Discovery of novel benzoxazinone derivatives as promising protoporphyrinogen IX oxidase inhibitors

BACKGROUND: Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) has emerged as a key target for developing new herbicides to protect crops from weeds. Herein, we disclose the development of two types of PPO inhibitors by modification of the benzoxazinone skeleton. RESULTS: Two types of structurally novel benzoxazinone derivatives containing hydantoin or 1,2,3-triazole fragments were designed based on active substructure splicing and derivatization strategies. Systematic post-emergence herbicidal activity studies and crop selectivity assessments indicate that some of the compounds exhibit excellent herbicidal activity and crop safety. For instance, compound A1 shows highly effective herbicidal activity against all tested weeds at a dosage of 150 g ai/ha. Particularly, its herbicidal activity against broadleaf weeds is comparable to that of flumioxazin. Meanwhile, compound A1 exhibits superior safety for wheat and maize compared to flumioxazin within the 75–150 g ai/ha dosage range. Molecular docking studies revealed that compound A1 and flumioxazin occupy the same active cave within Nicotiana tabacum PPO (NtPPO). It is noteworthy that the carbonyl group on the oxazolone moiety of both compound A1 and flumioxazin forms beneficial interactions with Arg-98 and Phe-392. CONCLUSION: Our research indicates that benzoxazinone derivatives containing either hydantoin or 1,2,3-triazole fragments serve as a promising chemical scaffold for the development of novel PPO-inhibiting herbicides.