Design, Synthesis, and Herbicidal Activity of Pyrimidinedione-Benzamide Derivatives as Potential Protoporphyrinogen IX Oxidase Inhibitors

Abstract Weeds cause significant yield losses worldwide, and herbicides are essential for their control. Protoporphyrinogen IX oxidase (PPO) is a well-validated herbicide target. In this study, a series of pyrimidinedione benzamide derivatives (A1–A37) were designed, synthesized, and evaluated for herbicidal activity. Most compounds showed excellent activity against dicotyledonous weeds at 37.5 g a.i./ha, and compounds A13 and A20 maintained over 80% inhibition of Amaranthus retroflexus even at 2.34 g a.i./ha. Compounds A7, A13, and A20 displayed broad-spectrum activity against eight weed species, favorable crop safety to wheat and corn, and low toxicity to honey bees. Surface plasmon resonance (SPR) assays confirmed their affinity to Nicotiana tabacum PPO (NtPPO) with KD values of 0.819–2.66 nM, and molecular docking combined with molecular dynamics simulations provided insights into their binding modes. These results suggest that A7, A13, and A20 could be promising PPO inhibitor candidates and provide a useful basis for further optimization.