Novel N-Phenylphthalimide Derivatives as Protoporphyrinogen IX Oxidase-Targeted Inhibitor Herbicides

The use of herbicides represents one of the effective weed management strategies. To create high-efficiency, low-risk protoporphyrinogen IX oxidase (PPO)-targeted herbicides, a set of novel N-phenylphthalimides bearing 1,3,4-oxadiazole and acylhydrazide fragments was designed and synthesized. Bioassays revealed that most of the compounds possessed potent herbicidal activity against six common weeds. Compound A9 exerted good inhibitory effects on Nicotiana tabacum PPO (NtPPO) with a Ki of 14.0 nM, outperforming commercial flumioxazin (46.3 nM) and flumiclorac-pentyl (52.0 nM). Molecular docking validated that A9 binds tightly to NtPPO via hydrogen bonds with Arg98 (2.8 Å), π-π stacking with Phe392, and π-alkyl sandwich interactions with Leu356/Leu372. Assays with PPO-deficient and PPO-complemented Escherichia coli strains, alongside AtPPO-overexpressing and mutant Arabidopsis, collectively verified A9 functions as a target-specific PPO inhibitor.