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     

Quantitative structure—activity relationships of light-dependent herbicidal 4-pyridone-3-carboxanilide derivatives II. Substituent effects of anilide and pyridone moieties

The variations in the light-dependent herbicidal activity against Echinochloa oryzicola of a number of 4-pyridone-3-carboxanilides with various substituents on the anilide and pyridone rings have been examined by use of physicochemical substituent parameters and regression analysis. The effects of substituents of the anilide ring were such that the activity was related parabolically not only with the substituent hydrophobicity (π) but also with the steric bulk parameter (E_s) of the bulkier ortho substituent. The effect of substituents at the 1-position of the pyridone ring was analysed with steric(STERIMOL L and B₅) and electronic(γ₁) parameters. That of substituents at the 5-position of the pyridone ring was explained by a parabolic function of a steric (MR) parameter. Analyses of the activity of 105 analogs confirmed that our previous selection of a candidate compound in this series for field trials was indeed appropriate in terms of physicochemical substituent effects.     

Quantitative structure—activity relationships of light-dependent herbicidal 4-pyridone-3-carboxanilides I. Effect of benzene ring substituents at the anilide moiety

A number of substituted 4-pyridone-3-carboxanilide derivatives show various degrees of light-dependent herbicidal activity. The effects of substituents at the anilide moiety on the activity against Echinochloa oryzicola were analysed quantitatively with physicochemical substituent parameters. The activity was shown to vary parabolically with total hydrophobicity (Σπ) of the anilide ring substituents as well as with the steric parameter (E_s) of the ortho-substituents. The E_s parameter for only the bulkier ortho-substituent, with the more negative value, but not for the two, was significant. The effect of substituents at the 1-position was expressible by indicator variables assigned to each 1-substituted series, the physicochemical rationalization being left for future analyses.     

Design and synthesis of N-(2,4=difluorophenyl)-2-(3-trifluoromethylphenoxy)-3-pyridinecarboxamide (diflufenican), a novel pre- and early post-emergence herbicide for use in winter cereals

The pre- and early post-emergence herbicidal activity of diflufenican, a novel herbicide, is reported and attention is drawn to its ability to control important weeds in winter cereals, including Galium aparine, Veronica hederifolia, Veronica persica and Viola arvensis, which are resistant to substituted-urea herbicides. The synthesis of a series of related compounds is described and the relationship between structure and activities against a range of plant species is examined in respect of changes in the phenyl, phenoxy and pyridine rings. The design and synthesis of a small number of compounds combining the best patterns of substitution in each of the rings is described. The resulting optimisation of herbicidal activity in the series is reported, together with field trial results comparing the herbicidal efficacy, crop selectivity and soil persistence of the most active structures.     

吡啶衍生物研究(IX):N-(1-甲氧羰基)乙基-N-[5-(2-氯吡啶-4-基)-1,3,4-噻二唑-2-基]酰胺的合成及除草活性

为了进一步研究前期发现的除草先导化合物2-仲丁氨基-5-(2-氯吡啶-4-基)-1，3，4-噻二唑(BCPT)的结构-活性关系并提高其除草活性，设计并合成了一系列N-(1-甲氧羰基)乙基-N-[5-(2-氯吡啶-4-基)-1，3，4-噻二唑-2-基]酰胺类化合物。其苗后除草活性测定结果表明，所有化合物的活性都远低于BCPT本身。说明BCPT可能具有与传统酰胺类除草剂不同的作用机制。     

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.     

