Discovery of Novel N-Phenylphthalimide Protoporphyrinogen IX Oxidase Inhibitors

Developing new compounds with improved bioactivity is a crucial objective in herbicide research. To discover new compounds with high biological activity, a series of N-phenylphthalimide derivatives containing ether and oxime ether moieties were designed and synthesized. The assays demonstrated significant inhibitory effects of certain compounds on Nicotiana tabacum PPO (NtPPO). Among them, compound A4 exhibited the most potent inhibition of NtPPO, with a K_i value of 9.05 nM, surpassing both flumioxazin (K_i = 52.0 nM) and flumiclorac-pentyl (K_i = 46.3 nM). In addition, compound A4 exhibited complete inhibition against six weed species (Setaria viridis, Echinochloa crus-galli, Digitaria sanguinalis, Amaranthus retroflexus, Abutilon theophrasti, and Portulaca oleracea) and caused only 30-50% damage to maize and rice at 150 g a.i./ha. Molecular simulation analysis demonstrated that compound A4 exhibited stable binding to NtPPO due to the formation of a strong hydrogen bond with Arg98 (2.8 Å), surpassing the interactions of flumiclorac-pentyl (3.2 Å) and flumioxazin (3.1 Å). These findings suggest that compound A4 holds potential as a novel PPO inhibitor for the management of agricultural weeds.