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 differential binding and biological efficacy of auxin herbicides

Background

Auxin herbicides have been used for selective weed control for 75 years and they continue to be amongst the most widely used weed control agents globally. The auxin herbicides fall into five chemical classes, with two herbicides not classified, and in all cases it is anticipated that recognition in the plant starts with binding to the Transport Inhibitor Response 1 (TIR1) family of auxin receptors. There is evidence that some classes of auxins act selectively with certain clades of receptors, although a comprehensive structure–activity relationship has not been available.

Results

Using purified receptor proteins to measure binding efficacy we have conducted quantitative structure activity relationship (qSAR) assays using representative members of the three receptor clades in Arabidopsis, TIR1, AFB2 and AFB5. Complementary qSAR data for biological efficacy at the whole-plant level using root growth inhibition and foliar phytotoxicity assays have also been analyzed for each family of auxin herbicides, including for the afb5-1 receptor mutant line.

Conclusions

Comparisons of all these assays highlight differences in receptor selectivity and some systematic differences between results for binding in vitro and activity in vivo. The results could provide insights into weed spectrum differences between the different classes of auxin herbicides, as well as the potential resistance and cross-resistance implications for this herbicide class. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.     

新型2-烷氧基取代苯甲酸香叶酯类蚜虫报警信息素类似物的设计、合成及生物活性

为了发现结构新颖的蚜虫行为控制剂,以课题组发现的高活性化合物 3e (2-羟基-3-甲氧基苯甲酸香叶酯)为先导,利用活性亚结构拼接的方法,设计合成了15个未见文献报道的新型2-烷氧基取代苯甲酸香叶酯类蚜虫报警信息素(E)-β-farnesene (EβF)衍生物,其结构经过核磁共振氢谱(1H NMR)、红外光谱(IR)和高分辨质谱(HRMS)的确证。蚜虫驱避活性测定结果表明,部分目标化合物在5 μg剂量下对豌豆蚜Acyrthosiphon pisum表现出不同程度的驱避活性,其中化合物 6i 活性最高,驱避率达到60.9%,与先导化合物 3e 的活性没有显著性差异。靶标蛋白结合实验证明,部分目标化合物与气味结合蛋白ApisOBP9具有较好的结合活性,尤其是化合物 6i 与ApisOBP9的结合常数达到(4.92±0.18) μmol/L。进一步的分子对接结果表明, 6i 与靶标ApisOBP9具有较好的结合作用力,能很好地结合到靶标蛋白的活性位点,其结合模式和先导化合物相似。本研究对后续化合物的结构优化具有重要参考价值。     

绿洲农田不同施肥处理对土壤养分和作物产量的影响

为充分了解绿洲农田农业生态系统养分循环规律,利用长期定位实验的方法,初步探讨了不同施肥处理下,绿洲农田的土壤养分及作物产量变化。结果表明:不同施肥处理对土壤养分含量有明显影响。其中,化肥与有机肥配合施用处理的土壤养分含量最高,无肥CK处理养分含量最低,尤其是化肥与有机肥配合施用处理的有机质、全N和碱解氮分别比对照区平均高1.5 g/kg0、.19 g/kg和10.5 mg/kg,其他各处理养分含量处于二者之间。结果还表明,作物产量与土壤养分含量相关,尤其是与土壤有机质、全N、碱解N的含量关系密切,制约产量的首要养分因素是N素,其次是P素。CK处理由于连年作物吸收及收获带走养分,使土壤的有效养分库消耗很快,致使作物产量逐渐降低。P、K处理作物产量变化趋势和CK处理基本一致,进一步表明了N素是影响绿洲农田作物产量的首要因素。对各处理的土壤养分和作物产量变化研究表明,化肥与有机肥配合施用处理作物产量最高,平均为4 010.8 kg/hm2,因此化肥与有机肥配合施用可能是提高绿洲农田土壤肥力,增加作物产量的最佳施肥方式。     

