Design, Synthesis, and Activity Evaluation of Novel Herbicide Safeners Derived from the Natural Product Quinine

Benzobicyclon, a 4-hydroxyphenylpyruvate dioxygenase inhibitor widely used in paddy fields, controls rice weeds but causes phytotoxicity in indica rice. To mitigate this injury, a series of novel quinoline derivatives was designed via active substructure splicing. Bioassays confirmed that most compounds effectively alleviated benzobicyclon phytotoxicity in indica rice. Content of chlorophyll and glutathione, and related detoxification enzymes activity assays revealed compound I-3 exhibited superior safening efficacy compared to commercial cyprosulfamide. Molecular overlay and molecular docking indicated close structural similarity to benzobicyclon, supporting competitive binding. DFT calculations further corroborated the bioactivity of compound I-3. ADMET prediction was similar to cyprosulfamide, and ecological assessment suggested low nontarget toxicity. Thus, I-3 is a promising lead structure for novel herbicide safeners.