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1.
For many years, the emphasis of industry discovery programs has been on finding new target sites of pesticides and finding pesticides that inhibit single targets. There had been an emphasis on genomics in finding single targets for potential pesticides. There is also the claim that registration of single target inhibiting pesticides is simpler if the mode of action is known. Conversely, if one looks at the evolution of resistance from an epidemiological perspective to ascertain which pesticides have been the most recalcitrant to evolutionary forces, it is those that have multiple target sites of action. Non‐target‐site resistances can evolve to multi‐target‐site inhibitors, but these resistances can often be overcome by structural modification of the pesticide. Industry has looked at pest‐toxic natural products as pesticide leads, but seems to have abandoned those where they can find no single target of action. Perhaps nature has been intelligent and evolved many natural products that are synergistic multi‐target‐site inhibitors, and that is why natural compounds have been active for millennia? We should be learning from nature while combining new chemistry technologies with vast accrued databases and computer aided design allowing fragment‐based discovery and scaffold hopping to produce multi‐target site inhibitors instead of single target pesticides. © 2019 Society of Chemical Industry  相似文献   

2.
The relentless need for the discovery and development of new agrochemicals continues as a result of driving forces such as loss of existing products through the development of resistance, the necessity for products with more favorable environmental and toxicological profiles, shifting pest spectra, and the changing agricultural needs and practices of the farming community. These new challenges underscore the demand for novel, high‐quality starting points to accelerate the discovery of new agrochemicals that address market challenges. This article discusses the efforts to identify the optimum ranges of physicochemical properties of agrochemicals through analysis of modern commercial products. Specifically, we reviewed literature studies examining physicochemical property effects and analyzed the properties typical of successful fungicides, herbicides, and insecticides (chewing and sap‐feeding pests). From the analysis, a new set of physicochemical property guidelines for each discipline, as well as building block class, are proposed. These new guidelines should significantly aid in the discovery of next‐generation agrochemicals. © 2018 Society of Chemical Industry  相似文献   

3.
A herbicide with a new mode of action has not been commercialized for more than 30 years. A recent paper describes a novel genomic approach to herbicide and herbicide mode of action discovery. Analysis of a microbial gene cluster revealed that it encodes genes for both the biosynthetic pathway for production of the sesquiterpene aspterric acid and an aspterric acid‐resistant form of dihydroxy acid dehydratase (DHAD), its target enzyme. Aspterric acid is weak compared with commercial synthetic herbicides, and whether DHAD is a good herbicide target is unclear from this study. Nevertheless, this genomic approach provides a novel strategy for the discovery of herbicides with new modes action. © 2018 Society of Chemical Industry  相似文献   

4.
The past 30 years have witnessed a period of significant expansion in the use of halogenated compounds in the field of agrochemical research and development. The introduction of halogens into active ingredients has become an important concept in the quest for a modern agrochemical with optimal efficacy, environmental safety, user friendliness and economic viability. Outstanding progress has been made, especially in synthetic methods for particular halogen‐substituted key intermediates that were previously prohibitively expensive. Interestingly, there has been a rise in the number of commercial products containing ‘mixed’ halogens, e.g. one or more fluorine, chlorine, bromine or iodine atoms in addition to one or more further halogen atoms. Extrapolation of the current trend indicates that a definite growth is to be expected in fluorine‐substituted agrochemicals throughout the twenty‐first century. A number of these recently developed agrochemical candidates containing halogen substituents represent novel classes of chemical compounds with new modes of action. However, the complex structure–activity relationships associated with biologically active molecules mean that the introduction of halogens can lead to either an increase or a decrease in the efficacy of a compound, depending on its changed mode of action, physicochemical properties, target interaction or metabolic susceptibility and transformation. In spite of modern design concepts, it is still difficult to predict the sites in a molecule at which halogen substitution will result in optimal desired effects. This review describes comprehensively the successful utilisation of halogens and their unique role in the design of modern agrochemicals, exemplified by various commercial products from Bayer CropScience coming from different agrochemical areas. Copyright © 2009 Society of Chemical Industry  相似文献   