棉粕腐植酸肥对土壤团聚体、酶及养分的影响

采用田间试验方法,以小麦新春38号作为供试品种,设置3个处理:空白对照、等养分复合肥和等养分棉粕腐植酸复合肥,研究了棉粕开发的腐植酸水溶性肥料对土壤团聚体、酶和养分的影响。结果表明:与不施肥处理相比较,腐植酸肥处理使土壤团聚体含量向2~0.25 mm和2 mm粒级有显著转移;土壤脲酶活性、过氧化氢酶和碱性磷酸酶活性显著提高,对蔗糖酶活性差异不明显;可显著提高碱解氮、速效钾和有效磷含量,腐植酸肥处理能平均提高全生育期0~20 cm土层碱解氮37.27%、速效磷42.24%、速效钾37.02%,20~40 cm土层碱解氮提高15.55%、速效磷提高61.52%、速效钾提高57.36%。与等养分复合肥处理相比,腐植酸肥处理使不同土层土壤团聚体百分含量向2~0.25 mm和2 mm粒级均有转移;前期抑制土壤脲酶活性,后期提高壤脲酶活性,提高过氧化氢酶和碱性磷酸酶活性,蔗糖酶活性差异不明显;可提高土壤中碱解氮含量,显著提高速效钾和速效磷含量,腐植酸肥处理可平均提高全生育期0~20 cm土层碱解氮5.92%、速效磷8.8%、速效钾4.29%,20~40 cm土层碱解氮提高1.9%、速效磷提高15.39%、速效钾提高8%。     

Phoma stem canker (<Emphasis Type="Italic">Leptosphaeria maculans/L. biglobosa</Emphasis>) of oilseed rape (<Emphasis Type="Italic">Brassica napus</Emphasis>): is the G<Subscript>2</Subscript> Disease Index a good indicator of the distribution of observed canker severities?

Several disease indices (DI) have been proposed to assess the severity of phoma stem canker at late growth stages. The DI commonly used in France (called G₂ DI) consists of integrating the distribution of the proportions of plants observed within six canker severity classes into a single index. This index uses arbitrarily chosen coefficients associated to each class of canker severity. A given value of this DI can therefore be obtained with different distributions among the canker severity classes. Consequently, it is important to assess to what extent the G₂ DI is representative of the distribution of plants in canker severity classes. We show in this study that the G₂ DI is a good indicator of the distribution of the observed canker severities, using a dataset from different years, sites and cultivars; this illustrates the robustness of the G₂ DI.     

Design of Inhibitors of Photosystem II using a Model of the D1 Protein

Several inhibitors belonging to structurally different chemical classes were used to analyze the predictive power of an initial model of the herbicide binding niche of the D1 protein belonging to photosystem II (PS II) from plants. In the case of small PS II inhibitors, the estimation of relative activities was hampered by uncertainty about the binding modes. To overcome this problem, a bulky substituent was introduced into the inhibitors to act as a hook, resulting in an unambiguous orientation in the model. The comparison of the modelling results and the experimentally determined IC₅₀ values of different triazines suggested that the previously assumed volume of the binding niche had to be reduced by 20%. After refinement of the model, it was possible to estimate qualitatively, the relative in-vitro activity for inhibitors belonging to different families, as long as an unambiguous binding mode could be deduced either from steric demands or from IC₅₀ values of mutant D1 proteins. The usefulness of the refined model is demonstrated by the successful de-novo design of a potent class of herbicides, the triazolopyrimidines.     