靶向乙酰胆碱酯酶和几丁质合成酶杀虫剂衍生化合物三维定量构效关系模型构建

为获得活性更佳且同时具备苯甲酰基脲类和氨基甲酸酯类活性的新型双靶标杀虫剂——N-氯磺基-N-甲基氨基甲酸酯衍生物,构建此类化合物的三维定量构效关系（three-dimensional quantitative structure-activity relationship,3D-QSAR）模型,以18种具有双靶标活性的N-氯磺基-N-甲基氨基甲酸酯衍生物为训练集,分别采用比较分子力场分析（comparative molecular field analysis,CoMFA）法和比较分子相似性指数分析（comparative molecular similarity index analysis,CoMSIA）法进行3D-QSAR模型的构建,基于3D-QSAR模型分析同一骨架取代基的变化带给化合物的活性变化,预测不同力场对化合物活性的影响,并对设计的衍生化合物进行活性预测分析。结果表明,经CoMFA法和CoMSIA法构建的3D-QSAR模型可信度高（交叉验证系数q²分别为0.728和0.563）,且有良好的活性预测能力（非交叉验证系数r²分别为0.954和0.981）。基于该模型得到的化合物预测活性与实际活性残差较小且存在良好的线性关系,进一步证明所得3D-QSAR模型的可靠性。通过分析3D-QSAR模型的力场分布,推测在R¹基团处引入位阻较大的疏水性基团、在R²基团苯环的邻位引入同时具有负电性和疏水性但不含卤素原子的基团、用负电性的大位阻基团取代R基团等均可提高N-氯磺基-N-甲基氨基甲酸酯的活性。基于此设计的20种衍生化合物的活性变化从正反两方面印证了该推测的合理性。研究成果可用于指导兼具苯甲酰基脲类和氨基甲酸酯类杀虫剂作用机制的N-氯磺基-N-甲基氨基甲酸酯衍生物的设计。     

A molecular graphics study of factors influencing herbicidal activity of oximes of 3-acyl-tetrahydro-2H-pyran-2,4-diones

Structure-activity relationships in oximes of a series of sixteen 3-acyltetrahydro-2H-pyran-2,4-diones, exhibiting a variety of pre- and postemergent herbicidal activities, have been studied by means of computer graphics methods. The most active compounds are potent grass-killers. This graminicidal activity appears to depend strongly on the size and shape of the substituent at the 6-position of the pyran. The activity correlates with both molar refractivity and fit to a hypothetical ‘receptor’ probably the active site of acetyl coenzyme A carboxylase. The herbicide sethoxydim and the pyrandione herbicides appear to mimic the transition state of the reaction catalyzed by acetyl-CoA carboxylase. The study has yielded a receptor model which defines clearly the three-dimensional binding reguirements of the pyran ring and the substituents at the 6 position. It is not capable of providing information on the structural requirements of the 3-acyl moiety. The model is capable of discriminating between active and inactive herbicidal compounds and provides a basis for the design of new herbicidal compounds with enhanced graminicidal activity.     

A comparative molecular field analysis study of obtusifoliol 14α-methyl demethylase inhibitors

This report describes the development of a Comparative Molecular Field Analysis (CoMFA) model from a set of obtusifoliol 14α-methyl demethylase (DM) inhibitors to aid in the design of herbicides targeting sterol biosynthesis. CoMFA is a three-dimensional (3-D) quantitative structure–activity relationship (QSAR) method that is useful in the probing of receptor binding sites when experimental structure data are unavailable. Conformational analysis and SAR of some rigid and active analogs were used to build the initial model using the active analog hypothesis. The model was subsequently used to design compounds that retain the active site shape requirements, but incorporate physical properties that favor soil-applied herbicidal action. In addition, a second-generation CoMFA model incorporating the newly designed inhibitors was developed and represents the current understanding of the DM binding site. This model was derived from a pharmacophore developed from two methods, the active analog approach as well as from the Catalyst program. The fact that two independent methods produced a similar pharmacophore strengthens the validity of the model. © 1999 Society of Chemical Industry     

