Vectorizing agrochemicals: enhancing bioavailability via carrier‐mediated transport

Systemicity of agrochemicals is an advantageous property for controlling phloem sucking insects, as well as pathogens and pests not accessible to contact products. After the penetration of the cuticle, the plasma membrane constitutes the main barrier to the entry of an agrochemical into the sap flow. The current strategy for developing systemic agrochemicals is to optimize the physicochemical properties of the molecules so that they can cross the plasma membrane by simple diffusion or ion trapping mechanisms. The main problem with current systemic compounds is that they move everywhere within the plant, and this non‐controlled mobility results in the contamination of the plant parts consumed by vertebrates and pollinators. To achieve the site‐targeted distribution of agrochemicals, a carrier‐mediated propesticide strategy is proposed in this review. After conjugating a non‐systemic agrochemical with a nutrient (α‐amino acids or sugars), the resulting conjugate may be actively transported across the plasma membrane by nutrient‐specific carriers. By applying this strategy, non‐systemic active ingredients are expected to be delivered into the target organs of young plants, thus avoiding or minimizing subsequent undesirable redistribution. The development of this innovative strategy presents many challenges, but opens up a wide range of exciting possibilities. © 2018 Society of Chemical Industry     

Status and outlook for acaricide and insecticide discovery

To guarantee sustainability and progress, the agrochemical industry is faced with several major challenges. Currently, loss of active ingredients due to consumer perception, changing grower needs and ever‐changing regulatory requirements is far higher than the number being introduced into the market. Therefore, there is a need to develop new products that can provide improved efficacy, selectivity and favorable environmental profiles. Strategies to achieve these goals are the search for acaricides and insecticides with new modes of action, or the discovery of novel molecules with activity on the most attractive target sites having resistance breaking properties against pest species. In this context, the introduction of halogen atoms or asymmetric centers into an active ingredient remains an important tool to modulate their properties, but so too is the pro‐pesticide concept. This review gives an overview of agrochemicals launched over the past 8 years, reflects new insights into known mechanisms of action, and describes the status and outlook for acaricide and insecticide discovery.     

Natural products as a source of agrochemicals and leads for chemical synthesis

The use of natural products as a source of new agrochemicals and the procedures that can be undertaken to discover such compounds are reviewed using examples from both the literature and our own experiences. The commercial successes obtained to date show that natural products are a powerful source of new agrochemicals. The results from a survey of the views of the agrochemical industry of natural product work indicated a high level of interest, with 16 of the 19 companies that replied being involved in natural product work either through in-house or external programmes of work. Possible approaches to the key challenges of atural product work, for example choice of sources and screens, avoiding known metabolites and obtaining sufficient compound for biological evaluation, are discussed.     

The unique role of halogen substituents in the design of modern agrochemicals

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     

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。     

Agrochemical industry development,trends in R&D and the impact of regulation

Over the last 20 years the share of the crop protection market attributable to the leading markets (North America, EU‐15 and Japan) that are the major focus of new active ingredient research and development (R&D) has declined. Greater growth has been recorded in developing markets, questioning the focus of current R&D strategy. R&D budgets within the major companies have seen a shift toward genetically modified (GM) trait development away from agrochemicals, such that the rate of new active ingredients entering development and subsequently being introduced has declined. As a result, the industry has become more reliant on older, off‐patent chemistry, although the availability of older products has been affected by re‐registration requirements, particularly in the EU. Current criteria often preclude the registration of broad‐spectrum agrochemicals, resulting in many new active ingredients being single site active, which is perceived to increase the potential for resistance development, particularly for herbicides, although this is not always the case. © 2019 The Author. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.     

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.     

Selecting the right compounds for screening: does Lipinski's Rule of 5 for pharmaceuticals apply to agrochemicals?

