Structure-Based Rational Design and Synthesis of Pyridazinone Herbicides Targeting Phytoene Desaturase

The application of herbicides plays a critical role in ensuring food security. However, the long-term overuse of herbicides can lead to a range of adverse effects. Therefore, it is essential to develop innovative and sustainable herbicides. A series of pyridazinone derivatives targeting phytoene desaturase (PDS) were designed and synthesized by using a structure-based drug design strategy. A bioassay showed that 16c (100%, 85%) exhibited stronger herbicidal activity against portulaca oleracea (P.o.) than that of norflurazon (NRF, 60%, 45%) in both post- and pre-emergence applications at a dosage of 150 g a.i./ha, while also showing greater safety to nontarget organisms. Meanwhile, levels of 15-cis-phytoene, carotenoids, and chlorophyll revealed that 16c effectively inhibited PDS activity. Molecular dynamics simulations and binding action assays confirmed that Arg195 is a key residue for the interaction between 16c and Synechococcus PDS (SynPDS). Therefore, 16c could be developed as a potent PDS inhibitor for herbicides.