含咪唑啉酮结构的吡唑类对羟基苯基丙酮酸双加氧酶抑制剂的除草活性及选择性研究

对羟基苯基丙酮酸双加氧酶（HPPD）是一种重要的除草剂作用靶标。为了发现具有高活性和高选择性的新型HPPD抑制型除草剂,对前期合成的23个含咪唑啉酮结构单元的吡唑类衍生物（2A~2W）进行了深入的生物活性评价和构效关系研究,比较了它们对拟南芥HPPD（AtHPPD）和人源HPPD（hHPPD）抑制活性的差异,从酶水平上总结了该类化合物的结构-活性关系和种属选择性规律,从活体植株水平研究了它们的除草活性。结果表明:部分化合物表现出良好的除草活性和作物安全性,其中化合物2E和2G在150 g/hm2剂量下对荠菜、繁缕、小藜和棒头草抑制活性达到80%以上,且其对作物的安全性也明显优于商品化除草剂硝磺草酮。此外,化合物2P在酶水平上的选择性倍数高达93倍,展示出良好的应用潜力。     

Modeling root absorption and translocation of 5-substituted analogs of the imidazolinone herbicide,imazapyr

Quantitative structure-activity relationships (QSAR) were developed between the physicochemical parameters of the 5-substituent of a series of analogs of the imidazolinone herbicide, imazapyr, and root absorption, translocation, inhibition of acetohydroxyacid synthase (AHAS), and herbicidal activity of the analogs. An optimum substituent lipophilicity (π = 1.85–2–3) for root absorption was identified for corn (Zea mays L.) and sunflower (Helianthus annuus L.). Translocation from roots to shoots was greatest for those analogs having either highly nonpolar or highly polar 5-substituents, indicating that both symplastic and apopiastic mechanisms may be functioning. In addition, translocation from roots was positively correlated with electron-withdrawing parameters of the 5-substituent, and a possible mechanism governing this relationship is discussed. Modeling in vitro AHAS inhibition was not successful, but models were developed for herbicidal activity as measured in an Arabidopsis thaliana (L.) Hevnh. bioassay. The whole-plant models described an optimum substituent lipophilicity (π = 0 71) which probably reflected the influence of this parameter on the component processes of absorption and translocation. Whole-plant activity was also greater for analogs having electron-donating 5-substituents; this result suggests that electron donation may be important for metabolism, or more likely, for AHAS inhibition.     

Characterization of new photosynthesis-inhibiting imidazolidine derivatives. 1. Interpretation of post-emergence herbicidal performance from photosynthesis-inhibiting activity and systemicity

An attempt was made to account for quantitatively measured herbicidal performance of foliage-applied 5-hydroxy-3-methyl-2–oxo-imidazolidine-1-carboxamide derivatives by their photosynthesis-inhibiting activity and systemicity. Photosynthesis-inhibiting activity was estimated from the increase of chlorophyll fluorescence intensity in Chlorella vulgaris Beijer cells measured by a microplate scanner, and systemicity was also evaluated by computer-aided chlorophyll fluorescence imaging. The highest herbicidal performance was recorded for N-cyclohexyl-5-hydroxy-3-methyl-2-oxo-imidazo～idine-l-carboxamide, a compound with the second strongest photosynthesis-inhibiting activity and intermediate systemicity. Though neither photosynthesis-inhibiting activity nor systemicity showed significant correlation with the actual herbicidal performance in simple regression analyses, a high predictability was found for a multiple regression on both parameters as two independent variables, suggesting that these two factors work cooperatively in the field performance.     

