Novel Pyrazole Amides as Potential 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors

Abstract

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for the development of new herbicides. HPPD inhibitors can hinder photosynthesis and induce weed death with bleaching symptoms. To explore the novel skeleton of HPPD inhibitors, a series of novel pyrazole amide derivatives were synthesized and evaluated for their inhibitory effects on Arabidopsis thaliana HPPD (AtHPPD) and herbicidal activities. Some compounds had excellent inhibitory activities against AtHPPD. Among them, compound B5 displayed top-rank inhibitory activity against AtHPPD with an IC50 value of 0.04 μM, which was obviously superior to that of topramezone (IC50 value of 0.11 μM). Furthermore, compounds B2 and B7 had 100% herbicidal activities in Petri dish assays against Portulaca oleracea and Amaranthus tricolor at 100 μg/mL. In particular, compound B7 not only possessed strong AtHPPD inhibitory activity but also exhibited significant preemergence herbicidal activity. However, compound B7 was completely harmless to soybean, cotton, and wheat. In addition, the molecular docking and microscale thermophoresis measurement experiment verified that compounds can bind well with AtHPPD via π–π interactions. The present work provides a new approach for the rational design of more effective HPPD inhibitors, and pyrazole amides could be used as useful substructures for the development of new HPPD inhibitors and preemergence herbicidal agents.

Discovery of Novel Pyrazole Derivatives with Improved Crop Safety as 4-Hydroxyphenylpyruvate Dioxygenase-Targeted Herbicides

“…The target pyrazole compounds, positive controls topramezone and mesotrione, were dissolved with DMSO and diluted to concentrations of 100 and 10 μg/mL. The experimental procedure was identical to that described in our previous report …”

“…The preemergence herbicidal activities of target compounds Z1 – Z22 were evaluated in accordance with the inhibition against the growth of the stems and roots of Amaranthus tricolor, Portulaca oleracea, and Echinochloa crusgalli using the Petri dish assay. , While topramezone and mesotrione were arranged as positive controls, compounds Z1 – Z22 were dissolved with 100 μL DMF and diluted to 100 and 10 μg/mL concentrations using a 0.1% Tween-80 solution. The experiment was conducted following our previous work . After observation for 5 days, the stem and root lengths of the weeds were measured and then the inhibition rate was calculated as the following formula …”

“…The experiment was conducted following our previous work . After observation for 5 days, the stem and root lengths of the weeds were measured and then the inhibition rate was calculated as the following formula i nhibition rate ⁢ 0.25em ( % ) = ( L control − L treatment ) / L control × 100 % …”

“…The experimental procedure was identical to that described in our previous report. 34 Preemergence Herbicidal Activity. The preemergence herbicidal activities of target compounds Z1−Z22 were evaluated in accordance with the inhibition against the growth of the stems and roots of Amaranthus tricolor, Portulaca oleracea, and Echinochloa crusgalli using the Petri dish assay.…”

“…Previously, we reported that atypical pyrazole amides could be used as HPPD inhibitors and showed excellent preemergence herbicidal activities. 34 Unfortunately, these pyrazole amides lacked effective postemergence herbicidal activities. To discover new HPPD-targeted herbicides that had superior postemergence herbicidal activities than before, taking the 4-benzoyl-pyrazole-5-ol as the core skeleton, which was the common substructure of commercial HPPD inhibitors such as topramezone, 35 a series of novel pyrazole derivatives were designed and synthesized by introducing the pharmaco- phore 36,37 with outstanding herbicidal activity into the carbonyl or the hydroxyl position of the core skeleton (Figure 1).…”