Apocynin as a Novel Natural Photosystem II Inhibitor: Target Identification and Structure-Based Design of Potent Herbicidal Derivatives

Abstract Natural products are an important source of lead compounds for novel pesticide discovery. In this study, we investigated the phytotoxicity and mode of action of the phenolic natural product apocynin. Chlorophyll fluorescence analysis indicated that apocynin induces leaf lesions by blocking photosystem II (PSII) electron transport beyond the primary quinone acceptor QA. Molecular docking and isothermal titration calorimetry (ITC) identified the D1 protein as the molecular target of apocynin, pinpointing His215 and His272 as critical binding residues. Guided by this interaction model, we designed thirty-six apocynin derivatives, among which two compounds (A4 and A6) with higher binding affinity and lower toxicity than apocynin were synthesized. Structure-activity relationship analysis further confirmed that both derivatives exhibit significantly stronger PSII inhibitory activity and superior herbicidal efficacy compared with the parent compound. This work establishes apocynin as a natural PSII inhibitor and highlights its phenolic scaffold as a promising platform for herbicide development.