Understanding the Effects of Ligand Configuration on Protoporphyrinogen IX Oxidase with Rationally Designed 3-(-Phenyluracil)but-2-enoates.

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is a promising target for green herbicide discovery. However, the ligand configuration effects on PPO activity were still poorly understood. Herein, we designed 3-(-phenyluracil)but-2-enoates using our previously developed active fragments exchange and link (AFEL) approach and synthesized a series of novel compounds with nanomolar ranges of PPO (NtPPO) inhibitory potency and promising herbicidal potency. Our systematic structure-activity relationship investigations showed that the isomers of 3-(-phenyluracil)but-2-enoates displayed improved bioactivity than their corresponding isomers. Using molecular simulation studies, we found that the isomers showed a relatively lower entropy change and could sample more stable binding conformation to the receptor than the isomers. Our density functional theory (DFT) calculations showed that the isomers showed higher chemical reactivity and lower electronic chemical potential than their corresponding isomers. Compound - emerged as the optimal compound with a value of 3.0 nM against NtPPO, exhibiting a broader spectrum of weed control than saflufenacil at 37.5-75 g ai/ha and also safe to maize at 75 g ai/ha, which could be considered as a promising lead herbicide for further development.