GARD™skin and GARD™potency: A proof-of-concept study investigating applicability domain for agrochemical formulations.

Several New Approach Methodologies (NAMs) for hazard assessment of skin sensitisers have been formally validated. However, data regarding their applicability on certain product classes are limited. The purpose of this project was to provide initial evidence on the applicability domain of GARD™skin and GARD™potency for the product class of agrochemical formulations. For this proof of concept, 30 liquid and 12 solid agrochemical formulations were tested in GARDskin for hazard predictions. Formulations predicted as sensitisers were further evaluated in the GARDpotency assay to determine GHS skin sensitisation category. The selected formulations were of product types, efficacy groups and sensitisation hazard classes representative of the industry's products. The performance of GARDskin was estimated by comparing results to existing in vivo animal data. The overall accuracy, sensitivity, and specificity were 76.2% (32/42), 85.0% (17/20), and 68.2% (15/22), respectively, with the predictivity for liquid formulations being slightly higher compared to the solid formulations. GARDpotency correctly subcategorized 14 out of the 17 correctly predicted sensitisers. Lack of concordance was justifiable by compositional or borderline response analysis. In conclusion, GARDskin and GARDpotency showed satisfactory performance in this initial proof-of-concept study, which supports consideration of agrochemical formulations being within the applicability domain of the test methods.

Multiple amino acid transporters as carriers load L-valine-phenazine-1-carboxylic acid conjugate into Ricinus sieve tubes for the phloem translocation.

Some transporters play important roles in the uptake and acropetal xylem translocation of vectorized agrochemicals. However, it is poorly understood the basipetally phloem-loading functions of transporters toward vectorized agrochemicals. Here, L-Val-PCA (L-valine-phenazine-1-carboxylic acid conjugate) uptake was demonstrated carrier-mediated. RcAAP2, RcANT7, and RcLHT1 showed a similarly up-regulated expression pattern from 62 transporter coding genes in Ricinus at 1 h after L-Val or L-Val-PCA treatment. Subcellular localization revealed that fusion RcAAP2-eGFP, RcANT7-eGFP and RcLHT1-eGFP proteins were expressed in the plasma membrane of mesophyll and phloem cells. Yeast assays found that RcAAP2, RcANT7, and RcLHT1 facilitated L-Val-PCA uptake. To further demonstrate the phloem-loading functions, using vacuum infiltration strategy, an Agrobacterium-mediated RNA interference (RNAi) protocol was constructed in seedlings. HPLC detection indicated that L-Val-PCA phloem sap concentrations were significantly decreased 54.5 %, 27.6 %, and 41.6 % after silencing for 72 h and increased 48.3 %, 52.6 %, and 52.4 % after overexpression, respectively. In conclusion, the plasma membrane-located RcAAP2, RcANT7, and RcLHT1 can loaded L-Val-PCA into Ricinus sieve tubes for the phloem translocation, which may aid in the utilization of transporters and molecular design of phloem-mobile fungicides target root or vascular pathogens.

Retrospective evaluation of the eye irritation potential of agrochemical formulations.

Multiple in vitro eye irritation methods have been developed and adopted as OECD health effects test guidelines. However, for predicting the ocular irritation/damage potential of agrochemical formulations there is an applicability domain knowledge gap for most of the methods. To overcome this gap, a retrospective evaluation of 192 agrochemical formulations with in vivo (OECD TG 405) and in vitro (OECD TG 437, 438, and/or 492) data was conducted to determine if the in vitro methods could accurately assign United Nations Globally Harmonized System for Classification and Labelling of Chemicals (GHS) eye irritation hazard classifications. In addition, for each formulation the eye irritation classification was derived from the classification of the contained hazardous ingredients and their respective concentration in the product using the GHS concentration threshold (CT) approach. The results herein suggest that the three in vitro methods and the GHS CT approach were highly predictive of formulations that would not require GHS classification for eye irritation. Given most agrochemical formulations fall into this category, methods that accurately identify non-classified agrochemical formulations could significantly reduce the use of animals for this endpoint.

Resolving binding pathways and solvation thermodynamics of plant hormone receptors.

