Novel Insights into Quinoline-Based Oxime Ether Derivatives with E/ Z Isomerization Possessing Antifungal Activity and Their Mechanism of Action

Numerous bioactive oxime ethers are utilized as pharmaceuticals and agrochemicals. However, the correlations among C═N-O bond E/Z isomerization, biological activity, and molecular targets of such compounds remain poorly elucidated. Herein, we constructed 54 novel quinoline-based oxime ether derivatives and illustrated their differential target-binding behavior of E/Z-isomers toward the putative target cytochrome bc₁. E-isomer A₂₃ exhibited the most potent activity against Colletotrichum sublineola with an EC₅₀ value of 0.68 μg/mL, markedly higher than that of its Z-isomer (4.12 μg/mL). It also exerted stronger inhibitory effects on cytochrome bc₁ with an IC₅₀ of 16.6 μg/mL relative to B₂₃ (26.9 μg/mL), which further disturbed mitochondrial function, thereby inducing ROS accumulation and cell membrane damage. A₂₃ showed high protective (86.9%) and curative (80.7%) effects with low toxicity. This study reveals great potential of novel quinoline oxime ethers for Fungal control and provides a new perspective for understanding how molecular configuration differences influence biological activity.