Discovery of Triketone–Indazolones\nas Novel\n4‑Hydroxyphenylpyruvate Dioxygenase Inhibiting-Based Herbicides

4-Hydroxyphenylpyruvate\ndioxygenase (HPPD) is a crucial\nherbicide\ntarget in current research, playing an important role in the comprehensive\nmanagement of resistant weeds. However, the limited crop selectivity\nand less effectiveness against grass weeds of many existing HPPD inhibitors,\nlimit their further application. To address these issues, a series\nof novel HPPD inhibitors with fused ring structures were designed\nand synthesized by introducing an electron-rich indazolone ring and\ncombining it with the classical triketone pharmacophore structure.\nThe cocrystal structure of representative compound <b>III-7</b> complexed with <i>Arabidopsis thaliana</i> HPPD (<i>At</i>HPPD) was obtained at 2.0 Å resolution to guide the\noptimization of the designed inhibitor. The optimization results showed\nthat 5-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,4-dimethyl-2-(3-(methylthio)phenyl)-1,2-dihydro-3<i>H</i>-indazol-3-one, <b>III-15</b>, was the most active <i>At</i>HPPD inhibitor, with an IC<sub>50</sub> value of 12 nM,\nnearly 30 times higher efficacy than mesotrione. Greenhouse herbicidal\nactivity tests demonstrated that compound <b>III-15</b> exhibited\nexcellent herbicidal potency at 30–120 g ai/ha. Notably, it\nmaintained high safety for peanuts even at 120 g ai/ha. Our results\nshowed that compound <b>III-15</b> is promising as a new candidate\nHPPD herbicide for use in the peanut fields.