Advances in Understanding the Toxicity of 4-Hydroxyphenylpyruvate Dioxygenase-Inhibiting Herbicides.

4-Hydroxyphenylpyruvate dioxygenase inhibiting herbicides (HIHs) represent a recent class (HRAC group 27) of herbicides that offer many advantages, such as broad-spectrum activity, crop selectivity, and low resistance rates. However, emerging studies have highlighted the potential toxicity of HIHs in the environment. This review aims to provide a comprehensive summary of the toxicity of HIHs toward nontarget organisms, including plants, microorganisms, animals, and humans. Furthermore, the present work discusses the ecological roles of these organisms in the environment and their significance in agriculture. By shedding light on the toxicity of HIHs, this study seeks to raise awareness among end users, including environmentalists, researchers, and farmers, regarding the potential ecological implications of these herbicides. Hopefully, this knowledge can contribute to informed decision-making and sustainable practices in green agriculture and environmental management.

New Insights into the Interactions between Herbicides: Trends from Recent Studies.

The use of herbicide combinations is a common practice in modern agriculture. However, unexpected results may be observed due to herbicide and weed diversity, therefore, highlighting the need for a predictive strategy. To this end, a data set was made based on recent studies. This data set included herbicide attributes, such as active ingredient, chemical family, and mode of action, and weed attributes, namely, species, clade, type of leaves, family, and lifespan. Globally, additive interactions (46.30%) were more frequent than antagonistic (29.09%) and synergistic (24.61%) ones. The occurrence of these herbicide interactions with regard to herbicide and weed features is also discussed. Moreover, mesotrione and glyphosate have been, respectively, identified as the most promising or inadequate herbicides in predicting beneficial mixtures. The resulting global trend could guide farmers in their choice of beneficial herbicide companions.

Structure-Guided Discovery of Silicon-Containing Subnanomolar Inhibitor of Hydroxyphenylpyruvate Dioxygenase as a Potential Herbicide.

4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) has been recognized as one of the most promising targets in the field of herbicide innovation considering the severity of weed resistance currently. In a persistent effort to develop effective HPPD-inhibiting herbicides, a structure-guided strategy was carried out to perform the structural optimization for triketone-quinazoline-2,4-diones, a novel HPPD inhibitor scaffold first discovered in our lab. Herein, starting from the crystal structure of Arabidopsis thaliana (At)HPPD complexed with 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(o-tolyl)quinazoline-2,4(1H,3H)-dione (MBQ), three subseries of quinazoline-2,4-dione derivatives were designed and prepared by optimizing the hydrophobic interactions between the side chain of the core structure at the R1 position and the hydrophobic pocket at the active site entrance of AtHPPD. 6-(2-Hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-(3-(trimethylsilyl)prop-2-yn-1-yl)quinazoline-2,4(1H,3H)-dione (60) with the best inhibitory activity against AtHPPD was identified to be the first subnanomolar-range AtHPPD inhibitor (Ki = 0.86 nM), which significantly outperformed that of the lead compound MBQ (Ki = 8.2 nM). Further determination of the crystal structure of AtHPPD in complex with compound 60 (1.85 Å) and the binding energy calculation provided a molecular basis for the understanding of its high efficiency. Additionally, the greenhouse assay indicated that 6-(2-hydroxy-6-oxocyclohex-1-ene-1-carbonyl)-1,5-dimethyl-3-propylquinazoline-2,4(1H,3H)-dione (28) and compound 60 showed acceptable crop safety against peanut and good herbicidal activity with a broad spectrum. Moreover, compound 28 also showed superior selectivity for wheat at the dosage of 120 g ai/ha and favorable herbicidal efficacy toward the gramineous weeds at the dosage of as low as 30 g ai/ha. We believe that compounds 28 and 60 have promising prospects as new herbicide candidates for wheat and peanut fields.

Hydrophobicity-oriented drug design (HODD) of new human 4-hydroxyphenylpyruvate dioxygenase inhibitors.

Involved in the tyrosine degradation pathway, 4-hydroxyphenylpyruvate dioxygenase (HPPD) is an important target for treating type I tyrosinemia. To discover novel HPPD inhibitors, we proposed a hydrophobicity-oriented drug design (HODD) strategy based on the interactions between HPPD and the commercial drug NTBC. Most of the new compounds showed improved activity, compound d23 being the most active candidate (IC50 = 0.047 µM) with about 2-fold more potent than NTBC (IC50 = 0.085 µM). Therefore, compound d23 is a potential drug candidate to treat type I tyrosinemia.

Cholinesterases and Engineered Mutants for the Detection of Organophosphorus Pesticide Residues.

Nowadays, pesticide residues constitute an increasing public health concern. Cholinesterases, acetylcholinesterase, and butyrylcholinesterase, are reported to be involved in detoxification processes owing to their capability of scavenging organophosphates and carbamates. Thus, these enzymes are targeted for the discovery of sensors aiming at detecting pesticide residues. In recent years, cholinesterase-based biosensors have attracted more and more attention in the detection of pesticides. Herein, this review describes the recent progress on the engineering of cholinesterases and the development of the corresponding sensors that could be used for the detection of organophosphorus pesticide residues.

4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals.

The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions.