Discovery of FM-604, a Benzyl-Substituted Pyrimidinedione PPO Inhibitor with Potent Postemergence Herbicidal Activity

Abstract Protoporphyrinogen IX oxidase (PPO) is a validated target for fast-acting herbicides. To identify low-dose PPO-inhibiting leads, 41 benzyl-substituted pyrimidinedione derivatives were designed by side-chain optimization of epyrifenacil and synthesized. In greenhouse postemergence screening, FM-604 provided 100% control of Zinnia elegans and Abutilon theophrasti and 80–85% control of Setaria glauca and Echinochloa crus-galli at the lowest rate tested (2.34 g a.i./ha). FM-604 inhibited Nicotiana tabacum PPO with an IC50 of 21.46 nM versus 30.29 nM for epyrifenacil. Docking and 100 ns molecular dynamics simulations suggested a stable binding mode involving Arg98, Asn67, and Phe392, while DFT calculations indicated a comparatively small HOMO–LUMO gap. These results identify FM-604 as a PPO-inhibiting lead for further optimization and evaluation.