Structural insights of 4-Hydrophenylpyruvate dioxygenase inhibition by structurally diverse small molecules

As one of the essential herbicide targets, 4-hydroxyphenylpyruvate dioxygenase (HPPD) has recently been typically used to produce potent new herbicides. In continuation with the previous work, several pyrazole derivatives comprising a benzoyl scaffold were designed and synthesized, and their inhibitory effects on Arabidopsis thaliana hydroxyphenylpyruvate dioxygenase (AtHPPD) and herbicidal activities were comprehensively evaluated in this study. Compound Z9 showed top-rank inhibitory activity to AtHPPD with an half-maximal inhibitory concentration (IC50) value of 0.05 μM, which was superior to topramezone (1.33 μM) and mesotrione (1.76 μM). Compound Z21 exhibited superior preemergence inhibitory activity against Echinochloa crusgalli, with stem and root inhibition rates of 44.3 and 69.6%, respectively, compared to topramezone (16.0 and 53.0%) and mesotrione (12.8 and 41.7%). Compounds Z5, Z15, Z20, and Z21 showed excellent postemergence herbicidal activities at a dosage of 150 g ai/ha, along with distinct bleaching symptoms and higher crop safety than topramezone and mesotrione, and they all were safe for maize, cotton, and wheat with injury rates of 0 or 10%. In addition, the molecular docking analysis also revealed that these compounds formed hydrophobic π–π interactions with Phe360 and Phe403 to AtHPPD. This study suggests that pyrazole derivatives containing a benzoyl scaffold could be used as new HPPD inhibitors to develop pre- and postemergence herbicides and be applied to additional crop fields.

Section: Introductionmentioning

confidence: 99%

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

Zeng

Zhang

Wang

et al. 2023

“…Great efforts have been and continue to be made in search for high-potency HPPD inhibitors. Fluorescent probes for visualizing HPPD in vivo also need ligands with high binding affinity. , Traditional HPPD inhibitors are mainly classified as triketone, pyrazole, and isoxazole derivatives. ,, In view of the inhibitor–HPPD interaction, optimization of the bidentate coordination with the metal ion and the π–π sandwich stacking with two phenylalanines are traditionally considered paramount for improving the binding affinity of HPPD inhibitors. As a result, structural modification has mainly focused on the introduction of different substituents on the 2-benzoylethen-1 core, , or introducing fused heterocycles, such as quinazolin-2,4-dione, isoindoline-1,3-dione, and 1,2,3-benzotriazine-4-one. ,,, The best inhibitors showed a one- or two-digit nanomolar and even subnanomolar inhibitory K i values .…”

Section: Introductionmentioning

confidence: 99%

“…36,37 Traditional HPPD inhibitors are mainly classified as triketone, pyrazole, and isoxazole derivatives. 14,33,38 In view of the inhibitor−HPPD interaction, optimization of the bidentate coordination with the metal ion and the π−π sandwich stacking with two phenylalanines are traditionally considered paramount for improving the binding affinity of HPPD inhibitors. As a result, structural modification has mainly focused on the introduction of different substituents on the 2-benzoylethen-1 core, 14,33 or introducing fused heterocycles, such as quinazolin-2,4-dione, isoindoline-1,3-dione, and 1,2,3-benzotriazine-4-one.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design

Dong

Yan

et al. 2023

Self Cite

High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the π−π sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the π−π sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors.

“…The most powerful strategy for managing weed controlling is the application of chemical herbicides. , However, with the long-term unscientific use of some herbicides (such as glyphosate and AHAS-inhibiting herbicides), many new challenges including serious environmental problems and weed resistance have emerged. − Therefore, there is still a strong demand for the research and development (R&D) of new herbicides, especially for those with a novel mode of action (MoA). These novel herbicides usually have the characteristics including being highly efficient, low toxicity, good crop selectivity, environmentally friendly, and broad-spectrum herbicidity. ,, With the demand of high activity, selectivity, and security, various key enzymes have been found to be potential targets for novel herbicide discovery. Protoporphyrinogen IX oxidase (PPO, E.C.…”

Section: Introductionmentioning

confidence: 99%

“…These novel herbicides usually have the characteristics including being highly efficient, low toxicity, good crop selectivity, environmentally friendly, and broad-spectrum herbicidity. 5,9,10 With the demand of high activity, selectivity, and security, various key enzymes have been found to be potential targets for novel herbicide discovery. Protoporphyrinogen IX oxidase (PPO, E.C.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of a Subnanomolar Inhibitor of Protoporphyrinogen IX Oxidase via Fragment-Based Virtual Screening

Zheng

Wang

Dong

et al. 2023

Self Cite

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4), a key functional enzyme existing in various organisms, is acknowledged to be one of the most important action targets in the development of herbicides due to its pivotal roles in chlorophyll and heme biosynthesis pathways. As our persistent research work on the discovery of novel PPO-inhibiting herbicides, a new compound methyl 2- ((5-(3-chloro-4,5,6,7-tetrahydro-2H-indazol-2-yl)-6-fluorobenzo[d]thiazol-2-yl)thio)acetate (8aj, K i = 16 nM) was screened out as a hit compound via a fragment-based virtual screening method performed in the Auto Core Fragment in silico Screening web server. Subsequently, through a fused process of "hit-to-lead" optimization guided by molecular simulation, a total of 30 3-chloro-4,5,6,7-tetrahydro-2H-indazol-benzo[d]thiazole derivatives were synthesized and characterized. The results of the enzymatic inhibition bioassay showed that more than half of the newly synthesized compounds displayed higher activity against Nicotiana tabacum PPO (NtPPO) than oxadiazon, a commercial PPO-inhibiting herbicide. In particular, compound 8ab, a subnanomolar inhibitor with a K i value of 380 pM against NtPPO, was discovered, which showed to be 71-fold more active than the commercial control oxadiazon (K i = 27 nM), and was proven to be the most potent PPO inhibitor so far. Furthermore, the greenhouse assay demonstrated that most of the synthetic compounds showed good herbicidal activity toward the tested weeds. Especially, compound 8ad (K i = 670 pM) showed the most promising post-emergence herbicidal activity with a broad spectrum of weed control even at a concentration as low as 37.5 g a.i./ha and relatively safe to rice at a dosage of 150 g a.i./ha, indicating that 8ad has the greatest potential to be developed as a new herbicide for weed control in paddy fields. This work provides a paradigm for the rational design and discovery of a novel PPO-inhibiting herbicide guided by the fragment-based drug design.