungal Agent.

Inspired by natural quinoline, a series of novel quinoline-4-ester derivatives featuring a biphenyl motif were designed and synthesized via six steps. All the target compounds were characterized by 1H NMR, 13C NMR, and HRMS. These compounds were evaluated for their fungicidal activity in vitro. The fungicidal activity results showed that all 13 compounds in this series had certain fungicidal activity against 10 types of fungus. Compounds 7a-7c possessed moderate fungicidal activity (31.3%) against Alternaria solani, whereas compound 7g exhibited moderate fungicidal activity (33.3%) against Physalospora piricola. Structure-activity relationships indicated ortho- or meta-methyl substituents will increase activity. Furthermore, the compound 7d was characterized by x-ray diffraction. Hirshfeld surface analysis identified that H···H (46.9%), H···C (11.7%), and H···X (7.3%) interactions are the dominant crystal packing force, whereas density functional theory (DFT) calculations provided the energy gap (ΔE = 4.15 eV), chemical softness (σ, 0.48) and chemical hardness (η, 2.07), and electrophilicity index (ω, 7.16) for further optimization.