Discovery of N-Phenylphthalimides Containing Ether Moiety as Potential Protoporphyrinogen IX Oxidase Inhibitors

The discovery of novel protoporphyrinogen IX oxidase (PPO) inhibitors has become a key focus in herbicide development. To explore new PPO inhibitors, a series of N-phenylphthalimide derivatives with ether moieties were designed and successfully synthesized. Among these, compound B18 (Ki = 10.3 nM) exhibited a strong inhibitory effect on NtPPO, outperforming flumiclorac-pentyl (Ki = 46.3 nM) and flumioxazin (Ki = 52.0 nM). It is noted that compounds A3, B18, B19, and B20 showed broad-spectrum herbicidal activity against the tested weeds at 75 g a.i./ha. In addition, results of molecular simulation and density functional theory (DFT) calculations indicated that compound B18 possessed not only a robust hydrogen bond with Arg98 of NtPPO but also superior chemical reactivity, electrostatic field, and strong polarity. Therefore, compound B18 may be regarded as a promising lead compound for the development of high-efficiency PPO inhibitors.