Shielding Metabolic Hotspots in the Triketone–Quinoline Scaffold Yields Potent 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) is an important target for modern herbicide discovery. To translate HPPD inhibitors into effective herbicide candidates, we developed a metabolism-oriented design strategy to improve the in vivo efficacy of triketone–quinoline HPPD inhibitors. By shielding the metabolic hotspots within the scaffold, we discovered a series of new analogues with broadly improved postemergence herbicidal activity and substantially enhanced inhibition of Arabidopsis thaliana HPPD ( At HPPD). Notably, 9i showed a K i value of 0.0012 μM toward At HPPD, outperforming mesotrione by an order of magnitude. 11b not only exhibited excellent weed control at 15.625–250 g ai/ha, but also showed high crop safety to wheat at 250 g ai/ha. Molecular simulations showed that quinoline substitutions could enhance π–π interactions with Phe360 and Phe403, improving bioactivity. Our work establishes a metabolism-guided optimization framework for herbicide discovery and provides a promising wheat-selective herbicide candidate.