Structure–Activity Relationships of Herbicidal Aryltriazolinones

A series of substituted aryltriazolinones, known to inhibit protoporphyrinogen oxidase, were prepared and their structure–activity requirements at positions 4 and 5 of the aromatic ring investigated. A QSAR equation obtained for substituents at the 5 position identified the hydrophobicity term π and the Sterimol minimum width B₁ as the two parameters affecting in-vitro biological activity. Greenhouse pre-emergence activity correlated with in-vitro activity and the hydrophobicity term π of the substituent at that position. It was found that the phenoxy-4-oxyacetate group at aromatic position 5 was an outlier and had to be considered separately. SAR analysis of substituents at aromatic position 4 revealed that two different models were required to explain all observed substituent effects. In the first model, where the 5 position was occupied by hydrogen, the 4-chlorobenzyloxy group at aromatic position 4 gave the best compound. The second model, where the 5 position of the aromatic ring was occupied by a group other than hydrogen, resulted in a QSAR equation, previously derived, which links substituent effects at position 4 with π and with the electronic para inductive term F_p. In this model the chloro group provides optimum biological activity. The need to separate the aryltriazolinone herbicides into several different classes in order to explain their substituent effects at aromatic positions 4 and 5 could be rationalized if more than one binding conformation, within the same binding site, is possible. © 1997 SCI     

Chloroaniline peroxidation by soybean peroxidases

4-chloroaniline was oxidized by soya cell-wall peroxidases in the presence of hydrogen peroxide. The main product, an orange compound with a maximal absorbance at 455 nm, was probably 4, 4′-dichloroazobenzene. The optimum pH of the reaction was 4. Michaelis constants, determined as described by Dalziel, were 21 mM for 4-chloroaniline and 94 μM for hydrogen peroxide. Syringaldazine was an uncompetitive inhibitor of 4-chloroaniline peroxidation (K_i =46 μM) and modified the progress of the reaction with the appearance of a lag period. By contrast, 4-chloroaniline was a non-competitive inhibitor of syringaldazine peroxidation with a K_i value of 21 mM_x at pH 7.5. Therefore, these two inhibiting effects were compatible with the presence of two binding sites for two different hydrogen donors. Both sites were linked by allosteric interactions. The inferences on chloroaniline binding are discussed.     

Control of Solenopsis invicta with delayed-action fluorinated toxicants

The fire ant, Solenopsis invicta Buren, was accidentally imported into the southern United States and has become a serious medical and agricultural pest of nine southeastern states and Puerto Rico. For a bait toxicant to be effective in fire ant control it must have delayed activity over a wide range of concentrations. Less than 1% of the 7500 compounds screened since 1958 has had delayed action. This paper describes several classes of fluorinated compounds that exhibit delayed activity. These compounds are used to illustrate the following three approaches to the discovery of delayed-action toxicants: (a) random screening of compounds for delayed action; (b) design of delayed activity through the synthesis of pro-insecticides; and (c) serendipity. As a result of these investigations two new classes of insecticides were discovered. A compound from one of these classes (tetrahydro-5,5-dimethyl-2(1H)-pyrimidinone (3-(4-(trifluoromethyl)phenyl)-1-(2-(4-(trifluoromethyl)phenyl)-ethynyl)-2-propenyl-idene) hydrazone, has been commercialised, while one or more compounds from the second new chemical class (fluorinated sulphonamides) are under development. Fluorinated delayed-action insecticides have made significant contributions to current fire ant control and will no doubt play a role in the future.     

Adsorption of glyphosate by soils

The adsorption of glyphosate in a slurry system by 9 soils was correlated with an arbitrary single point inorganic phosphate sorption index which gave a measure of unoccupied phosphate sorption capacity, but not with total phosphate sorption capacity at pH 2.6, the level of iron and aluminium soluble in Tamm's acid oxalate or with clay content, organic matter content or pH. It is concluded that inorganic phosphate excludes glyphosate from sorption sites. The extent of adsorption was higher than, though of the same order as, that of diuron though the two are not related. From consideration of the results of previous experiments with plants grown in culture solution it is suggested that the low phytotoxicity of glyphosate applied to the soil is not due simply to high adsorption. Rather it is the result of a combination of moderate adsorption and the low intrinsic activity of this compound when made available to the root system.     

