Jul 2026· Journal of Agricultural and Food Chemistry· Vol 74, pp. 21818-21828· 0 citations· 40 references
Medicine
Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a vital target for herbicide development. A series of pyrazole-quinoxaline conjugates were designed and synthesized via scaffold hopping and structural optimization. Bioassays revealed that B9 exhibited potent inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD) with an IC50 of 0.11 μM, outperforming mesotrione (0.22 μM) and topramezone (0.48 μM). B18 achieved 100% control over six weeds at 75 g a.i./ha and retained full efficacy against three broadleaf weeds even at 18.75 g a.i./ha. Furthermore, B18 produced less than 20% injury to rice, wheat, cotton, and peanut at 150 g a.i./ha, exhibiting superior crop safety to topramezone (47%-72%). Molecular docking elucidated the binding mechanism of B18 with AtHPPD via Fe2+ coordination, π-π interactions, and hydrogen bonds. Fluorescence titration and microscale thermophoresis assays further confirmed strong binding of B9 and B18 to AtHPPD. This study demonstrated that B18 is a promising, safe, and efficient HPPD-inhibiting herbicide candidate.
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is an attractive target for the development of bleaching herbicides. To develop novel HPPD inhibitors, 40 diketonitrile derivatives were designed by active-fragment splicing, synthesized, and characterized. In vitro inhibitory assays against Echinochloa crus-galli HPPD (EcHPPD) showed that compound III-2 exhibited the strongest activity, with a half-maximal inhibitory concentration (IC50) of 0.132 μM, outperforming mesotrione (0.277 μM). Preliminary bioassays demonstrated that compound III-2 had excellent herbicidal activity against E. crus-galli and Arabidopsis thaliana (AT) at a dose of 150 g a.i./ha. Crop safety evaluations revealed that compound III-2 was safer than the commercial herbicides mesotrione and isoxaflutole in sorghum and soybean. Molecular docking and molecular dynamics simulations revealed stable binding to HPPD, while electrostatic potential and density functional theory analyses demonstrated favorable electronic properties underlying its high activity. Compound III-2 represents a promising lead for developing novel HPPD-inhibiting diketonitrile herbicides.
Tengfei Ma, Siyi Yang, Ying Bian et al.· Journal of Agricultural and...· 0 citations
Herbicides are critical for agricultural weed management. Thirty-seven cycloalkyl-substituted pyrimidinedione derivatives were designed and synthesized via molecular hybridization to explore efficient herbicidal leads. All compounds displayed outstanding postemergence activity against broadleaf weeds, and several exhibited favorable activity against grass weeds. Compound 9i surpassed tiafenacil in greenhouse assays, providing 100% control of Zinnia elegans and Abutilon theophrasti at 2.34 g a.i./ha and 90% control of Echinochloa crus-galli at 9.38 g a.i./ha. Its inhibitory activity against protoporphyrinogen oxidase (PPO, IC50 = 9.55 nM) was slightly weaker than tiafenacil (6.85 nM), yet 9i achieved superior in vivo efficacy. Molecular docking analysis suggested that 9i shared a conserved binding mode with tiafenacil and may form an additional hydrogen bond between its cyano group and the Val475 residue of PPO. Density functional theory calculations indicated that its high clogP (4.34) facilitates plant penetration and transmembrane transport, explaining its excellent herbicidal activity independent of stronger PPO inhibition.
Hongyan Pei, Jialin Ye, Dongdong Liu et al.· Journal of Agricultural and...· 0 citations
4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is a promising target for new herbicide research. To develop new HPPD-inhibiting herbicides, we used a scaffold-hopping strategy by introducing a quinazolinone ring and combining it with the classic triketone pharmacophore, designing and synthesizing a series of novel HPPD inhibitors with a fused-ring architecture. The results showed that II-series of compounds exhibited excellent inhibitory activity against Arabidopsis thaliana (At) HPPD, with IC50 values 0.5- to 2.5-fold lower than those of mesotrione. Moreover, we obtained the crystal structure of AtHPPD-II-36 complex at a resolution of 1.8 Å. Importantly, II-36 exhibited high safety to wheat and outstanding herbicidal efficacy against Echinochloa crus-galli, Digitaria sanguinalis, and Bromus japonicus at a dosage of 30 g ai/ha. Our study provides a valuable example for designing novel HPPD inhibitors with enhanced herbicidal activity and improved crop selectivity.
