Design, Synthesis, and Biological Evaluation of Novel Biaryl-pyridine Derivatives with Potent Postemergence Herbicidal Activity.

Protoporphyrinogen oxidase (PPO) is an established herbicide target. Oxygen-substituted biaryl-pyridine derivatives were designed and synthesized through scaffold optimization. Greenhouse assays identified several compounds with strong postemergence activity at 150 g/ha. Compound 6a retained 75% inhibition against three broadleaf weeds at 9.375 g/ha and caused generally less crop injury than acifluorfen. No mortality or behavioral abnormalities were observed in honey bees treated with 6a or (±)-6b at 100 μg/bee. Molecular docking, molecular dynamics simulations, and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) analyses supported stable interactions of 6a and an (R)-6b model with Nicotiana tabacum PPO (NtPPO). Surface plasmon resonance (SPR) confirmed direct binding of 6a and (±)-6b to NtPPO, with KD values of 41.20 and 38.60 nM, respectively. Density functional theory (DFT) calculations further supported 6a as a promising herbicidal lead.