Plant hormones are small molecules that regulate plant growth, development, and responses to biotic and abiotic stresses. They are specifically recognized by the binding site of their receptors. In this work, we resolved the binding pathways for eight classes of phytohormones (auxin, jasmonate, gibberellin, strigolactone, brassinosteroid, cytokinin, salicylic acid, and abscisic acid) to their canonical receptors using extensive molecular dynamics simulations. Furthermore, we investigated the role of water displacement and reorganization at the binding site of the plant receptors through inhomogeneous solvation theory. Our findings predict that displacement of water molecules by phytohormones contributes to free energy of binding via entropy gain and is associated with significant free energy barriers for most systems analyzed. Also, our results indicate that displacement of unfavorable water molecules in the binding site can be exploited in rational agrochemical design. Overall, this study uncovers the mechanism of ligand binding and the role of water molecules in plant hormone perception, which creates new avenues for agrochemical design to target plant growth and development.

Morpholine Derivatives in Agrochemical Discovery and Development.

Derivatives of morpholine are biologically active organic compounds with special structures discovered in multiple drugs. As a result of the terminal pharmacophore of action and extraordinary activity, they attracted fair attention with regard to pesticide innovation and development. Analysis of brief structure-activity relationships and the summarization of the characteristics of pesticides containing morpholine fragments with efficient activity are key steps in the development of novel pesticides. This review primarily overviews morpholine compounds with insecticidal, fungicidal, herbicidal, antiviral, and plant growth regulation properties to provide educational insight for the creation of new morpholine-containing compounds.

Pursuing Green and Efficient Agriculture from Molecular Assembly: A Review of Solid-State Forms on Agrochemicals.

Achieving rapid global agricultural development while maintaining ecological harmony is a major challenge of the new millennium. Meeting this challenge requires the development of efficient and environmentally friendly agrochemicals, including pesticides and fertilizers. Molecular assembly, as a promising strategy, has garnered significant attention in recent years for the development of advanced solid-state forms of agrochemicals. In this review, we present the potential and recent advancements of solid-state forms, such as polymorphs, cocrystals/salts, solvates, inclusion compounds, and the amorphous state, for the production of high-efficiency and low-polluting agrochemical products. We provide an overview of the concepts and preparation methods of these solid-state forms, followed by an exploration of their applications in sustainable agriculture. Specifically, we highlight their value in enhancing pesticide solubility, enabling controlled release of chemical fertilizers, and reducing off-target risks. Lastly, we discuss the challenges and prospects associated with the utilization of solid-state forms for the advancement of environmentally friendly and efficient agriculture.

Design, synthesis, insecticidal activities and translocation of amino acid-tralopyril conjugates as vectorizing agrochemicals.

BACKGROUND: Conjugating amino acid moieties to active ingredients has been recognized as an effective method for improving the precise targeting of the active form to the specific site. Based on the vectorization strategy, a series of amino acid-tralopyril conjugates were designed and synthesized as novel proinsecticide candidates, with the potential capability of root uptake and translocation to the foliage of crops. RESULTS: Bioassay results showed excellent insecticidal activities of some conjugates, in particular, the conjugates 6b, 6e, and 7e, against the diamondback moth (Plutella xylostella), with equivalent insecticidal activity to chlorfenapyr (CFP). Importantly, conjugate 6e exhibited significantly higher in vivo insecticidal activity against P. xylostella than CFP. Furthermore, the systemic test experiments with Brassica chinensis demonstrated that conjugates 6e and 7e could be transported to the leaves, in contrast to CFP, which remained in the root. CONCLUSION: This study demonstrated the feasibility of amino acid fragment conjugation as a vectorization strategy for transporting non-systemic insecticides into the leaves of B. chinensis while maintaining in vivo insecticidal activity. The findings also provide insights for subsequent mechanism studies on the uptake and transport of amino acid-insecticide conjugates in plants. © 2023 Society of Chemical Industry.

Sulfur-based functional groups in agrochemistry.

