Natural products as sources of herbicides: current status and future trends

Although natural product-based discovery strategies have not been as successful for herbicides as for other pesticides or pharmaceuticals, there have been some notable successes. Phosphinothricin, the biosynthetic version of glufosinate, and bialaphos are phytotoxic microbial products that have yielded commercial herbicides. Cinmethylin, a herbicidal analogue of cineole, has been sold in Europe and Asia. The triketone herbicides are derivatives of the plant-produced phytotoxin leptospermone. These products represent only a small fraction of commercialized herbicides, but they have each introduced a novel molecular target site for herbicides. Analysis of the literature reveals that phytotoxic natural products act on a large number of unexploited herbicide target sites. The pesticide industry's natural product discovery efforts have so far concentrated on microbially derived phytotoxins, primarily from non-pathogenic soil microbes, involving the screening of large numbers of exotic isolates. Plant pathogens usually produce potent phytotoxins, yet they have received relatively little attention. Even less effort has been made to discover plant-derived phytotoxins. Bioassay-directed isolation has been the preferred method of discovery after a producing organism is selected. This laborious approach often leads to rediscovery of known compounds. Modern tandem separation/chemical characterization instrumentation can eliminate much of this problem by identification of compounds before they are bioassayed.     

光活化农药的研究与应用

结合作者近期的研究工作，对光活化农药的研究现状、作用机理、应用前景及其与新农药创 制的关系进行了综述。     

分子插件法及其在农药分子设计中的应用

新农药创制是一项艰难复杂的系统性工程,而新农药分子的设计是该工程的源头,也是最重要的一环。文章对传统的农药分子设计方法进行了简单的归纳总结,并在课题组多年新农药创制实践的基础上提出了一种新的设计方法——分子插件法,并以吡啶二芳酮和芳氧吡啶乙酮为例,介绍了分子插件的设计及其在新农药创制中的应用。该方法的优点在于可将功能基团模块化,便于快速衍生和筛选,从而大大缩短农药的创制周期,满足对速度竞争的要求。     

Herbicide research and development: challenges and opportunities

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.     

Fifty years of herbicide research: comparing the discovery of trifluralin and halauxifen‐methyl

Fifty years separate the commercialization of the herbicides trifluralin and halauxifen‐methyl. Despite the vast degree of technological change that occurred over that time frame, some aspects of their discovery stories are remarkably similar. For example, both herbicides were prepared very early in the iterative discovery process and both were developed from known lead compound structures by hypothesis‐driven research efforts without the use of in vitro assays or computer‐aided molecular design. However, there are aspects of the halauxifen‐methyl and trifluralin discovery stories that are substantially different. For example, the chemical technology required for the cost‐effective production of halauxifen‐methyl simply did not exist just two decades prior to its commercial launch. By contrast, the chemical technology required for the cost‐effective production of trifluralin was reported in the chemical literature more than two decades prior to its commercial launch. In addition, changes in regulatory environment since the early 1960s ensured that their respective discovery to commercial launch stories would also differ in substantial ways. Ultimately, the time and cost required to develop and register halauxifen‐methyl demanded a global initial business case while the lower registration hurdles that trifluralin cleared enabled a narrow initial business case mainly focused on the USA. © 2017 Society of Chemical Industry     

Perspective: present pesticide discovery paradigms promote the evolution of resistance – learn from nature and prioritize multi‐target site inhibitor design

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     

Physionomics and metabolomics-two key approaches in herbicidal mode of action discovery

BACKGROUND: For novel herbicides identified in greenhouse screens, efficient research is important to discover and chemically optimise new leads with new modes of action (MoAs). RESULTS: The metabolic and physiological response pattern to a herbicide can be viewed as the result of changes elicited in the molecular and biochemical process chain. These response patterns are diagnostic of a herbicide's MoA. At the starting point of MoA characterisation, an array of bioassays is used for comprehensive physiological profiling of herbicide effects. This physionomics approach enables discrimination between known, novel or multiple MoAs of a compound and provides a first clue to a new MoA. Metabolic profiling is performed with the use of treated Lemna paucicostata plants. After plant extraction and chromatography and mass spectrometry, changes in levels of approximately 200 identified and 300 unknown analytes are quantified. Check for known MoA assignment is performed by multivariate statistical data analyses. Distinct metabolite changes, which can direct to an affected enzymatic step, are visualised in a biochemical pathway view. Subsequent target identification includes metabolite feeding and molecular, biochemical and microscopic methods. CONCLUSION: The value of this cascade strategy is exemplified by new herbicides with MoAs in plastoquinone, auxin or very‐long‐chain fatty acid synthesis. Copyright © 2011 Society of Chemical Industry     

