AbstractBACKGROUND4‐Hydroxyphenylpyruvate dioxygenase (HPPD) plays an important role in addressing the issue of plant protection research. This study sheds new light on the differences in molecular scaffold from commercialized HPPD inhibitors.RESULTSThe compounds A1‐A18 and B1‐B27 were synthesized for in vitro and greenhouse experiments. The greenhouse experiment data indicated that compounds B14 and B18 displayed excellent herbicidal activity, which was higher compared to that of mesotrione. In vitro testing indicated that the compounds were HPPD inhibitors. Moreover, molecular simulation results show that the compounds B14, B18, and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD. Based on crop selectivity results, compounds B14 and B18 were selected for maize studies (injury≤10%), indicating its potential for weed control in maize fields.CONCLUSIONThese results showed that the pyrazole‐benzofuran structure could be used as possible lead compounds for the development of HPPD inhibitors. © 2020 Society of Chemical Industry