Design, Synthesis, and Metabolism Studies of -1,4-Diketophenyltriazinones as Protoporphyrinogen IX Oxidase Inhibitors.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is an established site for green herbicide discovery. In this work, based on structural analysis, we develop an active fragment exchange and link (AFEL) approach to designing a new class of -1,4-diketophenyltriazinones - as potent PPO (PPO) inhibitors. After systematic structure-activity relationship optimizations, a series of new compounds with values in the single-digit nanomolar range toward NtPPO and promising herbicidal activity were discovered. Among them, ( = 0.11 nM) displays 284- and 90-fold improvement in NtPPO inhibitory activity over trifludimoxazin ( = 31 nM) and saflufenacil ( = 10 nM), respectively. In addition, ( = 2.14 nM) not only exhibited good herbicidal activity at 9.375-37.5 g ai/ha but also showed high crop safety to rice at 75 g ai/ha by the postemergence application, indicating that could be developed as a potential herbicide for weed control in rice fields. Additionally, our molecular dynamic simulation clarified the molecular basis for the interactions of these molecules with NtPPO. The metabolism studies showed that could be converted to , which displayed higher herbicidal activity than . The density functional theory analysis showed that due to the effect of two sulfur atoms at the triazinone moiety, is more reactive than , making it more easily degraded . Our work indicates that the AFEL strategy could be used to design new molecules with improved bioactivity.