Discovery of Pyrimidinedione Derivatives Containing Oxime Ester/Carbamate Fragments as Potent Protoporphyrinogen IX Oxidase Inhibitors

Abstract To continue our research on developing PPO inhibitors, we replaced the triazinone core of compounds B, G, and H from our previous work with pyrimidinediones, employing a scaffold-hopping strategy to design and synthesize compounds I, J, and K. Compound I18 exhibited potent NtPPO inhibition (Ki = 10.9 nM) and broad-spectrum herbicidal activity comparable to saflufenacil, providing 100% control of 29 weeds at 75 g a.i./ha. It also showed improved crop safety, causing only 30% peanut injury and thus being safer than saflufenacil (80% injury), while exhibiting low toxicity to zebrafish and earthworms. Molecular docking revealed hydrophobic interactions with Leu356, Leu372, and Phe392, along with two unique side-chain hydrogen bonds involving Arg98 and Ser235. Its calculated binding free energy (ΔGcal = −30.579 kcal/mol) was more favorable than that of saflufenacil (−25.386 kcal/mol). These findings identify I18 as a promising, effective, and environmentally compatible PPO inhibitor for weed management.