Pesticide research

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Early twenty-first century pesticide research has focused on developing molecules that combine low use rates and that are more selective, safer, resistance-breaking and cost-effective. Obstacles include increasing pesticide resistance and an increasingly stringent regulatory environment. [1]

Contents

The sources of new molecules employ natural products, competitors, universities, chemical vendors, combinatorial chemistry libraries, [2] intermediates from projects in other indications and compound collections from pharmaceutical and animal health companies. [1]

History

Along with improved agrochemicals, seeds, fertilizers, mechanization, and precision farming, improved protection of crops from weeds, insects and other threats is highly sought. Developments over the past 1960–2013 period enabled reduced use rates, in the cases of the sulfonylurea herbicides (5), the piperidinylthiazole fungicides, and the emamectin insecticides and acaricides, reaching 99%, with concomitant environmental improvements. [1]

The rate of new molecule introductions has declined. The costs to bring a new molecule to market have risen from U.S. $152 million in 1995 to $256 million in 2005, as the number of compounds synthesized to deliver one new market introduction rose from 52,500 in 1995 to 140,000 in 2005. [1]

New active ingredient registrations with the US Environmental Protection Agency (EPA) over the 1997–2010 period included biological (B), natural product (NP), synthetic (S) and synthetic natural derived (SND) substances. Combining conventional pesticides and biopesticides, NPs accounted for the majority of registrations, with 35.7%, followed by S with 30.7%, B with 27.4% and SND with 6.1%. [3]

Research process

Candidate molecules are optimized through a design-synthesis-test-analysis cycle. While compounds eventually are tested on the target organism(s). However, in vitro assays are becoming more common. [1]

Parallels with pharmaceuticals

Agrochemicals and pharmaceuticals may operate via the same processes. In several cases, a homologous enzyme/receptor is addressed, and can potentially be of use in both contexts. One example is the triazole antimycotics or fungicides. However, the chemical environments encountered en route from the application site to the target generally require differing physicochemical properties, while the unit costs are generally much lower. [1] Agrochemicals typically have a lower number of hydrogen bond donors. [4] For example, over 70% of insecticides have no hydrogen bond donor, and over 90% of herbicides have two or fewer. Desirable agrochemicals have residual activity and persistence of effect lasting up to several weeks to allow large spray intervals. The majority of heterocycles found in agrochemicals are heteroaromatic. [1]

Structure-based design

Structure-based design is a multidisciplinary process that is relatively new in agrochemicals. As of 2013 no products on the market were the direct result of this approach. However, discovery programs have benefited from structure-based design, including that for scytalone dehydratase inhibitors as rice blast fungicides. [1] [5]

Structure-based design is appealing for crop researchers because of the many protein structures in the public domain, which increased from 13,600 to 92,700 between 200 and 2013. Many agrochemical crystals are now in the public domain. The structures of several interesting ion channels are now in the public domain. For example, the crystal structure of a glutamate-gated chloride channel in complex with ivermectin was reported in 2011 and represents a starting point for the design of novel insecticides. This structure led to a homology model for a related γ-aminobutyric acid (GABA)–gated chloride channel and a binding mode for the meta-diamides, another insecticide class. [1]

Fragment- and target-based design

Techniques such as fragment-based design, virtual screening and genome sequencing have helped generate drug leads. Published examples of fragment-based agrochemical design have been comparatively rare, although the method was used to generate new ACC inhibitors. A combination of in silico fragment-based design with protein ligand crystal structures yielded synthetically amenable compounds. Common to all inhibitors is the methoxyacrylate "warhead", whose interactions and position are well known from the strobilurin fungicides. Fragments were linked to the warhead to form a virtual library. [1]

The likelihood of finding active analogs on the basis of a screen hit from a novel scaffold can be increased by virtual screening. Because the pharmacophore of the reference ligand is well defined, a virtual library of potential herbicidal inhibitors of the enzyme anthranilate synthase was generated by keeping the core scaffold constant and attaching different linkers. The scores obtained from docking studies ranked these molecules. Resulting novel compounds showed a primary hit rate of 10.9%, much higher than for conventional high-throughput screening. Other tools like three-dimensional (3D) shape, atom-type similarity, or 2D extended connectivity fingerprints also retrieve molecules of interest out of a database with a useful success rate. Scaffold-hopping is also efficiently achieved by virtual screening, with 2D and 3D variants providing the best results. [1]

