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 <b>B14</b> exhibited the best inhibitory activity against both <i>Arabidopsis thaliana</i> HPPD (<i>At</i>HPPD) and <i>Nicotiana tabacum</i> PPO (<i>Nt</i>PPO) 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 <b>B14</b> showed more than 80% herbicidal activity against the test weeds at 150 g a.i./ha, while the damage rate of compound <b>B14</b> to cotton and peanut crops was only 20%. Molecular docking revealed that compound <b>B14</b> forms π<i>-</i>π interactions with amino acid residues Phe 360 and Phe 403 in <i>At</i>HPPD and exhibits strong hydrogen bonding with Arg 98 in <i>Nt</i>PPO (1.9 Å). In addition, metabolism analysis demonstrated that compound <b>B14</b> could be metabolized to compounds <b>2i</b> and <b>6c</b> in <i>Echinochloa crusgalli</i>, which may be the reason that affects the two phenotypes of weeds. This work indicated that compound <b>B14</b> can be used as a potential HPPD/PPO dual-target inhibitor, and it provides a novel framework for the rational design of multitarget inhibitors.