The element sulfur has an outstanding role in the crop protection chemistry because it is used in its elemental form as a multisite fungicide, but is also part of agrochemicals in the form of aromatic or aliphatic sulfur-containing rings or sulfur-based functional groups. This review gives an exhaustive overview over the latter category. Several fundamental agrochemical compound classes are named after a sulfur-based functionality, such as the dithiocarbamate fungicides and sulfonylurea herbicides. Altogether, 16 different sulfur-based functional groups are presented with their typical synthesis approaches and most important representatives in crop protection. © 2023 Society of Chemical Industry.

Ring Closure and Ring Opening as Useful Scaffold Hopping Tools in Agrochemistry.

Ring closing acyclic parts of a molecular scaffold or the opposite manipulation, opening rings to produce pseudo-ring structures, is an important scaffold hopping manipulation. Analogues derived from biologically active compounds through the utilization of such strategies are often similar in shape and physicochemical properties and, therefore, likely to exhibit similar potency. This review will demonstrate how several different ring closure techniques, such as replacing carboxylic functions by cyclic peptide mimics, incorporating double bonds into aromatic rings, tying back ring substituents to a bicyclic structure, cyclizing adjacent ring substituents to an annulated ring, bridging annulated ring systems to tricyclic scaffolds, and exchanging gem-dimethyl groups by cycloalkyl rings, but also ring opening led to the discovery of highly active agrochemicals.

Isosteric Ring Exchange as a Useful Scaffold Hopping Tool in Agrochemistry.

Replacing one ring in a molecule by a different carba- or heterocycle is an important scaffold hopping manipulation, because biologically active compounds and their analogues, which underwent such a transformation, are often similar in size, shape, and physicochemical properties and, therefore, likely in their potency as well. This review will demonstrate, how isosteric ring exchange led to the discovery of highly active agrochemicals and which ring interchanges have proven to be most successful.

Nanopesticides in comparison with agrochemicals: Outlook and future prospects for sustainable agriculture.

Agrochemicals are products of advanced technologies that use inorganic pesticides and fertilizers. Widespread use of these compounds has adverse environmental effects, leading to acute and chronic exposure. Globally, scientists are adopting numerous green technologies to ensure a healthy and safe food supply and a livelihood for everyone. Nanotechnologies significantly impact all aspects of human activity, including agriculture, even if synthesizing certain nanomaterials is not environmentally friendly. Numerous nanomaterials may therefore make it easier to create natural insecticides, which are more effective and environmentally friendly. Nanoformulations can improve efficacy, reduce effective doses, and extend shelf life, while controlled-release products can improve the delivery of pesticides. Nanotechnology platforms enhance the bioavailability of conventional pesticides by changing kinetics, mechanisms, and pathways. This allows them to bypass biological and other undesirable resistance mechanisms, increasing their efficacy. The development of nanomaterials is expected to lead to a new generation of pesticides that are more effective and safer for life, humans, and the environment. This article aims to express at how nanopesticides are being used in crop protection now and in the future. This review aims to shed some light on the various impacts of agrochemicals, their benefits, and the function of nanopesticide formulations in agriculture.

Dual-functional lignin-based hydrogels for sustained release of agrochemicals and heavy metal ion complexation.

An effective way of improving the efficiency of agrochemicals and improving crop yield and quality is by slow or sustained release, which is conducive to environmental protection. Meanwhile, the excessive amount of heavy metal ions in soil can create toxicity in plants. Here, we prepared lignin-based dual-functional hydrogels containing conjugated agrochemical and heavy metal ligands through free-radical copolymerization. The content of the agrochemicals (including plant growth regulator 3-indoleacetic acid (IAC) and herbicide 2,4-dichlorophenoxyacetic acid (DCP)) in the hydrogels were tuned by changing the hydrogel composition. The conjugated agrochemicals could slowly release through the gradual cleavage of the ester bond. As a result of the release of the DCP herbicide, the growth of lettuce was effectively regulated, thus confirming the feasibility and effectiveness of this system in application. At the same time, due to the presence of metal chelating groups (such as COOH, phenolic OH, and tertiary amine) the hydrogels could act as adsorbents or stabilizers towards heavy metal ions for improving the soil remediation and preventing the adsorption of these toxic metals by plant roots. Specifically, Cu(II) and Pb(II) could be adsorbed >380 and 60 mg/g, respectively.

