Discovery of Benzoxazole–Pyrimidinedione Hybrids as Novel Protoporphyrinogen Oxidase Inhibitors

Protoporphyrinogen oxidase (PPO) is a well-established target for herbicide discovery. However, the development of new PPO inhibitors featuring novel scaffolds remains highly desirable to address herbicide resistance and improve application performance. In this study, a scaffold-hopping strategy was employed to incorporate a benzoxazole motif into pyrimidinedione-based PPO inhibitor frameworks, leading to the design and synthesis of a series of benzoxazole–pyrimidinedione hybrids. Among the synthesized compounds, XII07 and XII08 showed herbicidal activity against selected dicotyledonous and monocotyledonous weed species in Petri dish assays, together with promising post-emergence and moderate-to-good pre-emergence activities in greenhouse assays, although their efficacy relative to flumioxazin varied among weed species. Protoporphyrin IX accumulation assays and molecular docking studies provided biochemical and computational evidence consistent with PPO inhibition as a potential mode of action. These findings suggest that benzoxazole–pyrimidinedione hybrids may represent a promising new class of PPO inhibitors and provide valuable insights for the rational design of next-generation herbicides.