Phytotoxic sites of action for molecular design of modern herbicides (Part 2): Amino acid, lipid and cell wall biosynthesis, and other targets for future herbicides

A bird's eye review was tried in Part 2 of this series, 'Phytotoxic sites of action for molecular design of modern herbicides', in order to select the best selection of known and some novel plant-specific targets for molecular design of modern herbicides, which affect amino acid, lipid and cell wall biosynthesis. Although amino acid biosynthesis pathways, particularly those for aromatic amino acids, ammonia assimilation and branched amino acids, have been confirmed as reasonable herbicidal target domains, the other targets affecting plant growth more markedly than inhibition of 5-enolpyruvylshikimate-3-phosphate synthase, glutamine synthetase and acetolactate synthase are discussed. In three essential enzymes involved in fatty acid biosynthesis in or in the vicinity of chloroplasts, acetyl-CoA carboxylase (ACCase), elongase(s) for very long chain fatty acids (VLCFA) and linolate monogalactosyldiacylglycerol desaturase, ACCase and elongase are more important targets for new herbicides. Although the effect of cellulose biosynthesis inhibitors is restricted to cell wall formation in growing plant cells only, there is a good chance to design the low-use rate herbicides also in this class of inhibitors. Other possible targets for new herbicides are also discussed.     

Target sites for herbicides: entering the 21st century

At present the use-rate of modern herbicides is in the range of 100-300 g AI ha-1, with a tendency to decline. The low use-rate (ca 10 g AI ha-1) of the original sulfonylurea and cyclic imide herbicides prompted agrochemical scientists to look for even more active compounds which led to the successive discoveries of many new herbicidal acetolactate synthase inhibitors and no less than 18 cyclic imides in the class of protoporphyrinogen-IX oxidase inhibitors in the 1990s. In this paper, mechanisms of action related to function and biosynthesis of chlorophylls, carotenoids, plastoquinone, amino acids, fatty acids and photosynthetic electron transport and other metabolic processes are discussed as plant-specific herbicidal target domains.     

磺酰脲类除草剂的降解机制及代谢产物的研究进展

磺酰脲类除草剂是一类高效,低毒和高选择性的除草剂,该类除草剂能有效防除阔叶杂草,其中有些品种对禾本科杂草也有一定的抑制作用。但同时因其用量低、对哺乳动物低毒以及独特的除草活性等特点而得到广泛应用。因此,了解磺酰脲类除草剂在土壤中的环境行为及归趋对于其科学合理使用、防止作物药害和保护农业生态环境具有非常重要的意义。根据笔者对磺酰脲类除草剂的深入研究,并总结归纳国内外的相关文献报道,对磺酰脲类除草剂的降解机制及其代谢产物的研究进行了综述,最后展望了磺酰脲类除草剂未来的发展趋势。     

Auxin herbicides: current status of mechanism and mode of action

Synthetic compounds that act like phytohormonal ‘superauxins’ have been among the most successful herbicides used in agriculture for more than 60 years. These so‐called auxin herbicides are more stable in planta than the main natural auxin, indole‐3‐acetic acid (IAA), and show systemic mobility and selective action, preferentially against dicot weeds in cereal crops. They belong to different chemical classes, which include phenoxycarboxylic acids, benzoic acids, pyridinecarboxylic acids, aromatic carboxymethyl derivatives and quinolinecarboxylic acids. The recent identification of receptors for auxin perception and the discovery of a new hormone interaction in signalling between auxin, ethylene and the upregulation of abscisic acid biosynthesis account for a large part of the repertoire of auxin‐herbicide‐mediated responses, which include growth inhibition, senescence and tissue decay in sensitive dicots. An additional phenomenon is caused by the quinolinecarboxylic acid quinclorac, which also controls grass weeds. Here, the accumulation of phytotoxic levels of tissue cyanide, derived ultimately from quinclorac‐stimulated ethylene biosynthesis, plays a key role in eliciting the herbicidal symptoms in sensitive grasses. Copyright © 2009 Society of Chemical Industry     

几种除草剂对稻田杂草的防除效果

选择田草绝、精克草星、稻草隆、草克净、巧手等进行田间试验，结果表明，5种药剂均具有良好的防效和安全性。     

Effectiveness and mode of action of phosphonate inhibitors of plant glutamine synthetase

