Oxime ester-linked N-phenylphthalimide derivatives as PPO inhibitors: structure-activity relationships, herbicidal activity, crop selectivity, and in silico safety assessment.

Protoporphyrinogen oxidase (PPO; EC 1.3.3.4) is an established herbicide target, yet resistance and crop-injury concerns continue to motivate new PPO-inhibiting chemotypes. Here, forty-eight oxime ester-linked N-phenylphthalimide derivatives bearing five-membered heterocycles were designed by molecular hybridization and synthesized. Greenhouse assays identified compound a6 as a lead with broad-spectrum post-emergence activity, including >90% inhibition of Ipomoea nil and Abutilon theophrasti at 37.5 g a.i. ha-1, and it provided 85% control at 14 days after treatment in a field trial at 300 g a.i. ha-1. In vitro enzyme assays showed that a6 and c12 inhibited Echinochloa crus-galli PPO (EcPPO) with half-maximal inhibitory concentrations (IC50) of 0.182 ± 0.004 and 0.184 ± 0.005 μM, respectively, comparable to flumioxazin. Compound a6 also exhibited favorable crop selectivity, causing ≤5% injury at 150 g a.i. ha-1 and ≤ 10% injury at 300 g a.i. ha-1 across six crops. Molecular docking using NtPPO (PDB ID: 1SEZ) suggested that a6 and c12 preserve the conserved Arg98 hydrogen-bond anchor and π-π stacking with Phe392. Molecular dynamics simulations were consistent with stable binding of a6 to the NtPPO structural template. Density functional theory analysis indicated that the electronic descriptors of a6 were comparable to those of the commercial reference. Finally, in silico physicochemical, toxicological, and environmental-fate profiling provided a preliminary view of developability and highlighted endpoints for follow-up evaluation. Overall, a6 represents a promising scaffold for further optimization toward PPO-inhibitor herbicides.