Synthesis, phloem mobility and induced plant resistance of synthetic salicylic acid amino acid or glucose conjugates.

BACKGROUND: The growing demand for food, combined with a strong social expectation for a diet produced with fewer conventional agrochemical inputs, has led to the development of new alternatives in plant protection worldwide. Among different possibilities, the stimulation of the plant innate immune system by chemicals represents a novel and promising way. The vectorization strategy of an active ingredient that we previously developed with fungicides can potentially extend to salicylic acid (SA) or its halogenated analogues. RESULTS: Using the click chemistry method, six new conjugates combining SA or two mono- or di-halogenated analogues with L-glutamic acid or ß-D-glucose via a 1,2,3-triazole nucleus have been synthesized. Conjugate 8a, which is derived from SA and glutamic acid, showed high phloem mobility in the Ricinus model, similar to that of SA alone despite a much higher steric hindrance. In vivo bioassays of the six conjugates against two maize pathogenic fungi Bipolaris maydis and Fusarium graminearum revealed that, unlike SA, the amino acid conjugate 8a with good phloem mobility exerted a protective effect not only locally at the application site, but also in distant stem tissues after foliar application. Moreover, compounds 8a and 8b induced up-regulation of both defense-related genes ZmNPR1 and ZmPR1 similar to their parent compounds upon challenge inoculation with B. maydis. CONCLUSION: The vectorization of salicylic acid or its halogenated derivatives by coupling them with an α-amino acid can be a promising strategy to stimulate SA-mediated plant defenses responses against pathogens outside the application site. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Nanotechnology in agriculture: Comparison of the toxicity between conventional and nano-based agrochemicals on non-target aquatic species.

Increased crop production is necessary to keep up with rising food demand. However, conventional agricultural practices and agrochemicals are unable to sustain further increases without serious risk of adverse environmental consequences. The implementation of nanotechnology in agriculture practices has been increasing in recent years and has shown tremendous potential to boost crop production. The rapid growth in development and use of nano-agrochemicals in agriculture will inevitably result in more chemicals reaching water bodies. Some unique properties of nanoformulations may also alter the toxicity of the AI on aquatic organisms when compared to their conventional counterparts. Results from studies on conventional formulations may not properly represent the toxicity of new nanoformulations in the aquatic environment. As a result, current guidelines derived from conventional formulations may not be suitable to regulate those newly developed nanoformulations. Current knowledge on the toxicity of nano-agrochemicals on aquatic organisms is limited, especially in an ecologically relevant setting. This review complies and analyzes 18 primary studies based on 7 criteria to provide a comprehensive analysis of the available toxicity information of nano-agrochemicals and their conventional counterparts on aquatic organisms. Our analysis demonstrates that the overall toxicity of nano-agrochemicals on non-target aquatic species is significantly lower as compared to conventional counterparts. However, further dividing formulations into three categories (organic, bulk and ionic) shows that some nanoformulations can be more toxic when compared to bulk materials but less toxic as compared to ionic formulations while organic nanopesticides do not show a general trend in overall toxicity. Moreover, our analysis reveals the limitations of current studies and provides recommendations for future toxicity studies to ensure the effective and sustainable application of nano-agrochemicals, which will be beneficial to both the agrochemical industry and regulatory agencies alike.

The power of cross-indication testing: agrochemicals originally stemming from a different indication.

Cross-indication testing is the assaying of final compounds, but also their intermediates or side products, from one agrochemical indication against target species of other product lines. This approach has proven to be a highly successful source of lead compounds, which led to several important crop protection products. This review article describes, which herbicides came from fungicides and insecticides, how fungicides have been obtained from herbicide and insecticide leads and which insecticides have their roots in herbicide and fungicide chemistry. © 2022 Society of Chemical Industry.

Insertion of Small Flexible Linkers as a Useful Scaffold Hopping Tool in Agrochemistry.

