Design, synthesis, and molecular simulation studies of N-phenyltetrahydroquinazolinones as protoporphyrinogen IX oxidase inhibitors

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 Ki 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.