Design, synthesis, and biological evaluation of sulfur-linked ester-substituted pyridazinone derivatives as protoporphyrinogen oxidase inhibitors.

Pyridazinone-based protoporphyrinogen oxidase (PPO) inhibitors are an important class of herbicidal lead structures, but the influence of sulfur-linked cycloalkyl ester side chains on this scaffold has not been systematically investigated. In this study, twenty-seven sulfur-linked ester-substituted pyridazinone derivatives were designed, synthesized, and evaluated for post-emergence herbicidal activity against two broadleaf weeds and two grass weeds. Most compounds showed high activity against the tested broadleaf species at the highest dose, whereas grass-weed control was more strongly affected by the side-chain structure. Among them, compound 10ba, bearing a sulfur-linked diester-containing cyclopropane side chain, exhibited the best overall activity. Under the tested greenhouse conditions, 10ba provided complete control of Zinnia elegans, Abutilon theophrasti, Setaria glauca, and Echinochloa crus-galli at 37.5 g a.i./ha and showed higher overall weed-control activity than flufenpyr-ethyl at the lower application rates. In an in vitro NtPPO inhibition assay, 10ba displayed an IC50 value of 14.31 nM, compared with 29.82 nM for flufenpyr-ethyl. Structure-activity relationship analysis suggested that cyclopropane-containing analogues were generally more favorable than their cyclobutane counterparts and that diester substitution improved grass-weed control relative to monoester substitution. Molecular docking and molecular dynamics simulations indicated that the diester side chain of 10ba may provide additional polar contacts within the PPO active site. DFT and molecular electrostatic potential analyses further supported the presence of localized electron-rich regions around the diester carbonyl groups. These results identify sulfur-linked cyclopropane diester substitution as a promising side-chain modification strategy for the further optimization of pyridazinone-based PPO inhibitors.