Large numbers of compounds are now available through combinatorial chemistry and from compound vendors to screen for lead‐level agrochemical activity. The likelihood that compounds with whole‐organism activity will be discovered can be increased if compounds with physicochemical parameters consistent with transport to the target site are selected for screening. Certain ranges of simple parameters (molecular mass, log P, hydrogen‐bond donors and acceptors, rotatable bonds) have been correlated with oral bioavailability of drugs. The distribution of these parameters for commercial insecticides and post‐emergence herbicides was examined and ranges consistent with whole‐organism activity are proposed for the two classes of agrochemical. The most significant difference identified between drugs and these two classes of agrochemicals was the lower numbers of hydrogen‐bond donors allowed in the latter cases. The frequency with which certain functional groups occur in drugs and agrochemicals was also compared. © 2001 Society of Chemical Industry     

The importance of trifluoromethyl pyridines in crop protection

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     

Progress of modern agricultural chemistry and future prospects

Agriculture is facing an enormous challenge: it must ensure that enough high‐quality food is available to meet the needs of a continually growing population. Current and future agronomic production of food, feed, fuel and fibre requires innovative solutions for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands, renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chemistry has to support farmers to manage these tasks. Today, the so‐called ‘side effects’ of agrochemicals regarding yield and quality are gaining more importance. Agrochemical companies with a strong research and development focus will have the opportunity to shape the future of agriculture by delivering innovative integrated solutions. This review gives a comprehensive overview of the innovative products launched over the past 10 years and describes the progress of modern agricultural chemistry and its future prospects. © 2015 Society of Chemical Industry     

Propesticides and their use as agrochemicals

The synthesis of propesticides is an important concept in design of modern agrochemicals with optimal efficacy, environmental safety, user friendliness and economic variability. Based on increasing knowledge of the biochemistry and genetics of major pest insects, weeds and agricultural pathogens, the search for selectivity has become an ever more important part of pesticide development and can be achieved by appropriate structural modifications of the active ingredient. Propesticides affect the absorption, distribution, metabolism and excretion parameters, which can lead to biological superiority of these modified active ingredients over their non‐derivatised analogues. Various selected commercial propesticides testify to the successful utilisation of this concept in the design of agrochemicals. This review describes comprehensively the successful utilisation of propesticides and their role in syntheses of modern agrochemicals, exemplified by selected commercial products coming from different agrochemical areas. © 2015 Society of Chemical Industry     

Synthesis and application of trifluoromethylpyridines as a key structural motif in active agrochemical and pharmaceutical ingredients

Herein, we provide a brief overview of the synthesis and applications of trifluoromethylpyridine (TFMP) and its derivatives in the agrochemical and pharmaceutical industries. Currently, the major use of TFMP derivatives is in the protection of crops from pests. Fluazifop-butyl was the first TFMP derivative introduced to the agrochemical market, and since then, more than 20 new TFMP-containing agrochemicals have acquired ISO common names. Several TFMP derivatives are also used in the pharmaceutical and veterinary industries; five pharmaceutical and two veterinary products containing the TFMP moiety have been granted market approval, and many candidates are currently undergoing clinical trials. The biological activities of TFMP derivatives are thought to be due to the combination of the unique physicochemical properties of the fluorine atom and the unique characteristics of the pyridine moiety. It is expected that many novel applications of TFMP will be discovered in the future.     

Carbocyclic coformycin: a case study of the opportunities and pitfalls in the industrial search for new agrochemicals from nature

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.     

合成生物学助力链霉菌天然产物农药创制与产业化

病虫草害防控是国家总体安全建设的重要组成部分。微生物天然产物农药是病虫草害绿色防控体系的重要成员, 在保障国家粮食安全、生态安全和农产品质量安全, 筑牢国家生物安全屏障中具有重要作用。链霉菌以能够产生丰富的次级代谢产物而著称, 是天然产物农药的资源宝库, 也是重要的天然产物药物的工业生产菌。然而, 随着病虫草害抗药性增强, 新发、突发病虫草害增多等问题不断涌现, 以及天然产物研究面临新骨架、高活性化合物发现难度增大, 工业菌株产量提升困难等瓶颈, 链霉菌天然产物农药创制与应用正面临巨大挑战。合成生物学作为一门交叉学科, 突破了生物学研究的传统模式, 为天然产物药物研发提供了新的思路与策略。本文综述了近年来合成生物学在链霉菌研究领域的技术革新, 以及合成生物学在推动链霉菌天然产物资源发现、天然产物高效生物制造等方面的研究进展, 并对合成生物学助力链霉菌天然产物农药的创制与产业化进行了展望。     