5.
There is an on-going need for the discovery and development of new insecticides due to the loss of existing products through the development of resistance, the desire for products with more favorable environmental and toxicological profiles, shifting pest spectrums, and changing agricultural practices. Since 1960, the number of research-based companies in the US and Europe involved in the discovery of new insecticidal chemistries has been declining. In part this is a reflection of the increasing costs of the discovery and development of new pesticides. Likewise, the number of compounds that need to be screened for every product developed has, until recently, been climbing. In the past two decades the agrochemical industry has been able to develop a range of new products that have more favorable mammalian vs. insect selectivity. This review provides an analysis of the time required for the discovery, or more correctly the building process, for a wide range of insecticides developed during the last 60 years. An examination of the data around the time requirements for the discovery of products based on external patents, prior internal products, or entirely new chemistry provides some unexpected observations. In light of the increasing costs of discovery and development, coupled with fewer companies willing or able to make the investment, insecticide resistance management takes on greater importance as a means to preserve existing and new insecticides.  相似文献   

6.
Natural products (NPs) have long been used as pesticides and have broadly served as a source of inspiration for a great many commercial synthetic organic fungicides, herbicides and insecticides that are in the market today. In light of the continuing need for new tools to address an ever‐changing array of fungal, weed and insect pests, NPs continue to be a source of models and templates for the development of new pest control agents. Interestingly, an examination of the literature suggests that NP models exist for many of the pest control agents that were discovered by other means, suggesting that, had circumstances been different, these NPs could have served as inspiration for the discovery of a great many more of today's pest control agents. Here, an attempt is made to answer questions regarding the existence of an NP model for existing classes of pesticides and what is needed for the discovery of new NPs and NP models for pest control agents. © 2014 Society of Chemical Industry  相似文献   

7.
A number of well known polychlorinated chemicals are toxicologically and environmentally unsafe. Because of their persistence they are in the focus of public discussions against chlorine chemistry. However, chlorinated organic chemicals in the molecular weight range between 200 and 600 constitute an important and indispensable segment in the arsenal of existing biologically active chemicals used as pharmaceuticals or crop‐protection agents. Over the course of time it has been found empirically that the introduction of a chlorine atom into one or more specific positions of a biologically active molecule may substantially improve the intrinsic biological activity. In some cases the presence of a chlorine atom is crucial for significant activity in compounds derived both from nature and chemical synthesis. But in other cases chlorination diminishes or abolishes biological activity, as shown for chlordane homologues. Thus a chlorine atom, like any other substituent, is a modulator of activity. Almost all non‐reactive chlorinated chemicals and chlorine‐free chemicals are devoid of any biological activity at the highest concentration typically used in primary screening tests for discovery of useful biological properties. The influence of a substituent such as chlorine on the biological activity of a potential drug or crop protection agent still has to be established empirically in biological experiments designed to detect desired activity or toxicological properties. Sometimes chlorine does prove to be the optimum for improvement of activity. Long‐term rigorous investigations of several hundred chlorinated compounds, registered by the authorities as pharmaceutical drugs or crop‐protection agents, show that the generalisation ‘all chlorinated chemicals are dangerous’, deduced from the negative toxicological properties of a hundred chlorinated and reactive compounds of low molecular weight that are relevant in terms of safe working conditions in the chemical industry and for ecological safety, is not justified. Chlorinated compounds are not necessarily toxic or dangerous. Highly reactive chemicals or polychlorinated compounds cannot be compared with regard to toxicological properties with unreactive compounds having a low degree of chlorination. The chlorine atom, as one of many possible substituents used in synthetic organic chemistry, will remain in the future one of the important tools for probing structure–activity relationships in life science research and as a molecular component in commercialised compounds, in order to provide safer, more selective and more environmentally compatible products with higher activity for medicine and agriculture. © 1999 WILEY‐VCH Verlag GmbH  相似文献   

