Design of <i>N</i> -Phenyltriazinone Derivatives with Ether-Linked Oxadiazole Moieties as Protoporphyrinogen IX Oxidase Inhibitors

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) has long been recognized as a validated target in herbicide development. In this research, through structural analysis, we devised an Active Fragment Exchange and Link (AFEL) methodology to engineer a new category of <i>N</i>-phenyltriazinone derivatives. These compounds feature ether-connected oxadiazole moieties and serve as potent inhibitors of <i>Nicotiana tabacum</i> PPO (NtPPO). Following systematic structure-activity relationship (SAR) optimization, 34 novel compounds were identified. These compounds exhibit nanomolar <i>K</i>_i values against NtPPO and show promising herbicidal activity, with some compounds demonstrating lower <i>K</i>_i values compared to saflufenacil. Greenhouse herbicidal activity assays revealed that compound <b>Iq</b> exhibited the highest efficacy, achieving 100% inhibition against tested broadleaf weeds at 37.5 g a.i./ha, comparable to saflufenacil. Compound <b>Iq</b> exhibited better crop safety for maize at 150 g a.i./ha relative to saflufenacil. Molecular docking simulations revealed that the oxadiazole ring in compound <b>Iq</b> forms two hydrogen bonds with the Arg98 residue of NtPPO. These findings suggest that compound <b>Iq</b> has the potential to be a novel PPO inhibitor for managing agricultural weeds.