三氟羧草醚类似物的合成及除草活性

以2,5-二羟基苯甲酸甲酯和三氟羧草醚为起始原料,设计合成了3个系列20个新的三氟羧草醚类似物,通过核磁共振氢谱、碳谱对其结构进行了表征。分别采用小杯法和室内盆栽法测定了目标化合物的除草活性。结果表明,化合物 III-02 [5-(2-氯-4-三氟甲基苯氧基)-2-硝基苯甲酸-(6-甲基苯并噻唑-2-基)酯]对单子叶杂草的除草活性明显高于对照药剂三氟羧草醚,其对稗草Echinochloa crusgalli和马唐Digitaria sanguinalis根茎生长的EC₅₀值分别为2.03、0.93 μg/mL和1.49、0.52 μg/mL;在有效成分100 g/hm2的施药剂量下,化合物 III-02 对单子叶杂草稗草、马唐及狗尾草Setaria viridis的防治效果均在85%以上,明显高于三氟羧草醚,对阔叶杂草马齿苋Portulaca oleracea、反枝苋Amaranthus retroflexus及苘麻Abutilon theophrasti的防治效果可达100%。初步构效关系表明,2-硝基苯甲酰衍生物的除草活性明显优于其2-甲氧基衍生物,三氟羧草醚苯甲酸酯衍生物对单子叶杂草的除草活性明显高于其苯甲酰胺衍生物。     

The importance of whole plant studies in determining the biochemical mode of action of herbicides,as shown by studies with the experimental compound 6-chloro-2-trifluoromethyl-imidazo(4, 5-b)pyridine

The experimental herbicides 6-chloro-2-trifluoromethyl-imidazo(4,5b)pyridine and 2-t-butyl-6-chloroimidazo(4,5-b)pyridine inhibit the Hill reaction of isolated chloroplasts by 50% at 1.5 and 2.4 pm, respectively. The first compound also uncouples plant and animal oxidative phosphorylation at about 50 pm, whilst the second compound is not an uncoupler, Surprisingly, light does not affect the herbicidal action of either compound on whole plants, so it is unlikely that the herbicidal activity is due to inhibition of the Hill reaction. Since both compounds probably act by the same mechanism, uncoupling of oxidative phosphorylation cannot be the site of herbicidal action, which therefore remains unknown. A study of the metabolism of 6-chloro-2-trifluoromethyl-imidazo(4,5-b)pyridine shows the occurrence of hydroxylation of the pyridine ring in rat and maize and conversion to trifluoroacetic acid in the latter.     

Pyrazole phenyl ether herbicides inhibit protoporphyrinogen oxidase

Two isomeric pairs of pyrazole phenyl ether herbicides [AH 2.429, 4-chloro-1-methyl-5-(4-nitrophenoxy)-3-(trifluoromethyl)-1H-pyrazole; AH 2.430, 4-chloro-1-methyl-3-(4-nitrophenoxy)-5-(trifluoromethyl)-1H-pyrazole; AH 2.431, 5-((4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)-2-nitrobenzoic acid; and AH 2.432, 5-((4-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)-2-nitrobenzoic acid were evaluated for herbicidal activity in both intact plants and in tissue sections. Their capacity to induce accumulation of porphyrins in tissue sections and to inhibit protoporphyrinogen oxidase (Protox) in vitro were determined. In whole plant tests, the order of herbicidal activity was AH 2.430 AH 2.431 > AH 2.429 > AH 2.432. AH 2.430 consistently caused light-dependent membrane leakage in both green and far-red light grown cucumber cotyledon and barley primary leaf tissue sections after incubation for 20 hr in darkness in 0.1 mM solutions. The same treatment caused marked increases in protoporphyrin IX (PPIX) content during the 20-hr dark incubation. AH 2.429 and 2.431 were less effective and not effective in all tissues in causing herbicidal damage and PPIX accumulation. AH 2.432 was ineffective in tissue section assays. Mg-PPIX levels were not significantly affected by any of the compounds. Protochlorophyllide levels were decreased by AH 2.430 and 2.431 in barley and increased by AH 2.429, 2.431, and 2.432 in cucumber. A positive relationship was found between herbicidal activity and the amount of PPIX that was caused to accumulate by each compound. All of the compounds inhibited Protox activity. Positive correlations were found between herbicidal activity in planta over a 300-fold range and in vitro Protox inhibition and the amount of PPIX caused to accumulate in vivo. These data support the view that the pyrazole phenyl ethers exert their herbicidal activity entirely through inhibition of Protox.     

