Discovery of Cycloheptanone-Pyrrole Derivatives with α-Hydroxycarboxylate Fragments as Novel Dihydroxy Acid Dehydratase-Targeting Herbicides

Dihydroxy acid dehydratase (DHAD) is a promising herbicide target, but no commercial DHAD inhibitors exist yet. The natural product aspterric acid (AA) has been shown to act on DHAD, inspiring us to discover novel cycloheptanone-pyrrole compounds (6aa-6ay) featuring α-hydroxycarboxylate fragments as potential DHAD-targeting herbicides. In Arabidopsis thaliana seed germination assays, most compounds demonstrated 100% inhibition at 200 μg/mL, comparable to that of the positive control penoxsulam. In greenhouse herbicidal activity tests, compound 6ag demonstrated over 85% control effectiveness against Eclipta prostrata, Amaranthus retroflexus, and Setaria viridis at a dosage of 150 g ai/ha, while also showing safety for rice. The binding model of 6ag with DHAD is similar to that of AA with DHAD, and the K_d value of 6ag binding to DHAD is 20 μM, indicating that 6ag acts with DHAD. With both herbicidal efficacy and crop safety, 6ag represents a promising novel lead compound for DHAD inhibitors.