BACKGROUND: Aiming at the rational design of new herbicides, the availability of the three‐dimensional structure of the target enzyme greatly enhances the optimisation of lead compounds and the design of derivatives with increased activity. Among the most widely exploited herbicide targets is glutamine synthetase. Recently, the structure of a cytosolic form of the maize enzyme has been described, making it possible to verify whether steric, electronic and hydrophobic features of a compound are in agreement with inhibitor–protein interaction geometry. RESULTS: Three series of compounds (aminophosphonates, hydroxyphosphonates and aminomethylenebisphosphonates) were evaluated as possible inhibitors of maize glutamine synthetase. Aminomethylenebisphosphonate derivatives substituted in the phenyl ring retained the inhibitory potential, whereas variations in the scaffold, i.e. the replacement of the second phosphonate moiety with a hydroxyl or an amino residue, resulted in a significant loss of activity. A kinetic characterisation showed a non‐competitive mechanism against glutamate and an uncompetitive mechanism against ATP. A docking analysis suggested the mode of bisphosphonate binding to the active site. CONCLUSION: Results made it possible to define the features required to maintain or enhance the biological activity of these compounds, which represent lead structures to be further exploited for the design of new substances endowed with herbicidal activity. Copyright © 2009 Society of Chemical Industry     

Development of herbicides for paddy rice in Japan

The history of the development of herbicides for mechanized paddy rice production in Japan can be characterized by a combination of products with several ingredients, by large availability in formulation, and by application methods for labor saving in accordance with natural and social conditions of the country, for instance, around 40% of national land located in hilly and mountainous areas, small size paddy fields consolidated in approximately 0.3 ha on average and so on. As for combination products, one‐shot herbicides that can control both annual and perennial weeds, including grasses, sedges and broadleaved weeds, mainly with sulfonylureas have been a major means of rice production since the 1980s. One‐shot herbicides have been improved by using newly developed chemicals with excellent herbicidal efficacy, such as acetolactate synthase (ALS), 4‐hydroxyphenylpyruvate dioxygenase (4‐HPPD), protoporphyrinogen oxidase (PPO) and very‐long‐chain fatty acid elongase (VLCFAE) inhibitors, and by combining ingredients that are effective against sulfonylurea‐resistant (SU‐R) biotypes of lowland weeds. The latest type of one‐shot herbicides can control noxious species such as Eleocharis kuroguwai as well as other ordinal species. Regarding herbicide formulation, “1 kg granule,” “Jumbo,” “Flowable,” “Diffusion granule” and so on have been developed to save farmers the troubles of applying herbicides. As for application methods, “at‐transplanting application,” “at‐irrigation inlet application” and utilization of radio‐controlled helicopters or boats were put into practical use as labor‐saving technology. As a result, farmers were spared the severe hand‐weeding work under blazing heat during the summer season. Japan Association for Advancement of Phyto‐Regulators (JAPR) have promoted and contributed to the development of herbicides through collaboration with agrochemical companies and research organizations since it was founded in 1964. In this paper, I explain the development progress of herbicide using materials on the mode of action, the trend of one‐shot herbicides, the feature of a labor‐saving formulation and the working hours for weed management in rice production.     

Using a selectivity index to evaluate logarithmic spraying in grass seed crops

BACKGROUND: Grass seed crops are minor crops that cannot support the development of selective herbicides for grass weed control in grass seed crops. An option is to screen for selective herbicides with the use of logarithmic spraying technology. The aim of this paper is to assess selectivity of various herbicides in grass seed crops by using dose–response curves. RESULTS: Six grass species were subjected to logarithmic spraying with 11 herbicides and with Poa pratensis L. as a weed. The ratio between the doses that caused 10% of damage to the crop and 90% of damage to the weed was used as a selectivity index. Compounds with selectivity indices above 2 can be safely used in a crop. The two ACCase herbicides clodinafop‐propargyl and fenoxaprop‐P‐ethyl and a mixture of the two ALS herbicides mesosulfuron and iodosulfuron could be used selectively to control P. pratensis in Festuca rubra L., although the selectivity indices in no instances were greater than the desired 2.0. CONCLUSION: The logarithmic sprayer can be a rapid screening tool for identifying compounds with favourable selectivity indices. Good experimental design is needed to alleviate rates being systematically distributed and confounded with growth rate and soil fertility gradients. Copyright © 2009 Society of Chemical Industry     

The Design and Synthesis of Inhibitors of Imidazoleglycerol Phosphate Dehydratase as Potential Herbicides

The discovery and exploration of a new class of broad-spectrum post-emergent herbicides with a novel mode of action, namely the disruption of histidine biosynthesis via inhibition of imidazoleglycerol phosphate dehydratase (IGPD; E.C. 4.2.1.19), are described. Clear structural similarities between the first member, produced during an attempt to produce analogues of glyphosate, and intermediates in histidine biosynthesis were noted. Several series of targets were designed, to mimic both the enzyme substrate and a putative reaction intermediate, and synthesised. Some examples were found to be both extremely potent inhibitors of the enzyme, having K_i values as low as 0·3 nM , and phloem-mobile herbicides with levels of weed control similar to those shown by glyphosate. Further logical progress awaits a high-resolution X-ray structure determination of an enzyme-inhibitor complex. © 1997 SCI     