Genome-sequencing, gene knockout or antisense knockdown techniques have provided agrochemists with a method for validating potential new biochemical targets. However, genes such as avirulence genes are not essential for the organism and many potential targets lack known inhibitors. Examples of this procedure include the search for new herbicidal compounds of the nonmevalonate, such as the discovery of new inhibitors of 2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (IspD, Enzyme Commission (EC) number 2.7.7.60) with the best expressing a half-maximal inhibitory concentration (IC50) of 140 nM in the greenhouse at 3 kg/ha (2.7 lb/acre). Thanks to an x-ray crystal structure of Arabidopsis thaliana, IspD enzyme cocrystallized with the inhibitor, a more potent inhibitor with an IC50 of 35 nM was designed. Mitochondrial serine hydroxymethyltransferase (SHMT) inhibitors were also found. Three hundred thousand compounds were tested against the SHMT enzyme, producing 24 hits. Among those hits, a subclass was followed with in vivo screening and compounds were promoted to field trials. [1]

Plant activation

Plant activators are compounds that activate a plant's immune system in response to invasion by pathogens. They play a crucial role in crop survival. Unlike pesticides, plant activators are not pathogen specific and are not affected by drug resistance, making them ideal for use in agriculture. Wet-rice farmers across East Asia use plant activators as a sustainable means to enhance crop health. [6] [7]

The activation of plant responses is often associated with arrested growth and reductions in yield, for reasons that remain unclear. The molecular mechanisms governing plant activators are largely unknown. [6]

Screening can distinguish compounds that independently induce immune responses from those that do so exclusively in the presence of some pathogen. Independent activators can be toxic to cells. Others enhance resistance only in the presence of pathogens. In 2012, five activators that protected against Pseudomonas bacteria by priming immune response without directly activating defense genes. The compounds inhibit two enzymes that inactivate the defense hormone salicylic acid (SA glucosyltransferases or SAGTs), providing enhanced disease resistance. [6]

Related Research Articles

<span class="mw-page-title-main">Pesticide</span> Substance used to destroy pests

Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lampricide. The most common of these are herbicides, which account for approximately 50% of all pesticide use globally. Most pesticides are intended to serve as plant protection products, which in general, protect plants from weeds, fungi, or insects. As an example, the fungus Alternaria solani is used to combat the aquatic weed Salvinia.

<span class="mw-page-title-main">Insecticide</span> Pesticide used against insects

Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to be a major factor behind the increase in the 20th-century's agricultural productivity. Nearly all insecticides have the potential to significantly alter ecosystems; many are toxic to humans and/or animals; some become concentrated as they spread along the food chain.

Fungicides are pesticides used to kill parasitic fungi or their spores. They are most commonly chemical compounds, but may include biocontrols and fungistatics. Fungi can cause serious damage in agriculture, resulting in critical losses of yield, quality, and profit. Fungicides are used both in agriculture and to fight fungal infections in animals. Fungicides are also used to control oomycetes, which are not taxonomically/genetically fungi, although sharing similar methods of infecting plants. Fungicides can either be contact, translaminar or systemic. Contact fungicides are not taken up into the plant tissue and protect only the plant where the spray is deposited. Translaminar fungicides redistribute the fungicide from the upper, sprayed leaf surface to the lower, unsprayed surface. Systemic fungicides are taken up and redistributed through the xylem vessels. Few fungicides move to all parts of a plant. Some are locally systemic, and some move upward.

<span class="mw-page-title-main">Agrochemical</span> Any chemical used in agriculture

An agrochemical or agrichemical, a contraction of agricultural chemical, is a chemical product used in industrial agriculture. Agrichemical refers to biocides and synthetic fertilizers. It may also include hormones and other chemical growth agents.

A biopesticide is a biological substance or organism that damages, kills, or repels organisms seen as pests. Biological pest management intervention involves predatory, parasitic, or chemical relationships.

<span class="mw-page-title-main">Enzyme inhibitor</span> Molecule that blocks enzyme activity

An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a specific chemical reaction by binding the substrate to its active site, a specialized area on the enzyme that accelerates the most difficult step of the reaction.

Acibenzolar-<i>S</i>-methyl Chemical compound

Acibenzolar-S-methyl is the ISO common name for an organic compound that is used as a fungicide. Unusually, it is not directly toxic to fungi but works by inducing systemic acquired resistance, the natural defence system of plants.

