Novel Insights into Quinoline-Based Oxime Ether Derivatives with <i>E</i> / <i>Z</i> 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.