Synthesis and Evaluation of Halogenated 5-(2-Hydroxyphenyl)pyrazoles as Pseudilin Analogues Targeting the Enzyme IspD in the Methylerythritol Phosphate Pathway

This work reports halogenated 5-(2-hydroxyphenyl)pyrazoles as pseudilin analogues with the potential to target the enzyme IspD in the MEP pathway. Such analogues were designed using the bioisosteric replacement of the pseudilin core structure and synthesized via an efficient three-step route. With AtIspD-based screening and pre- and post-emergence herbicidal test, these compounds were demonstrated to have considerable activities against AtIspD with IC50 up to 3.27 μM and against model plants rape and barnyard grass with moderate to excellent activities. At a rate of 150 g per hectare in greenhouse test, three compounds exhibited higher or comparable herbicidal activities than pseudilin. Molecular docking of representative compounds into the allosteric site of AtIspD revealed a binding mode similar to that of pseudilin. The established bioisosterism and synthesis method in this work may serve as an important tool for the development of new herbicides and antimicrobials targeting IspD in the MEP pathway.