8.
The work undertaken to isolate the novel, herbicidally active compound, carbocyclic coformycin, to obtain sufficient quantities of the compound for full biological evaluation, and to identify its biochemical mode of action is summarised. Although the compound was extremely active against some weed species, limitations in its spectrum of activity precluded further development. Carbocyclic coformycin exerts its biological action through a novel mode of action by the inhibition of the enzyme adenosine 5′-phosphate deaminase (EC 3.5.4.6) following phosphorylation in planta. From this work, the potential benefits of natural product research in the discovery of new agrochemicals are highlighted along with some of the possible pitfalls. © 1998 SCI.  相似文献   

9.
Weeds continue to evolve resistance to all the known modes of herbicidal action, but no herbicide with a new target site has been commercialized in nearly 20 years. The so-called 'new chemistries' are simply molecules belonging to new chemical classes that have the same mechanisms of action as older herbicides (e.g. the protoporphyrinogen-oxidase-inhibiting pyrimidinedione saflufenacil or the very-long-chain fatty acid elongase targeting sulfonylisoxazoline herbicide pyroxasulfone). Therefore, the number of tools to manage weeds, and in particular those that can control herbicide-resistant weeds, is diminishing rapidly. There is an imminent need for truly innovative classes of herbicides that explore chemical spaces and interact with target sites not previously exploited by older active ingredients. This review proposes a rationale for a natural-products-centered approach to herbicide discovery that capitalizes on the structural diversity and ingenuity afforded by these biologically active compounds. The natural process of extended-throughput screening (high number of compounds tested on many potential target sites over long periods of times) that has shaped the evolution of natural products tends to generate molecules tailored to interact with specific target sites. As this review shows, there is generally little overlap between the mode of action of natural and synthetic phytotoxins, and more emphasis should be placed on applying methods that have proved beneficial to the pharmaceutical industry to solve problems in the agrochemical industry.  相似文献   

10.
The pyridine ring, substituted by a trifluoromethyl substituent has been successfully incorporated into molecules with useful biological properties. During the period 1990 to September 2017, 14 crop protection products bearing a trifluoromethyl pyridine have been commercialized or proposed for an ISO common name, covering fungicides, herbicides, insecticides and nematicides. Chemical processes have been developed to provide trifluoromethyl pyridine intermediates, from non‐fluorinated pyridine starting materials, at scale and with affordable costs of goods. These attractive starting materials were readily adopted by research chemists, and elaborated through simple chemical modifications into new active ingredients. In a second approach, substituted trifluoromethyl pyridine rings have been constructed from acyclic, trifluoromethyl starting materials, which again has served to identify new active ingredients. Molecular matched pair analysis reveals subtle, yet important differences in physicochemical and agronomic properties of trifluoromethyl pyridines compared with the phenyl analogues. This review focuses on the past 27 years, seeking to identify reasons behind the success of such research programmes, and inspire the search for new crop protection chemicals containing the trifluoromethyl pyridine ring. © 2017 Society of Chemical Industry  相似文献   

11.
BACKGROUND: For the last 15 years the agrochemical industry has focused on using genetic modification to put genes that confer resistance to existing commercial herbicides into crop plants rather than on discovering new herbicides with novel modes of action. The widespread appearance of weeds resistant to those herbicides is now causing the industry to revive their herbicide discovery programs. RESULTS: Elucidation of quantitative structure–activity relationships (QSARs) played a major role in the discovery and development of existing commercial herbicides, but the advent of genetically modified crops has caused published work (at least) in the area to drift from the industrial arena into academic studies. The focus has also turned inward, to refining models for established herbicide targets instead of elucidating new ones. CONCLUSION: This perspective highlights the importance of QSARs and quantitative structure–property relationships (QSPRs) to herbicide discovery in an historical context and provides some guidance as to how they might profitably be applied going forward. Copyright © 2011 Society of Chemical Industry  相似文献   

12.

BACKGROUND

Fenpicoxamid is a new fungicide for control of Zymoseptoria tritici, and is a derivative of the natural product UK‐2A. Its mode of action and target site interactions have been investigated.