Safe nanotechnologies for increasing the effectiveness of environmentally friendly natural agrochemicals

Natural compounds and living organisms continue to play a limited role in crop protection, and few of them have reached the market, despite their attractiveness and the efforts made in research. Very often these products have negative characteristics compared to synthetic compounds, e.g., higher costs of production, lower effectiveness, lack of persistence, and inability to reach and penetrate the target plant. Conversely, nanotechnologies are having an enormous impact on all human activities, including agriculture, even if the production of some nanomaterials is not environmentally friendly or could have adverse effects on agriculture and the environment. Thus, certain nanomaterials could facilitate the development of formulated natural pesticides, making them more effective and more environmentally friendly. Nanoformulations can improve efficacy, reduce effective doses, and increase shelf‐life and persistence. Such controlled‐release products can improve delivery to the target pest. This review considers certain available nanomaterials and nanotechnologies for use in agriculture, discussing their properties and the feasibility of their use in sustainable crop protection, in particular, in improving the effectiveness of natural bio‐based agrochemicals. © 2019 Society of Chemical Industry     

海藻糖酶结构及其抑制剂的农用活性研究进展

海藻糖是一种非还原性二糖,在昆虫、真菌等有害生物体内参与能量代谢、逆境恢复、几丁质合成等过程。海藻糖酶 (EC 3.2.1.28) 由于其对海藻糖代谢及其含量调控具有重要作用,且在农业有害生物和哺乳动物体内存在功能差异,已成为开发新型农用化学品的安全型候选靶标。本文对海藻糖酶的晶体结构、海藻糖酶与底物/抑制剂的互作机制研究进展进行了综述;同时对具有农用活性的海藻糖酶抑制剂,如井冈霉素、天然产物salbostatin和trehazolin及其合成类似物、脱氧野尻霉素及其合成类似物、天然生物碱及其合成类似物以及胡椒碱及其类似物的研究进展进行了概述,并重点论述了以胡椒碱为骨架的化合物在农业有害生物防治上的应用。本综述可为靶向海藻糖酶结构进行新型胡椒碱类结构的农用化学品设计与发现提供参考。     

Manufacture of optically active materials: An agrochemicals perspective

Against a background of the growing importance of single enantiomer agrochemicals, practical technologies for their production are reviewed. Methods range from extraction of natural products through to asymmetric synthesis and encompass physical, chemical and biological techniques.     

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     

Innovative approaches to exploit host plant metabolites in malaria control

Malaria is the most important vector‐borne disease in sub‐Saharan Africa (SSA). Recent reports indicate that the levels of malaria‐associated mortality and morbidity in SSA have remained the same. Malaria vectors have modified their feeding behavior in response to the selective pressure from indoor‐based interventions, and there is emerging malaria parasite resistance to artemisinin‐based combination therapies. These challenges have created an altered malaria landscape, especially within local scales in some malaria‐endemic countries in SSA. To address these challenges, complementary new strategies are urgently required for malaria control. This paper argues that to develop the next generation of vector and chemotherapeutic tools for malaria control, especially based on natural products with novel modes of action, a better understanding of mosquito bioecology and, more importantly, plant sugar feeding is needed. © 2019 Society of Chemical Industry     

近红外光谱法快速测定农药中溴氰菊酯含量

用近红外(NIR)光谱技术结合偏最小二乘法(PLS)进行了敌杀死乳油中有效成分溴氰菊酯含量的快速检测。通过比较敌杀死乳油与常用溶剂的近红外光谱,确定了乳油中使用的溶剂为二甲苯。在敌杀死乳油中加入二甲苯或溴氰菊酯原药来配制不同浓度的校正集,采用PLS建立了有效成分溴氰菊酯的分析模型,模型的决定系数R2、校正标准差(SEC)、交互验证参差均方根(RMSECV)值分别为0.999 9,0.013和0.022。结果表明:近红外光谱技术可以准确测定商品农药制剂中有效成分含量,方法简便、快速,适用于溴氰菊酯制剂的现场、在线分析。