Discovery of (4-Phenyl-4H-1,2,4-triazol-3-yl)methyl Phenylcarbamate as Potent Dual-Inhibitors Targeting Phytoene Desaturase and ζ-Carotene Desaturase.

The development of dual-target herbicides provides an effective approach to emerging weed resistance. Given the high structural similarity of phytoene desaturase (PDS) and ζ-carotene desaturase (ZDS), it is possible to explore the dual-inhibitors targeting PDS and ZDS with high potency. In this work, two series of compounds (I-1 to I-20; II-1 to II-20) were designed and synthesized from our previously reported lead compound 8e. The bioassay results indicated that II-13 exhibited the highest postemergence herbicidal activity (95%) against three dicotyledonous weeds and 85% against the monocotyledonous weed POLFU at 750 g a.i./ha. Meanwhile, compound I-20 displayed the best pre-emergence herbicidal activity at 187.5 g a.i./ha. Subsequently, surface plasmon resonance and molecular dynamics simulation assays further validated the dual binding capacity of II-13 to PDS and ZDS. These results demonstrate that it is feasible to target two key enzymes in the carotenoid biosynthesis pathway to enhance herbicidal activity.