类胡萝卜素生物合成抑制剂研究进展

概述了类胡萝卜素生物合成抑制剂类除草剂的作用机理以及八氢番茄红素去饱和酶(phytoene desaturase, PD酶)抑制剂的结构-活性关系。简要介绍了进入商品化开发应用的类胡萝卜素生物合成抑制剂类除草剂品种以及它们的除草活性。     

The structure-activity relationship in herbicidal monosubstituted sulfonylureas

BACKGROUND: The herbicide sulfonylurea (SU) belongs to one of the most important class of herbicides worldwide. It is well known for its ecofriendly, extreme low toxicity towards mammals and ultralow dosage application. The original inventor, G Levitt, set out structure–activity relationship (SAR) guidelines for SU structural design to attain superhigh bioactivity. A new approach to SU molecular design has been developed. RESULTS: After the analysis of scores of SU products by X‐ray diffraction methodology and after greenhouse herbicidal screening of 900 novel SU structures synthesised in the authors' laboratory, it was found that several SU structures containing a monosubstituted pyrimidine moiety retain excellent herbicidal characteristics, which has led to partial revision of the Levitt guidelines. CONCLUSIONS: Among the novel SU molecules, monosulfuron and monosulfuron‐ester have been developed into two new herbicides that have been officially approved for field application and applied in millet and wheat fields in China. A systematic structural study of the new substrate–target complex and the relative mode of action in comparison with conventional SU has been carried out. A new mode of action has been postulated. Copyright © 2011 Society of Chemical Industry     

酮醇酸还原异构酶抑制剂的设计、合成及除草活性

酮醇酸还原异构酶(KARI)是一个有前景的除草剂靶标酶,有关其抑制剂的设计研究鲜有报道。在文献报道的菠菜KARI酶复合物0.165 nm高分辨率晶体结构基础上,利用分子对接DOCK 4.0方法进行MDL/ACD三维数据库搜寻,得到了279个与KARI酶结合能较低的小分子结构信息,并从中选取部分小分子进行化学合成,进而测试了其除草活性。在合成的17个化合物中,发现个别化合物对油菜 (抑制率70.8 %) 和稗草 (抑制率48.8 %)具有较好的生长抑制活性。     

不同除草剂对11种冬小麦田阔叶杂草的防除效果比较

小麦田除草剂的长期使用,造成麦田杂草群落发生变化。为建立不同区域优势杂草种类的化学防除技术,本研究采用室内盆栽法测定了14种除草剂对11种冬小麦田阔叶杂草的防除效果。结果表明,灭草松可以较好地防除冬小麦田野老鹳草、牛繁缕、大巢菜、紫堇、小藜、阿拉伯婆婆纳、播娘蒿、猪殃殃、麦家公等阔叶杂草;吡草醚对野老鹳草、牛繁缕、小藜、阿拉伯婆婆纳、播娘蒿、猪殃殃、麦家公、荠菜等8种杂草防效突出。辛酰溴苯腈可很好地防除牛繁缕、大巢菜、小藜、阿拉伯婆婆纳、播娘蒿、麦家公等6种阔叶杂草;唑草酮对野老鹳草、牛繁缕、阿拉伯婆婆纳、播娘蒿、猪殃殃等5种杂草防效突出。这4种除草剂及其适用浓度与其他供试药剂相比杀草谱更为广泛,对阔叶杂草防效较好。根据不同区域优势杂草种类,合理选用高效除草剂进行防除。     

The action of herbicides on fatty acid biosynthesis and elongation in barley and cucumber

BACKGROUND: Herbicides that affect lipid metabolism have been used commercially for many years. Here, napropamide, diphenamid, dimethachlor and cafenstrole are compared; these have all been classified by the Herbicide Resistance Action Committee (HRAC) as K₃ herbicides and inhibitors of cell division and/or synthesis of very‐long‐chain fatty acids (VLCFAs). In addition, spiro‐decanedione A and pinoxaden dione are compared as inhibitors of lipid synthesis through inhibition of acetyl‐CoA carboxylase (ACCase). RESULTS: Whereas the chloracetamide dimethachlor and the carboxyamide cafenstrole potently inhibited VLCFA synthesis in both barley and cucumber, the acetamides napropamide and diphenamid which are also classified as K₃ herbicides and likewise the unclassified herbicide cinmethylin did not. The graminicide pinoxaden dione inhibited de novo fatty acid synthesis in barley, but not in cucumber, and correspondingly inhibited the plastid form of maize ACCase much more than the cytosolic form (IC₅₀ values of 0.1 and 17 µM ). By contrast, spiro‐decanedione A exhibited herbicidal effects not only on grasses but also on broad leaves, strongly inhibited maize cytosolic ACCase and inhibited synthesis of VLCFAs in cucumber. CONCLUSIONS: The acetamides napropamide and diphenamid, which do not inhibit VLCFA synthesis, should be classified separately from K₃ herbicides that do. Pinoxaden dione and spiro‐decanedione A represent new classes of chemicals acting on plant lipid synthesis. Copyright © 2010 Society of Chemical Industry     

