Discovery of a Potent Thieno[2,3-]pyrimidine-2,4-dione-Based Protoporphyrinogen IX Oxidase Inhibitor through an Structure-Guided Optimization Approach.

A key objective for herbicide research is to develop new compounds with improved bioactivity. Protoporphyrinogen IX oxidase (PPO) is an essential target for herbicide discovery. Here, we report using an structure-guided optimization approach of our previous lead compound and designed and synthesized a new series of compounds -. Systematic bioassays led to the discovery of a highly potent compound , 1-methyl-3-(2,2,7-trifluoro-3-oxo-4-(prop-2-yn-1-yl)-3,4-dihydro-2-benzo[][1,4]oxazin-6-yl)thieno[2,3-]pyrimidine-2,4(1,3)-dione, which exhibited an excellent and wide spectrum of weed control at the rates of 30-75 g ai/ha by the postemergence application and is relatively safe on maize at 75 g ai/ha. Additionally, the value of to PPO (NtPPO) was found to be 2.5 nM, showing 3-, 12-, and 18-fold higher potency relative to compound ( = 7.4 nM), trifludimoxazin ( = 31 nM), and flumioxazin ( = 46 nM), respectively. Furthermore, molecular simulations further suggested that the thieno[2,3-]pyrimidine-2,4-dione moiety of could form a more favorable π-π stacking interaction with the Phe392 of NtPPO than the heterocyclic moiety of compound . This study provides an effective strategy to obtain enzyme inhibitors with improved performance through molecular simulation and structure-guided optimization.