Comparative analysis of neonicotinoid binding to insect membranes: I. A structure-activity study of the mode of [3H]imidacloprid displacement in Myzus persicae and Aphis craccivora

Neonicotinoids bind selectively to insect nicotinic acetylcholine receptors with nanomolar affinity to act as potent insecticides. While the members of the neonicotinoid class have many structural features in common, it is not known whether they also share the same mode of binding to the target receptor. Previous competition studies with [3H]imidacloprid, the first commercialised neonicotinoid, indicated that thiamethoxam, representing a novel structural sub-class, may bind in a different way from that of other neonicotinoids. In the present work we analysed the mode of [3H]imidacloprid displacement by established neonicotinoids and newly synthesized analogues in the aphids Myzus persicae Sulzer and Aphis craccivora Koch. We found two classes of neonicotinoids with distinct modes of interference with [3H]imidacloprid, described as direct competitive inhibition and non-competitive inhibition, respectively. Competitive neonicotinoids were acetamiprid, nitenpyram, thiacloprid, clothianidin and nithiazine, whereas thiamethoxam and the N-methyl analogues of imidacloprid and clothianidin showed non-competitive inhibition. The chloropyridine or chlorothiazole heterocycles, the polar pharmacophore parts, such as nitroimino, cyanoimino and nitromethylene, and the cyclic or acyclic structure of the pharmacophore were not relevant for the mode of inhibition. Consensus structural features of the neonicotinoids were defined for the two mechanisms of interaction with [3H]imidacloprid binding. Furthermore, two sub-classes of non-competitive inhibitors can be discriminated on the basis of their Hill coefficients for imidacloprid displacement. We conclude from the present data that the direct competitors share the binding site with imidacloprid, whereas non-competitive compounds, like thiamethoxam, bind to a different site or in a different mode.     

Affinity and mobility of fungicidal dialkyl dithiolanylidenemalonates in rice plants

The affinity of certain fungicide analogs to rice plant varied progressively, showing a linear decrease with decreasing length of, or branching of, the alkyl chains, and correlated well with the hydrophobic parameter, log P. The more hydrophobic the compound was, the higher was the affinity to rice plant. Compound mobility in rice plant also varied regularly. The resulting relationship between hydrophobicity and mobility of these fungicide analogs suggested that the situation in rice plant is quite analogous to rice-plant column chromatography, by which the affinity to rice plant was determined. The major factor preventing movement within the plants seems to be interaction with sites in the rice plant leading to partition or binding and the resulting loss from the transpiration stream.     

Sorption of tetrachlorvinphos insecticide (Gardona) to the hemolymph of Periplaneta americana

Tetrachlorvinphos insecticide (Gardona, SI) 8447) sorbs to the hemolymph of the American cockroach via noncovalent bonding. The amount sorbed is dependent upon both the concentration of hemolymph and tetrachlorvinphos used. Acrylamide disc gel electrophoresis and Sephadex column chromatography of the complex revealed that tetrachlorvinphos binds to a variety of proteins in the hemolymph. No one protein serves as a specific carrier.These studies show that 80% of the LD₅₀ dose of tetrachlorvinphos can bind to the hemolymph contained in a single roach. The observed LD₅₀ value could then be considered as an inflated value, since the hemolymph can sorb large quantities of tetrachlorvinphos and thereby reduce the concentration of free compound available for inducing a toxic event. An alternative possibility, however, should not be overlooked. The binding of tetrachlorvinphos to hemolymph can be looked upon as a transport mechanism, whereby the compound is transported throughout the roach, to dissociate from the “carrier” proteins, and to penetrate into or through the cell membrane at the appropriate time. This would have the effect of actually enhancing the toxicity of the compound.     