Wan-Jie Zhang, Yu-Jun Dong, Shao-Meng Zhou et al.· Journal of Agricultural and...· 0 citations
The use of herbicides represents one of the effective weed management strategies. To create high-efficiency, low-risk protoporphyrinogen IX oxidase (PPO)-targeted herbicides, a set of novel N-phenylphthalimides bearing 1,3,4-oxadiazole and acylhydrazide fragments was designed and synthesized. Bioassays revealed that most of the compounds possessed potent herbicidal activity against six common weeds. Compound A9 exerted good inhibitory effects on Nicotiana tabacum PPO (NtPPO) with a Ki of 14.0 nM, outperforming commercial flumioxazin (46.3 nM) and flumiclorac-pentyl (52.0 nM). Molecular docking validated that A9 binds tightly to NtPPO via hydrogen bonds with Arg98 (2.8 Å), π–π stacking with Phe392, and π–alkyl sandwich interactions with Leu356/Leu372. Assays with PPO-deficient and PPO-complemented Escherichia coli strains, alongside AtPPO-overexpressing and mutant Arabidopsis, collectively verified A9 functions as a target-specific PPO inhibitor.
Wang Geng, Yan Li, Wei Zhang et al.· Journal of Agricultural and...· 0 citations
4-Hydroxyphenylpyruvate dioxygenase (HPPD; EC 1.13.11.27) is an important target for modern herbicide discovery. To translate HPPD inhibitors into effective herbicide candidates, we developed a metabolism-oriented design strategy to improve the in vivo efficacy of triketone-quinoline HPPD inhibitors. By shielding the metabolic hotspots within the scaffold, we discovered a series of new analogues with broadly improved postemergence herbicidal activity and substantially enhanced inhibition of Arabidopsis thaliana HPPD (AtHPPD). Notably, 9i showed a Ki value of 0.0012 μM toward AtHPPD, outperforming mesotrione by an order of magnitude. 11b not only exhibited excellent weed control at 15.625-250 g ai/ha, but also showed high crop safety to wheat at 250 g ai/ha. Molecular simulations showed that quinoline substitutions could enhance π-π interactions with Phe360 and Phe403, improving bioactivity. Our work establishes a metabolism-guided optimization framework for herbicide discovery and provides a promising wheat-selective herbicide candidate.
Min Li, Han Xiao, Si-Mei Zhou et al.· Journal of Agricultural and...· 0 citations
The application of herbicides plays a critical role in ensuring food security. However, the long-term overuse of herbicides can lead to a range of adverse effects. Therefore, it is essential to develop innovative and sustainable herbicides. A series of pyridazinone derivatives targeting phytoene desaturase (PDS) were designed and synthesized by using a structure-based drug design strategy. A bioassay showed that 16c (100%, 85%) exhibited stronger herbicidal activity against portulaca oleracea (P.o.) than that of norflurazon (NRF, 60%, 45%) in both post- and pre-emergence applications at a dosage of 150 g a.i./ha, while also showing greater safety to nontarget organisms. Meanwhile, levels of 15-cis-phytoene, carotenoids, and chlorophyll revealed that 16c effectively inhibited PDS activity. Molecular dynamics simulations and binding action assays confirmed that Arg195 is a key residue for the interaction between 16c and Synechococcus PDS (SynPDS). Therefore, 16c could be developed as a potent PDS inhibitor for herbicides.
Chao Chen, Yan Li, Wei Zhang et al.· Journal of Agricultural and...· 0 citations