Discovery of Novel Pyrazole–Quinazoline-2,4-dione Hybrids as 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been identified as one of the most significant targets in herbicide discovery for resistant weed control. In a continuing effort to discover potent novel HPPD inhibitors, we adopted a ring-expansion strategy to design a series of novel pyrazole-quinazoline-2,4-dione hybrids based on the previously discovered pyrazole-isoindoline-1,3-dione scaffold. One compound, 3-(2-chlorophenyl)-6-(5-hydroxy-1,3-dimethyl-1<i>H</i>-pyrazole-4-carbonyl)-1,5-dimethylquinazoline-2,4(1<i>H</i>,3<i>H</i>)-dione (<b>9bj</b>), displayed excellent potency against <i>At</i>HPPD, with an IC₅₀ value of 84 nM, which is approximately 16-fold more potent than pyrasulfotole (IC₅₀ = 1359 nM) and 2.7-fold more potent than mesotrione (IC₅₀ = 226 nM). Furthermore, the co-crystal structure of the <i>At</i>HPPD-<b>9bj</b> complex (PDB ID 6LGT) was determined at a resolution of 1.75 Å. Similar to the existing HPPD inhibitors, compound <b>9bj</b> formed a bidentate chelating interaction with the metal ion and a π-π stacking interaction with Phe381 and Phe424. In contrast, <i>o</i>-chlorophenyl at the N3 position of quinazoline-2,4-dione with a double conformation was surrounded by hydrophobic residues (Met335, Leu368, Leu427, Phe424, Phe392, and Phe381). Remarkably, the greenhouse assay indicated that most compounds displayed excellent herbicidal activity (complete inhibition) against at least one of the tested weeds at the application rate of 150 g of active ingredient (ai)/ha. Most promisingly, compounds <b>9aj</b> and <b>9bi</b> not only exhibited prominent weed control effects with a broad spectrum but also showed very good crop safety to cotton, peanuts, and corn at the dose of 150 g of ai/ha.