RESULTS

UK‐2A strongly inhibited cytochrome c reductase, whereas fenpicoxamid was much less active, consistent with UK‐2A being the fungicidally active species generated from fenpicoxamid by metabolism. Both compounds caused rapid loss of mitochondrial membrane potential in Z. tritici spores. In Saccharomyces cerevisiae, amino acid substitutions N31K, G37C and L198F at the Qi quinone binding site of cytochrome b reduced sensitivity to fenpicoxamid, UK‐2A and antimycin A. Activity of fenpicoxamid was not reduced by the G143A exchange responsible for strobilurin resistance. A docking pose for UK‐2A at the Qi site overlaid that of antimycin A. Activity towards Botrytis cinerea was potentiated by salicylhydroxamic acid, showing an ability of alternative respiration to mitigate activity. Fungitoxicity assays against Z. tritici field isolates showed no cross‐resistance to strobilurin, azole or benzimidazole fungicides.

CONCLUSION

Fenpicoxamid is a Qi inhibitor fungicide that provides a new mode of action for Z. tritici control. Mutational and modeling studies suggest that the active species UK‐2A binds at the Qi site in a similar, but not identical, fashion to antimycin A. © 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.  相似文献   

13.
Auxinic herbicides mimic the effects of natural auxin. However, in spite of decades of research, the site(s) of action of auxinic herbicides has remained unknown and many physiological aspects of their function are unclear. Recent advances in auxin biology provide new opportunities for research into the mode of action of auxinic herbicides. Of considerable interest is the discovery of auxin receptors (TIR1 and possibly ABP1) that may lead to the discovery of auxinic herbicide site(s) of action. Knowledge of auxin-conjugating enzymes and auxin signal transduction components may shed new light on herbicide activity, selectivity in dicots, and mechanisms leading to phytotoxicity in sensitive plants. Analysis of genes induced in response to auxin may provide a novel approach for detection of off-target herbicide injury in crops. For example, the auxin-responsive gene GH3 is highly and specifically induced in response to auxinic herbicides in soybean, and may offer a novel method for diagnosing auxinic herbicide injury. Advances in our understanding of auxin biology will provide many new avenues and opportunities for auxinic herbicide research in the future.  相似文献   

14.
Herbicides with new modes of action are badly needed to manage the evolution of resistance of weeds to existing herbicides. Yet no major new mode of action has been introduced to the market place for about 20 years. There are probably several reasons for this. New potential products may have remained dormant owing to concerns that glyphosate-resistant (GR) crops have reduced the market for a new herbicide. The capture of a large fraction of the herbicide market by glyphosate with GR crops led to significantly diminished herbicide discovery efforts. Some of the reduced herbicide discovery research was also due to company consolidations and the availability of more generic herbicides. Another problem might be that the best herbicide molecular target sites may have already been discovered. However, target sites that are not utilized, for which there are inhibitors that are highly effective at killing plants, suggests that this is not true. Results of modern methods of target site discovery (e.g. gene knockout methods) are mostly not public, but there is no evidence of good herbicides with new target sites coming from these approaches. In summary, there are several reasons for a long dry period for new herbicide target sites; however, the relative magnitude of each is unclear. The economic stimulus to the herbicide industry caused by the evolution of herbicide-resistant weeds, especially GR weeds, may result in one or more new modes of action becoming available in the not too distant future.  相似文献   

15.
Herbicide research and development: challenges and opportunities   总被引：2，自引：0，他引：2  
The high adoption of chemical weed control and the broad range of solutions already available to manage most weed problems are significant hurdles to the development and launch of new herbicides. Business potentials are influenced by the high technical and biological standards provided by existing herbicides, as well as the intense competition in the marketplace. Other factors adding complexity are agronomic, structural and technological changes, including the introduction of herbicide‐tolerant crops, and the high costs of development for new active ingredients, mainly due to increasing regulatory requirements. In the light of increasing weed resistance to widely used herbicides, securing diversity in agronomy as well as weed management is a key to efficient crop production in future. In order to support this objective, new herbicides, preferably with new modes‐of‐action, will need to be discovered and developed.  相似文献   