Natural products for pest control: an analysis of their role,value and future

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     

Molecular biology as virtual biology: Limitations of molecular biology in pesticide discovery

Much discussion has focused upon the concept that a ‘rational’, molecular biology-based strategy could revolutionize pesticide discovery. The personal viewpoint presented here is that such a concept is fundamentally flawed because it is based on false assumptions about the extent to which biological systems are genetically determined. It is argued that, even at the very low level of biological complexity represented by the structures and functions of individual proteins, the predictive capacity of molecular biology remains too weak to form a reliable basis for industrial research strategy, even when coupled with almost unlimited computing power. Expectations that molecular genetics could somehow speed up the discovery process and replace other methods of enquiry may thus be over-optimistic and an awareness of its limitations is essential to avoid the wasteful allocation of research resources. This article aims to highlight some of the limitations of which those who are not actively engaged in molecular biology may be unaware and which some of those who are so engaged may choose to ignore. Comments and counter-arguments are actively invited.     

Biological characterization of sulfoxaflor, a novel insecticide

BACKGROUND: The commercialization of new insecticides is important for ensuring that multiple effective product choices are available. In particular, new insecticides that exhibit high potency and lack insecticidal cross‐resistance are particularly useful in insecticide resistance management (IRM) programs. Sulfoxaflor possesses these characteristics and is the first compound under development from the novel sulfoxamine class of insecticides. RESULTS: In the laboratory, sulfoxaflor demonstrated high levels of insecticidal potency against a broad range of sap‐feeding insect species. The potency of sulfoxaflor was comparable with that of commercial products, including neonicotinoids, for the control of a wide range of aphids, whiteflies (Homoptera) and true bugs (Heteroptera). Sulfoxaflor performed equally well in the laboratory against both insecticide‐susceptible and insecticide‐resistant populations of sweetpotato whitefly, Bemisia tabaci Gennadius, and brown planthopper, Nilaparvata lugens (Stål), including populations resistant to the neonicotinoid insecticide imidacloprid. These laboratory efficacy trends were confirmed in field trials from multiple geographies and crops, and in populations of insects with histories of repeated exposure to insecticides. In particular, a sulfoxaflor use rate of 25 g ha^?1 against cotton aphid (Aphis gossypii Glover) outperformed acetamiprid (25 g ha^?1) and dicrotophos (560 g ha^?1). Sulfoxaflor (50 g ha^?1) provided a control of sweetpotato whitefly equivalent to that of acetamiprid (75 g ha^?1) and imidacloprid (50 g ha^?1) and better than that of thiamethoxam (50 g ha^?1). CONCLUSION: The novel chemistry of sulfoxaflor, its unique biological spectrum of activity and its lack of cross‐resistance highlight the potential of sulfoxaflor as an important new tool for the control of sap‐feeding insect pests. Copyright © 2010 Society of Chemical Industry     

新型杀菌化合物靶标识别及其靶向候选药剂设计概述

新型杀菌剂的创制在农业可持续发展和克服抗药性中具有重要作用。由于杀菌剂作用机制或靶标是新杀菌剂分子设计合成和创制开发的重要基础,因此作用机制或靶标研究的滞后会阻碍新先导化合物的发现或新品种的创制。鉴于此,本文对目前杀菌剂作用靶标的识别及靶向杀菌剂的分子设计进行了概述。首先阐述了基于转录组学、蛋白质组学的研究和药物亲和层析技术在靶标识别中的应用;其次概述了多学科交叉的方法在分子靶标验证中的应用;最后以strobilurin A为先导的Qo位点抑制剂、以肉桂酸为先导的卵菌抑制剂、以萎锈灵为先导的琥珀酸脱氢酶和植物免疫激活剂等不同类型的靶向杀菌剂为例进行了举例说明。     

