Herbicidal mechanism of Isovanillic acid and computational structure-guided design of high-potency derivatives
He Wang1, Yanjing Guo1, Yu Ji1
1State Key Laboratory of Agricultural and Forestry Biosecurity, Natural Small-Molecule Pesticides Laboratory, College of Life Sciences, Nanjing Agricultural University, Nanjing, P. R. China.
Background:
Natural products are a valuable resource for exploring novel pesticides and play a crucial role in weed management. Isovanillic acid (IVA), a bioactive compound produced by plants, exhibits various active functions. However, studies on IVA's herbicidal activity and its mechanism of action remain scarce. This study demonstrates that IVA acts as a natural photosystem II (PSII) inhibitor, providing new insights into its phytotoxicity.
Results:
IVA significantly inhibited photosynthetic activity in Chlamydomonas reinhardtii and induced visible leaf lesions on Ageratina adenophora. Phytotoxicity bioassays confirmed that IVA has a broad-spectrum activity, highlighting its potential as a bioherbicide. Chlorophyll fluorescence studies demonstrated that IVA primarily disrupts PSII electron flow beyond plastoquinone QA, ultimately inactivating PSII reaction centers. Isothermal titration calorimetry (ITC) experiment confirmed the binding affinity between D1 protein and IVA, while molecular docking analysis further identified histidine 215 of the D1 protein as IVA's key binding residue-a mechanism shared with classical phenolic PSII herbicides. Using the IVA-D1 protein interaction model, 41 IVA derivatives were designed and ranked based on free energy calculations and toxicity predictions. Among these, three optimized compounds (D11, D12 and D13) with higher predict binding affinity but lower mammalian toxicity than IVA were screened and synthesized. Structure-activity relationship analysis revealed that these derivatives achieved approximately twofold stronger PSII inhibition and significantly enhanced herbicidal efficacy compared to the parent compound.
Conclusion:
These results identify IVA as a novel natural PSII inhibitor and a strategic scaffold for discovering new high-efficacy herbicidal derivatives. © 2025 Society of Chemical Industry.
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