Discovery of <i>N</i>-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 <i>N</i>-phenylphthalimide derivatives with ether moieties were designed and successfully synthesized. Among these, compound <b>B18</b> (<i>K</i>_i = 10.3 nM) exhibited a strong inhibitory effect on <i>Nt</i>PPO, outperforming flumiclorac-pentyl (<i>K</i>_i = 46.3 nM) and flumioxazin (<i>K</i>_i = 52.0 nM). It is noted that compounds <b>A3</b>, <b>B18</b>, <b>B19</b>, and <b>B20</b> 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 <b>B18</b> possessed not only a robust hydrogen bond with Arg98 of <i>Nt</i>PPO but also superior chemical reactivity, electrostatic field, and strong polarity. Therefore, compound <b>B18</b> may be regarded as a promising lead compound for the development of high-efficiency PPO inhibitors.