Novel Phenylpyrazole Derivatives Containing Carbonic Ester Moieties as Protoporphyrinogen IX Oxidase Inhibitors

Protoporphyrinogen IX oxidase (PPO) is an essential enzyme in the chlorophyll synthesis process in plants, making it a major target for the advancement of environmentally safe herbicides. In order to develop new PPO inhibition herbicides, a series of novel pyrazole derivatives containing carbonic ester moieties were synthesized based on the active splicing principle and structural simplification strategy. In bioassays, it was found that the majority of the target compounds had a good inhibitory effect on Nicotiana tabacum PPO (NtPPO) and displayed herbicidal activity against the tested weeds. Among them, compound A20 (K_i = 15.2 nM) not only exhibited an inhibitory effect on NtPPO superior to that of pyraflufen-ethyl (K_i = 31.1 nM) and fluazolate (K_i = 18.3 nM) but also showed more than 90% herbicidal activity against dicotyledonous weeds at 9.375 g of a.i./ha, and its herbicidal activity was better than that of pyraflufen-ethyl and fluazolate. Additionally, compound A20 caused lower damage to wheat, rice, corn, soybeans, peanuts, and cotton compared to pyraflufen-ethyl and fluazolate. Molecular docking revealed that there are two hydrogen bonds between compound A20 and the Arg98 (2.8 and 3.0 Å) residue of NtPPO, which were stronger than those of pyraflufen-ethyl (2.9 Å) and fluazolate (2.9 and 3.6 Å). Density functional theory calculations clarified the differences of the target compounds in herbicidal activity. The current study suggests that compound A20 shows potential as a PPO inhibitor for creating an ecofriendly herbicide to manage weeds in agricultural fields.