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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 \u03bcM, while surface plasmon resonance analysis revealed an apparent dissociation constant Kd of 3.83 \u03bcM. Molecular docking combined with site-directed mutagenesis displayed that II-12 binds to SvDHODH through a critical H-bond interaction with Arg189. 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