A perspective on the role of quantitative structure-activity and structure-property relationships in herbicide discovery

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     

Herbicides – a two‐edged sword*

Summary Weeds cause yield losses and reductions in crop quality. Prior to the introduction of selective herbicides, the drudgery of manual weeding forced farmers to adhere to a suit of weed management tactics by carefully combining crop rotation, appropriate tillage and fallow systems. The introduction of selective herbicides in the late 1940s and the constant flow of new herbicides in the succeeding decades provided farmers with a new tool, ‘the chemical hoe’, putting them in a position to consider weed control more independently of the crop production system than hitherto. The reliance on herbicides for weed control, however, resulted in shifts in the weed flora and the selection of herbicide‐resistant biotypes. In the 1980s, the public concern about side‐effects of herbicides on the environment and human health resulted in increasingly strict registration requirements and, in some countries, political initiatives to reduce the use of pesticides were launched. Today, the number of new herbicides being introduced has decreased significantly and integrated weed management has become the guiding concept. Farmers also have the option of growing herbicide‐resistant crops where the biology of the crop has been adapted to tolerate herbicides considered safe to humans and environmentally benign. This paper discusses some of the recent developments in herbicide discovery, technology and fate, and sketches important future developments.     

The discovery of pyridalyl: a novel insecticidal agent for controlling lepidopterous pests

Synthesis of analogues of two compounds with known insecticidal activity, both of which contain a 3,3-dichloro-2-propenyloxy group, produced 2-(trifluoromethyl)-4-phenoxyphenyl 3,3-dichloro-2-propenyl ether, which had weak activity against lepidopterous larvae. Structural modifications around this lead compound led to the development of pyridalyl [Pleo, S-1812; 2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5-(trifluoromethyl)-2-pyridyloxy]propyl ether], which belongs to a new class of insecticides. Pyridalyl gives very good control of various lepidopterous and thysanopterous pests on cotton and vegetables, without phytotoxicity. It controls populations of Heliothis virescens F and Plutella xylostella (L) which are resistant to various currently used insecticides. It also produces unique insecticidal symptoms, so it may have a different mode of action from other existing insecticides. Pyridalyl is also less harmful than existing insecticides to various beneficial arthropods, so it should provide an important tool in IPM and insecticidal management programmes for the control of lepidopterous and thysanopterous pests. The first market introduction is expected in Japan and some Asian countries in the years between 2004 and 2005.     

Deep‐sequencing revealed Citrus bark cracking viroid (CBCVd) as a highly aggressive pathogen on hop

Newly emerging or re‐emerging diseases are a constant and significant threat to agricultural production, so prompt and accurate identification of the causative agents is required for rapid and appropriate disease management. Classical methods of pathogen detection can be successfully supplemented by next‐generation sequencing (NGS), whereby sequence analysis can help in the discovery of new or emerging diseases. In 2007, hop growers in Slovenia reported the appearance of severely stunted hop plants, a phenomenon that spread rapidly within hop gardens and among farms. Classical diagnostic methods were unable to detect a new pathogen; therefore, single step high‐throughput parallel sequencing of total RNA and small RNAs from plants with and without symptoms was employed to identify a novel pathogen. The sequences were assembled de novo and also mapped to reference genomes, resulting in identification of a novel sequence of Citrus bark cracking viroid (CBCVd) in the stunted hop plants. Furthermore, the presence of this novel pathogen on hop was confirmed by RT‐PCR analysis of 59 plants with symptoms from 15 hop gardens, representing the main outbreak locations identified by systematic disease monitoring, and small RNA Illumina sequencing of the bulked RNA sample. The high infectivity of the newly identified CBCVd was also confirmed by biolistic inoculation of two hop cultivars, which developed aggressive symptoms in controlled conditions. This study shows the feasibility of deep sequencing for the identification of causative agents of new diseases in hop and other plants.     

Insecticide discovery: An evaluation and analysis

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.