<span class="mw-page-title-main">Dicarboximide fungicides</span>

Dicarboximidefungicides are a family of agricultural fungicides that include vinclozolin, iprodione, and procymidone. Dicarboximides are believed to inhibit triglyceride biosynthesis in sclerotia-forming fungi, including Botrytis cinerea. These fungicides turn into 3,5-dichloroaniline in soil rapidly. Repeated use of dicarboximides over several years reduce their effectiveness. Resistance has developed against all dicarboximides in many plant species, including vines, strawberries and protected crops, and are recommended to be used in conjunction with other fungicides.

<span class="mw-page-title-main">Azoxystrobin</span> Chemical compound

Azoxystrobin is a broad spectrum systemic fungicide widely used in agriculture to protect crops from fungal diseases. It was first marketed in 1996 using the brand name Amistar and by 1999 it had been registered in 48 countries on more than 50 crops. In the year 2000 it was announced that it had been granted UK Millennium product status.

<span class="mw-page-title-main">Sulfentrazone</span> Chemical compound

Sulfentrazone is the ISO common name for an organic compound used as a broad-spectrum herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase. It was first marketed in the US in 1997 by FMC Corporation with the brand name Authority.

<span class="mw-page-title-main">Saflufenacil</span> Chemical compound

Saflufenacil is the ISO common name for an organic compound of the pyrimidinedione chemical class used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase to control broadleaf weeds in crops including soybeans and corn.

<span class="mw-page-title-main">Mesotrione</span> Chemical compound used as an herbicide

Mesotrione is the ISO common name for an organic compound that is used as a selective herbicide, especially in maize. A synthetic inspired by the natural substance leptospermone, it inhibits the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) and is sold under brand names including Callisto and Tenacity. It was first marketed by Syngenta in 2001.

<span class="mw-page-title-main">Fluxapyroxad</span> Chemical compound

Fluxapyroxad is a broad-spectrum pyrazole-carboxamide fungicide used on a large variety of commercial crops. It stunts fungus growth by inhibiting the succinate dehydrogenase (SQR) enzyme. Application of fluxapyroxad helps prevent many wilts and other fungal infections from taking hold. As with other systemic pesticides that have a long chemical half-life, there are concerns about keeping fluxapyroxad out of the groundwater, especially when combined with pyraclostrobin. There is also concern that some fungi may develop resistance to fluxapyroxad.

<span class="mw-page-title-main">Oxycarboxin</span> Chemical compound

Oxycarboxin is an organic chemical used in agriculture to protect crops from fungal diseases. It was first marketed by Uniroyal in 1969 using their brand name Plantvax. The compound is an anilide which combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).

<span class="mw-page-title-main">Sedaxane</span> Chemical compound

Sedaxane is a broad spectrum fungicide used as a seed treatment in agriculture to protect crops from fungal diseases. It was first marketed by Syngenta in 2011 using their brand name Vibrance. The compound is an amide which combines a pyrazole acid with an aryl amine to give an inhibitor of succinate dehydrogenase.

<span class="mw-page-title-main">Carboxin</span> Chemical compound used to kill fungi

Carboxin is a narrow-spectrum fungicide used as a seed treatment in agriculture to protect crops from fungal diseases. It was first marketed by Uniroyal in 1969 using their brand name Vitavax. The compound is an anilide which combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).

<span class="mw-page-title-main">Fomesafen</span> PPOi herbicide

Fomesafen is the ISO common name for an organic compound used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase (PPO) which is necessary for chlorophyll synthesis. Soybeans naturally have a high tolerance to fomesafen, via metabolic disposal by glutathione S-transferase. As a result, soy is the most common crop treated with fomesafen, followed by other beans and a few other crop types. It is not safe for maize/corn or other Poaceae.

<span class="mw-page-title-main">Butafenacil</span> Chemical compound

Butafenacil is the ISO common name for an organic compound of the pyrimidinedione chemical class used as an herbicide. It acts by inhibiting the enzyme protoporphyrinogen oxidase to control broadleaf and some grass weeds in crops including cereals and canola.

<span class="mw-page-title-main">Boscalid</span> Chemical compound used to kill fungi

Boscalid is a broad spectrum fungicide used in agriculture to protect crops from fungal diseases. It was first marketed by BASF in 2002 using their brand name Endura. The compound is an biphenyl amide derived inhibitor of succinate dehydrogenase.

<span class="mw-page-title-main">Pydiflumetofen</span> Chemical compound used to kill fungi

Pydiflumetofen is a broad spectrum fungicide used in agriculture to protect crops from fungal diseases. It was first marketed by Syngenta in 2016 using their brand name Miravis. The compound is an amide which combines a pyrazole acid with a substituted phenethylamine to give an inhibitor of succinate dehydrogenase.

References

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Further reading