Synthesis,structure and herbicidal activity of pyrazol-4-yl alkyl ketone derivatives

Novel 5-amino-1-phenylpyrazol-4-yl alkyl ketones were synthesised and their herbicidal properties evaluated. Active compounds in the series induced accumulation of protoporphyrin IX in etiolated cucumber cotyledons and caused light-dependent herbicidal effects in 21-day-old cucumber plants. Structural features of the pyrazoles that contributed to herbicidal potency were found to be a high degree of halogen substitution in the 1-phenyl ring, no substitution in the pyrazole 3-position, and an ethyl group as the alkyl component of the ketone. The structure of 1-[5-amino-1-(2,4,6-trichlorophenyl)pyrazol-4-yl]-2-methylpropan-1-one was determined by X-ray crystallography.     

Synthesis and herbicidal activity of 1,4-benzoxazin-3-one sulfonylureas

A series of 1,4-benzoxazin-3-ones with a sulfonylurea group attached at either the 5 or 8 position have been synthesised and found to show moderate herbicidal activity. Similarly, a series of 1,4-benzothiazin-3-ones, including some of the related S-oxides and S-dioxides, with a sulfonylurea group linked at the 8 position, have been prepared and been found to be herbicidal. In both series of compounds many substituent variations were made but none of the compounds showed any useful crop selectivities.     

(4-亚甲基-5-羰基-3-四氢呋喃基)-苯甲酸甲酯衍生物的合成及其杀菌活性

为了探索天然产物Cedarmycins衍生物的结构与活性关系,以α-亚甲基-β-羟甲基-γ-丁内酯为起始原料,经过与不同取代的羧酸缩合,合成了19个新的(4-亚甲基-5-羰基-3-四氢呋喃基)-苯甲酸甲酯衍生物。杀菌活性测定结果表明,该类衍生物具有广谱的杀菌活性,尤其对水稻纹枯病菌Rhizoctonia solani和辣椒疫霉Phytophthora capsici显示出很强的杀菌活性,其中化合物2e(R=2,4-2Cl)对这2种病菌的EC50值约为1.6 mg/L。     

Synthesis and herbicidal activities of novel 3-(substituted benzyloxy or phenoxy)-6-methyl-4-(3-trifluoromethylphenyl)pyridazine derivatives

BACKGROUND: 4‐(3‐Trifluoromethylphenyl)pyridazine represents a new series of compounds with bleaching and herbicidal activities. RESULTS: A total of 43 novel 3‐(substituted benzyloxy or phenoxy)‐6‐methyl‐4‐(3‐trifluoromethylphenyl)pyridazine derivatives were synthesised, and their bleaching and herbicidal activities were evaluated through Spirodela polyrrhiza and greenhouse tests. Some compounds exhibited excellent herbicidal activities, even at a dose of 7.5 g ha^?1. CONCLUSION: The results showed that a substituted phenoxy group at the 3‐position of the pyridazine ring and the electron‐withdrawing group at the para ‐position on the benzene ring were essential for high herbicidal activity. Copyright © 2011 Society of Chemical Industry     

5-(2-呋喃基)-1,3-环己二酮衍生物的合成及除草活性

为了研究环己三酮类除草剂结构与活性的关系,以2-呋喃甲醛为起始原料,经过与丙酮的羟醛缩合(aldol condensation)反应、与丙二酸二乙酯的迈克尔加成反应、以及分子内的羟醛缩合环化反应,最后与酰氯发生重排反应合成了一系列新的5-(2-呋喃基)-1,3-环己二酮衍生物,所有目标化合物的结构均经过核磁共振氢谱、碳谱及高分辨质谱的确证。初步除草活性测定结果表明,与天然的AB5046A相比,2-苯甲酰基-5-(2-呋喃基)衍生物的活性明显降低,而2-乙酰基和丙酰基衍 生物则显示出更高的除草活性,如化合物 T3 在100 μ g/mL下对油菜生长的最高抑制率达82.9%。