Synthesis and Biological Activity Evaluation of Benzoxazinone-Pyrimidinedione Hybrids as Potent Protoporphyrinogen IX Oxidase Inhibitor
Bai-Feng Zheng, Yang Zuo, Guang-Yi Huang, Zhi-Zheng Wang, Jin-Yi Ma, Qiong‐You Wu, Guang‐Fu Yang
Abstract
Protoporphyrinogen IX oxidase (PPO/Protox, E.C. 1.3.3.4) is recognized as one of the most important targets for herbicide discovery. In this study, we report our ongoing research efforts toward the discovery of novel PPO inhibitors. Specifically, we identified a highly potent new compound series containing a pyrimidinedione moiety and bearing a versatile building block-benzoxazinone scaffold. Systematic bioassays resulted in the discovery of compound 7af, ethyl 4-(7-fluoro-6-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2 H )-yl)-3-oxo-2,3-dihydro-4 H -benzo[ b ][1,4]oxazin-4-yl)butanoate, which exhibited broad-spectrum and excellent herbicidal activity at the dosage of 37.5 g a.i./ha through postemergence application. The inhibition constant ( K i ) value of 7af to Nicotiana tabacum PPO ( Nt PPO) was 14 nM, while to human PPO ( h PPO), it was 44.8 μM, indicating a selective factor of 3200, making it the most selective PPO inhibitor to date. Moreover, molecular simulations further demonstrated the selectivity and the binding mechanism of 7af to Nt PPO and h PPO. This study not only identifies a candidate that showed excellent in vivo bioactivity and high safety toward humans but also provides a paradigm for discovering PPO inhibitors with improved performance through molecular simulation and structure-guided optimization.