Discovery of 3-Carboxyl-4-pyrazolamides as Promising Herbicidal Scaffolds Targeting Dihydroorotate Dehydrogenase.

Enhancing innovation in herbicide discovery is imperative to combat weed resistance and safeguard global food security. To develop novel herbicide targeting dihydroorotate dehydrogenase (DHODH), a series of 3-carboxy-4-pyrazole amide lead scaffold bearing ester or acid substituents were designed and synthesized. Bioassay evaluation revealed that compound II-12 achieved an 81% growth inhibition activity against Setaria viridis at 135 g ai/ha in postemergence greenhouse assays, with herbicidal efficacy comparable or higher than that of several commercial products. Moreover, II-12 exhibited favorable crop safety toward four upland crops at the same dosage. In vitro enzyme inhibition assays demonstrated that II-12 inhibited SvDHODH with a half-maximal inhibition concentration value of 8.589 μM, while surface plasmon resonance analysis revealed an apparent dissociation constant Kd of 3.83 μM. Molecular docking combined with site-directed mutagenesis displayed that II-12 binds to SvDHODH through a critical H-bond interaction with Arg189. Collectively, these results identify II-12 as a promising DHODH-targeting herbicide candidate.