Design, Synthesis and Proteomics-Based Analysis of Novel Triazinone Derivatives Containing Amide Structures as Safer Protoporphyrinogen IX Oxidase Inhibitors

Resistant weeds severely threaten crop yields as they compete with crops for resources required for survival. Trifludimoxazin, a Protoporphyrinogen IX oxidase (PPO) inhibitor, can effectively control resistant weeds. However, its crop safety record is unsatisfactory. Consequently, a scaffold-hopping strategy is employed in this study to develop a series of new triazinone derivatives featuring an amide structure. Most compounds depicted excellent herbicidal activity across a broad spectrum at 37.5-150 g ai/ha, among which (R)-I-5 was equivalent to flumioxazin. (R)-I-5 demonstrated significant crop tolerance to rice and wheat, even at 150 g ai/ha. (R)-I-5 exhibited superior pharmacokinetic features compared to flumioxazin and trifludimoxazin. This was depicted by the absorption, distribution, metabolism, excretion, and toxicity predictions. Notably, proteomics-based analysis was applied for the first time to investigate variations among plant proteins before and after Herbicide application, shedding light on the conservative and divergent roles of PPO.