Novel <i>N</i>-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 <i>N</i>-phenyltriazinone carboxylic acid derivatives and assessed their function as PPO inhibitors. Bioassay revealed that compound <b>D5</b> exhibited excellent inhibitory activity against <i>Nicotiana tabacum</i> PPO (<i>Nt</i>PPO) with a <i>K</i>_i of 33.7 nM, comparable to that of trifludimoxazin (<i>K</i>_i = 31.1 nM). Compound <b>D5</b> also exhibited remarkable postemergence herbicidal activity against five weed species (<i>Setaria faberii</i>, <i>Echinochloa crusgalli</i>, <i>Amaranthus retroflexus</i>, <i>Abutilon juncea</i>, and <i>Portulaca oleracea</i>) 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 <b>D5</b> stably binds <i>Nt</i>PPO 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 <i>N</i>-phenyltriazinone carboxylic acid derivative <b>D5</b> is a promising PPO inhibitor for agricultural weed control.