Design, Synthesis, and Bioactivity of 2,4-Diphenylquinoline Derivatives as Novel 1-Deoxy-d-xylulose-5-phosphate Synthase Inhibitors

The development of 1-deoxy-d-xylulose-5-phosphate synthase (DXPS) inhibitors still needs an innovative extension with novel chemotypes to avoid Herbicide resistance. Herein, a series of 2,4-diphenylquinoline derivatives were designed, synthesized, and structurally optimized from lead compound 24 via stepwise A/B/C-ring modification. Greenhouse assays identified a-3 (3-CF₃ A-ring) as the most potent analogue, exhibiting the higher herbicidal activity (71.4% inhibition on DESSO at 375 g a.i./ha) and dosage tolerance than 24. The mechanism of compound a-3 targeting DXPS proteins has been also identified using surface plasmon resonance binding assay, physiological biomarker measurement, substrate accumulation, and molecular docking. The key active motifs between a-3 and DXPS have been further defined based on the structure-activity relationships. This work will further expand the structural diversity of DXPS inhibitors with higher bioactivity.