State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, and Department of Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, PR China.
State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, and Department of Chemical Biology, Collaborative Innovation Center of Chemical Science and Engineering, College of Chemistry, Nankai University, Tianjin 300071, PR China.
Bioorg Med Chem. 2021 Jun 1;39:116165. doi: 10.1016/j.bmc.2021.116165. Epub 2021 Apr 21.
Discovering new protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors is a promising direction for agrochemical research. Herein, we reported the discovery and in silico structure-guided optimization of N-phenyltetrahydroquinazolinones 1 and 2 as new PPO inhibitors. Most of the obtained compounds 1 and 2 exhibited significantly enhanced Nicotiana tabacum PPO (NtPPO) inhibitory potency than that of flumioxazin. Promisingly, 1-(tert-butoxy)-1-oxopropan-2-yl 2-chloro-4-fluoro-5-(4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)benzoate, 2o, with a K value of 4 nM, showed ten folds more enhanced NtPPO-inhibiting potency than flumioxazin. Additionally, compounds 2b and 2i showed a broad spectrum of broadleaf weeds control at 37.5-150 g ai/ha, and selective for wheat at 150 g ai/ha in the post-emergent application. The molecular simulation studies revealed the vital basis between N-phenyltetrahydroquinazolinones and NtPPO. The present work indicated that the N-phenyltetrahydroquinazolinone motif might be a potential scaffold for herbicide discovery.
发现新的原卟啉原氧化酶（PPO，EC 1.3.3.4）抑制剂是农用化学品研究的一个有前途的方向。本文报道了 N-苯基四氢喹唑啉酮 1 和 2 作为新型 PPO 抑制剂的发现和基于结构的计算机辅助优化。所获得的大部分化合物 1 和 2 对烟草原卟啉原氧化酶（NtPPO）的抑制活性均明显强于氟噁嗪。令人欣喜的是，1-(叔丁氧基)-1-氧代丙-2-基 2-氯-4-氟-5-(4-氧代-5,6,7,8-四氢喹唑啉-3(4H)-基)苯甲酸酯 2o，K 值为 4 nM，对 NtPPO 的抑制活性比氟噁嗪强 10 倍。此外，化合物 2b 和 2i 在 37.5-150 g ai/ha 剂量下对阔叶杂草有广谱防治效果，在 150 g ai/ha 剂量下对小麦具有选择性。分子模拟研究揭示了 N-苯基四氢喹唑啉酮与 NtPPO 之间的重要关系。本研究表明，N-苯基四氢喹唑啉酮结构可能是除草剂发现的潜在支架。
