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

• DOI: 10.1021/acs.jafc.1c05665
• Publication Date: 2021-11-20T00:40:57Z
• Authors: Da-Wei Wang; Hang Zhang; Shu-Yi Yu; Rui-Bo Zhang; Lu Liang; Xia Wang; Huang-Ze Yang; Zhen Xi
• Keywords: Moiety; Protoporphyrinogen oxidase

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