Design, synthesis, herbicidal activity evaluation, and molecular docking of novel cyclohexenone derivatives...

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD), as a key enzyme for tyrosine decomposition, is a highly regarded herbicide target. In this work, a series of cyclohexenone derivatives containing a substituted pyrazole group were designed and synthesized by active fragment splicing method for screening new HPPD inhibitors.

The bioassay results indicated that some target compounds exhibited noticeable inhibitory activity against Capsella bursa-pastoris (CB), Portulaca oleracea (PO), Echinochloa crus-galli (EC) and Setaria viridis (SV). As an outstanding representative, compound 8n showed excellent inhibitory activity against four tested weeds with the rates more than 90% at 225 active ingredient per hectare (a.i./ha) dosage, especially with a rate more than 90% against CB at 75 a.i./ha dosage, comparable to the control herbicide mesotrione. Compound 8n also demonstrated satisfactory safety for the crops wheat, maize, sorghum and rice. Furthermore, the molecular docking, molecular dynamics (MD) simulations and frontier molecular orbital analysis revealed that compound 8n had strong interaction with the target protein AtHPPD, which could tightly bind with amino acid residues in the active pocket to generate its herbicidal activity.

This study suggested that compound 8n could be used as a valuable lead molecular structure for the design of novel HPPD inhibitors, while providing an important foundation for the development of new herbicides. © 2025 Society of Chemical Industry.