Novel N-Phenyltriazinone Carboxylic Acid Derivatives as Promising Protoporphyrinogen IX Oxidase Inhibitors

Protoporphyrinogen IX oxidase (PPO) is a critical target for new herbicide development. We used a scaffold hopping strategy to develop 49 novel N-phenyltriazinone carboxylic acid derivatives and assessed their function as PPO inhibitors. Bioassay revealed that compound D5 exhibited excellent inhibitory activity against Nicotiana tabacum PPO (NtPPO) with a Ki of 33.7 nM, comparable to that of trifludimoxazin (Ki = 31.1 nM). Compound D5 also exhibited remarkable postemergence herbicidal activity against five weed species (Setaria faberii, Echinochloa crusgalli, Amaranthus retroflexus, Abutilon juncea, and Portulaca oleracea) at an ultralow concentration (9.375 g a.i./ha), and it showed broad-spectrum herbicidal activity and relatively high safety in wheat, rice, and peanut at 150 and 75 g a.i./ha, respectively. In molecular simulations, compound D5 stably binds NtPPO via π–π stacking with Phe392 and a sandwiched π–alkyl interaction with the key amino acids Leu356 and Leu372. This study shows that the novel N-phenyltriazinone carboxylic acid derivative D5 is a promising PPO inhibitor for agricultural weed control.