1,3,4(2H)-isoquinolinetrione herbicides: Novel redox mediators of photosystem I

A series of 1,3,4(2H)-isoquinolinetriones have been found to be fast-acting post-emergence herbicides, producing symptoms of desiccation. These redox-active compounds are very potent stimulators of the light-dependent consumption of oxygen at photosystem I in isolated chloroplasts. Pulse radiolysis studies on 2-ethyl-1,3,4(2H)-isoquinolinetrione have shown it to have free-radical properties which could enhance the generation of superoxide radicals in plants. Electrochemical studies further support a redox mediator mode of action for the series. The compounds were found to be unstable towards hydrolysis, and this was considered to be a major factor limiting the overall herbicidal effects. Other parameters, related to uptake and/or translocation, which may limit the full expression of the herbicidal activity of certain compounds, are discussed.     

QSAR and 3D-QSAR analysis of structurally diverse ALS inhibitors: sulfonylureas and triazolopyrimidine-2-sulfonamides

For the purpose of better understanding the molecular mechanism of action of sulfonylurea and sulfonamide herbicides, the quantitative relationship between their structure and herbicidal activity against rape, Brassica campestris L, was analysed using physicochemical parameters and regression analysis and comparative molecular field analysis (CoMFA). The results showed that the structure–activity relationships of the two sets of compounds were identical, which suggested that the two different sets of compounds affect a common region of the receptor site. The CoMFA results were consistent with those derived from traditional QSAR analysis. Combining the traditional QSAR analysis with the CoMFA results, we can conclude that the variations in the herbicidal activity of the two sets of ALS inhibitors were governed dominantly by the three-dimensional steric and electrostatic field parameters of molecules participating in the interaction with the receptor site and there is apparently an optimum electronic property (Σσ or pKa) for the molecules to fit the receptor. © 1999 Society of Chemical Industry     

Aryl chain analogues of the biotin vitamers as potential herbicides. Part 3

Novel aryl chain isosters and analogues of 7-keto-8-aminopelargonic acid (KAPA) and 7,8-diaminopelargonic acid (DAPA), the vitamer intermediates involved in the biosynthetic pathway of biotin, possessing chain lengths of eight carbon atoms, were prepared and evaluated as potential herbicides. In the greenhouse test the most active compounds were the fluorinated derivative 9d and the selenophenyl/furan mixture 17m/17p, which were most active against Foxtail millet. In the more sensitive Arabidopsis test the most active substances were 9a and 17m, which displayed GR(50) (concentration of active compound causing 50% growth inhibition) values of 0.2 and 0.5 mg kg(-1) respectively (values of < 50 mg kg(-1) are considered herbicidal).     

The control of Achillea millefolium in the Snowy Mountains of Australia

The response of Achillea millefolium L. to herbicides was measured to determine the effectiveness of the current recommendations and to test alternative herbicides. Five plots at each of the three replicate sites were selected and randomly treated with one of the four herbicides: dicamba/2,4‐D, glyphosate, metsulfuron‐methyl and triclopyr/picloram. After 12 months, the recommended treatment, dicamba/2,4‐D, did not cause a significant reduction in aerial biomass compared with untreated controls and the number of flowering stems was significantly increased in treated plots. Metsulfuron‐methyl and triclopyr/picloram caused a significant reduction in A. millefolium aerial biomass but did not affect the number of flowering stems. Glyphosate produced a significant reduction in aerial biomass and was less effective. These results suggest that the current recommendation for A. millefolium might be improved. Site‐specific effects such as aspect may also influence the effectiveness of herbicides on this species.     

具有除草活性植物病原真菌毒素的作用模式

作用模式得到明确的具有除草活性的植物病原真菌毒素为数不多,主要是危害农作物的病原真菌产生的植物毒素,目前只有少数几个具有除草活性的杂草病原真菌植物毒素的作用模式得到鉴定。而近些年来,新获得的绝大多数具有除草活性的杂草病原真菌植物毒素的作用模式尚未得到鉴定。在作用模式已经明确的具有除草活性的植物病原真菌毒素中,除了极个别与有些化学合成除草剂共享相同作用模式,绝大多数具有与现有化学合成除草剂完全不同的作用模式和独特的分子靶标位点,很有希望开发成为新型除草剂。本文重点介绍了目前已经得到鉴定的具有除草活性的植物病原真菌毒素的作用模式。