16.
Natural products that have been used commercially as crop protection agents   总被引：4，自引：0，他引：4  
Many compounds derived from living organisms have found a use in crop protection. These compounds have formed the basis of chemical synthesis programmes to derive new chemical products; they have been used to identify new biochemical modes of action that can be exploited by industry-led discovery programmes; some have been used as starting materials for semi-synthetic derivatives; and many have been used or continue to be used directly as crop protection agents. This review examines only those compounds derived from living organisms that are currently used as pesticides. Plant growth regulators and semiochemicals have been excluded from the review, as have living organisms that exert their effects by the production of biologically active secondary metabolites.  相似文献   

17.
With the anticipated population growth in the coming decades, the changing regulatory environment, and the continued emergence of resistance to commercial pesticides, there is a constant need to discover new lead chemistries with novel modes of action. We have established a portfolio of approaches to accelerate lead generation. One of these approaches capitalizes on the rich bioactivity of natural products (NPs), highlighted by the numerous examples of NP‐based crop protection compounds. Within Corteva Agriscience and the affiliated preceding companies, NPs have been a fruitful approach, for nearly three decades, to identifying and bringing to the market crop protection products inspired by or originating from NPs, . Included in these NP‐based crop protection products are the spinosyns family of insecticides, and those from more recent areas of NP‐based fungicidal chemistry, as highlighted in this perspective. © 2019 Society of Chemical Industry  相似文献   

18.
There are inaccuracies in the chemical families of the WSSA and HRAC herbicide classification systems which could limit their practical use in herbicide‐based weed management strategies. In essence, these inaccuracies could be divided into four parts: (i) the nomenclature of many of the chemical families is not correct, (ii) distinct active ingredients are grouped in same chemical families, (iii) many chemical families have been repeated in at least two modes of action/herbicide groups, and (iv) many active ingredients have not been assigned to chemical family, herbicide group or mode of action. The aim of this study was to revise the current classifications and to propose corrections for the current ones. Detailed investigations on chemical structure of the active ingredients of the registered herbicides showed that some moieties have the same mechanisms of action. According to this study, these moieties have been assigned to the names of chemical families and active ingredients are then classified within the chemical families accordingly. This study has 119 chemical families, compared with 145 in the WSSA system and 58 in the HRAC system. A major priority of this study is the number of active ingredients covered; we included 410 active ingredients with known mechanisms of action and herbicide groups, more than 100 active ingredients more than the current classification systems. Overall, this study provides better opportunities for the management of resistance to herbicides through the application of improved pure and applied knowledge.  相似文献   

19.
BACKGROUND: The spotted wing Drosophila, Drosophila suzukii (Matsumura, 1931) (Diptera: Drosophilidae), is an invasive pest of small‐fruit crops. Unlike most other Drosophila, this insect is able to oviposit into and damage ripe and ripening fruit, making it unmarketable. Because this is a new pest in the United States, it is necessary to identify registered insecticides to manage this insect effectively in conventional and organic production systems. RESULTS: The present laboratory bioassays and field trials identified a number of insecticides representing various modes of action that are effective in controlling D. suzukii. Products that performed well in the laboratory bioassay also performed well in the field, indicating that screening of new chemistries in the laboratory is a worthy exercise. Field application of pyrethoids, organophosphates or spinosyns provided 5–14 days of residual control of D. suzukii. The efficacy of the neonicotinoids as adulticides was not satisfactory compared with the other contact‐mode‐of‐action chemistries. Based on the zero tolerance by the small‐fruit industry and the individual effects mentioned above, neonicotinoids are not currently recommended for D. suzukii management. CONCLUSIONS: There are effective insecticides registered for controlling D. suzukii infestations in susceptible small‐fruit crops. Copyright © 2011 Society of Chemical Industry  相似文献   

20.
Three 2,4‐diaminopyrimidines were tested against several insect species. They were active against lepidopteran pests with LC50 values <3 mg liter−1 for most species tested. They were also active against two‐spotted spider mite, Tetranychus urticae, (LC50 10–40 mg liter−1). Folinate, but not hypoxanthine or thymidine was found to be an effective rescue agent, requiring a concentration of 100 mg liter−1 diet to rescue half of the intoxicated larvae. The results confirm dihydrofolate reductase to be the site of action for these insecticides and are consistent with the mode of action of folinate rescue in mammals. © 2000 Society of Chemical Industry  相似文献   

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