Inserting small flexible linkers of only one- to three-atom chain lengths into a molecular backbone is an important scaffold hopping manipulation. Analogues derived from biologically active compounds through the utilization of such a strategy are often similar in shape and physicochemical properties and, therefore, likely to exhibit similar potency. This review will demonstrate how the elongation with oxygen, amino, methylene, ethylene, vinyl, ethynyl, and CH2O bridges led to the discovery of highly active agrochemicals.

Innovation in insecticide discovery: Approaches to the discovery of new classes of insecticides.

The continuing demand for agrochemical insecticides that can meet increasing grower, environmental, consumer and regulatory requirements creates the need for the development of new solutions for managing crop pest insects. The development of resistance to the currently available insecticidal products adds another critical driver for new insecticidal active ingredients (AIs). One avenue to meeting these challenges is the creation of new classes of insecticidal molecules to act as starting points and prototypes stimulating further spectrum, efficacy and environmental impact refinements. A new class of insecticides is foreshadowed by the first molecule exemplifying that class (first-in-class, FIC) and offers one measure of innovation within the agrochemical industry. Most insecticides owe their discovery to competitor-inspired (i.e. competitor patents/products) or next-generation (follow-on to a company's pre-existing product) strategies. In contrast, FIC insecticides primarily emerge from a bioactive hypothesis approach, with the largest segment resulting from the exploration of new areas of chemistry/heterocycles and underexploited motifs. Natural products also play an important role in the discovery of FIC insecticides. Understanding the origins of these FIC compounds and the approaches used in their discovery can provide insights into successful strategies for future FIC insecticides. This review analyses information on historic and recently introduced FIC insecticides. Its main objective has been to identify the most successful discovery strategies for identifying new agrochemical solutions to meet the challenge of minimizing crop losses resulting from insects. © 2022 Society of Chemical Industry.

Importance of chemical polymorphism in modern crop protection.

The development of agrochemical products faces many scientific challenges. After selection of an agrochemical candidate its properties will have to be optimized to guarantee best bioavailability and stability under many different conditions in various formulation types. These challenges are influenced by the solid-state properties of the active ingredient and this makes the selection of an optimized solid-state form of modern agrochemicals at early development stages very valuable. The increasing awareness of the solid state of agrochemicals is reflected in the importance of polymorphism patent applications, which may enhance the risk of litigations. This review aims to present strategies for the solid-form selection process of agrochemical development candidates. It introduces the different techniques for crystallization and analytics and demonstrates the influence of the solid state on different formulation types. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Reversal of Functional Groups as a Useful Scaffold Hopping Tool in Agrochemistry.

Reverting the orientation of a functional group by exchanging molecular parts of it is an important scaffold hopping manipulation, as biologically active compounds and their analogs, which underwent such a transformation, are often similar in shape and physicochemical properties and therefore likely in their potency as well. This review will demonstrate, how the inversion of carboxamides, sulfonamides, carbamates, oximes, hydrazones, O,S-acetals, and ethers led to the discovery of highly active agrochemicals.

Field application of nanoliposomes delivered quercetin by inhibiting specific hsp70 gene expression against plant virus disease.

BACKGROUND: The annual economic loss caused by plant viruses exceeds 10 billion dollars due to the lack of ideal control measures. Quercetin is a flavonol compound that exerts a control effect on plant virus diseases, but its poor solubility and stability limit the control efficiency. Fortunately, the development of nanopesticides has led to new ideas. RESULTS: In this study, 117 nm quercetin nanoliposomes with excellent stability were prepared from biomaterials, and few surfactants and stabilizers were added to optimize the formula. Nbhsp70er-1 and Nbhsp70c-A were found to be the target genes of quercetin, through abiotic and biotic stress, and the nanoliposomes improved the inhibitory effect at the gene and protein levels by 33.6 and 42%, respectively. Finally, the results of field experiment showed that the control efficiency was 38% higher than that of the conventional quercetin formulation and higher than those of other antiviral agents. CONCLUSION: This research innovatively reports the combination of biological antiviral agents and nanotechnology to control plant virus diseases, and it significantly improved the control efficiency and reduced the use of traditional chemical pesticides.