Discovery of Pyrazole-Fusaric Acid Derivatives as the Potential Herbicidal Lead Compounds Targeting Both Transketolase and Protoporphyrinogen Oxidase.

Transketolase (TKL, EC 2.2.1.1) was confirmed as a potential new target for herbicides. In this study, a series of pyrazole-fusaric acid derivatives 9a-9o were designed and synthesized via structural optimization of compound 7r. Among them, compound 9f exhibited good inhibition on Digitaria sanguinalis and Amaranthus retroflexus (inhibition >95%) even at 10 mg/L via the small cup method. It exhibited excellent inhibition against D. sanguinalis and A. retroflexus (inhibition >90%, 150 g ai/ha) via the pot bioassay superior to the positive control. Significantly, it showed good crop safety to maize, wheat, soybean, and cotton (the phytotoxicity <10%, 375 g ai/ha). Additionally, compound 9f exhibited excellent inhibition on both SvTKL and NtPPO (IC50: 0.11, 1.00 mg/L). Both molecular docking and molecular dynamics simulation confirmed that the complexes for SvTKL-9f and NtPPO-9f demonstrated strong stability. Altogether, there is potential to discover novel dual-target-inhibiting herbicide candidates by further structurally optimizing compound 9f.