4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays an important role in addressing the issue of plant protection research. In a continuing effort to discover novel HPPD inhibitors, we adopted a bioisosterism strategy to design a series of novel arylthioacetic acid scaffold based on the previously discovered aryloxyacetic acid scaffold. This study sheds new light on the discovery of novel HPPD inhibitors. The compounds A1-A30 and B1-B39 were prepared through an efficient synthetic route for in vitro and glasshouse experiments (herbicidal activities, herbicidal activity spectrum, and crop selectivity). Preliminary bioassay results reveal that these derivatives are promising Arabidopsis thaliana HPPD inhibitors, compounds A11 (Ki = 0.021 μmol L-1 ) and B20 (Ki = 0.022 μmol L-1 ), which exhibit similar activities to that of mesotrione (Ki = 0.020 μmol L-1 ). The glasshouse experiments data indicated that compounds B34 displayed excellent herbicidal activity, which was higher compared to that of mesotrione. Moreover, molecular simulation results show that the compounds B20, B34, and mesotrione shared similar interplay with surrounding residues, which led to a perfect interaction with the active site of Arabidopsis thaliana HPPD. Based on herbicidal results, compound B34 was selected for crop selectivity studies (corn injury ≤ 10%), indicating its potential for weed control in corn fields. These bioassay results showed that the compound B34 could be used as a possible lead compound for the development of HPPD inhibitors. © 2020 Society of Chemical Industry.