Identification of Novel Pyrazole-Diphenyl Ether Hybrids as Potential HPPD/PPO Dual-Target Inhibitors

4-Hydroxyphenylpyruvate dioxygenase (HPPD) and protoporphyrinogen oxidase (PPO) are recognized as pivotal targets for the development of environmentally friendly herbicides. In this work, a series of pyrazole derivatives containing a diphenyl ether moiety were designed and synthesized as dual-targeted HPPD/PPO inhibitors using pharmacophore merging and linking design strategies. The bioassays demonstrated that compound B14 exhibited the best inhibitory activity against both Arabidopsis thaliana HPPD (AtHPPD) and Nicotiana tabacum PPO (NtPPO) with the IC₅₀ values of 0.12 and 0.51 μM, which were superior to topramezone (0.42 μM) and acifluorfen (1.36 μM). Furthermore, compound B14 showed more than 80% herbicidal activity against the test weeds at 150 g a.i./ha, while the damage rate of compound B14 to cotton and peanut crops was only 20%. Molecular docking revealed that compound B14 forms π-π interactions with amino acid residues Phe 360 and Phe 403 in AtHPPD and exhibits strong hydrogen bonding with Arg 98 in NtPPO (1.9 Å). In addition, metabolism analysis demonstrated that compound B14 could be metabolized to compounds 2i and 6c in Echinochloa crusgalli, which may be the reason that affects the two phenotypes of weeds. This work indicated that compound B14 can be used as a potential HPPD/PPO dual-target inhibitor, and it provides a novel framework for the rational design of multitarget inhibitors.