Invasion syndromes：hypotheses on relationships among invasive species attributes and characteristics of invaded sites

As invasion science accepts that there is no single causal factor for biological invasion,the identification of groups of traits that are often associated,or "syndromes",is a logical move forward.Invasion syndromes are proposed to identify suites of site conditions(biotic and environmental)that render a site vulnerable to invasion by different types of invaders.This paper proposed four invasion syndromes which relate invader attributes(competitive ability,niche construction,phenotypic plasticity,and phenological niche separation)to the biotic characteristics(biodiversity and enemies)and environmental conditions(resource abundance and fluctuation)of invaded sites.The four invasion syndromes described in this paper are a development of hypotheses of how the many factors that influence species invasion might be associated.Invasion Syndrome 1 proposes that sites with relatively high resource abundance and high diversity should be vulnerable to invasion by species with high competitive ability.Invasion Syndrome 2 hypothesizes that sites with relatively low resource abundance and low diversity should be vulnerable to invasion by species with niche construction ability.Invasion Syndrome 3 postulates that sites with moderate or fluctuating resources and moderate diversity should be vulnerable to invasion by species with high phenotypic plasticity.Invasion Syndrome 4 hypothesizes that species introduced into a site where it has phenological niche separation from natives will not have to contend with interference from the biotic community at a site(diversity or natural enemies)and may invade where ever site environmental conditions suit its life history.Further work is needed to support,contradict,or refine these hypotheses and almost certainly will identify more invasion syndromes.     

A degree-day concept for estimating degradation time under field conditions

Development of degradation rate information for crop protection products in soil is typically a time consuming and costly process. Therefore, development of methodology that would allow extrapolation of limited degradation information to wider field conditions in a predictive fashion would be desirable. This study presents an approach that uses a modified heat unit model to estimate organic compound degradation time using limited datasets. The model requires daily soil or air temperature and volumetric water content. Predictions based on the model for three different compounds in five different field studies were within 80% of measured values based on soil analysis. Results from this research indicate that the model was able to predict compound half-life values across all sites with r2 = 0.99.     

Prediction of the binding mode of imidacloprid and related compounds to house-fly head acetylcholine receptors using three-dimensional QSAR analysis

The binding activity of imidacloprid and related compounds to nicotinic acetylcholine receptors (nAChR) of house flies was measured by use of radioactive α-bungarotoxin as a ligand. Variations in the activity were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results suggest that one conformer among the four stable ones is active and provide support for one of the proposed binding models for this class of compound, in which the nitrogen atom of the pyridine ring and the nitrogen atom at the 1-position of the imidazolidine ring interact with the hydrogen-donating and electron-rich sites of nAChR, respectively. The CoMFA field map showed that the nitroimino moiety and a portion of the imidazolidine ring were mainly surrounded by a sterically and electrostatically sensitive region of nAChR. © 1998 Society of Chemical Industry     

Novel mode of action of spinosad: Receptor binding studies demonstrating lack of interaction with known insecticidal target sites

The ability of spinosyn A to either enhance or displace binding to selected insecticidally-relevant receptors was investigated using a number of radioligands including, [³H]imidacloprid and [³H]ivermectin in tissues from the ventral nerve cord (VNC) membranes of the American cockroach, Periplaneta americana and head membranes from the housefly, Musca domestica. In these insect neural tissues, spinosyn A does not appear to alter the binding of a number of radioligands suggesting that spinosyn A does not interact directly with a variety of known receptors, including nicotinic or γ-aminobutyric acid (GABA)-based insecticidal target sites. However, available data are consistent with spinosyn A interacting with a site distinct from currently known insecticidal target sites, thus supporting a novel insecticidal mechanism of action for the spinosyns.     

Glyphosate: a once-in-a-century herbicide

Since its commercial introduction in 1974, glyphosate [N-(phosphonomethyl)glycine] has become the dominant herbicide worldwide. There are several reasons for its success. Glyphosate is a highly effective broad-spectrum herbicide, yet it is very toxicologically and environmentally safe. Glyphosate translocates well, and its action is slow enough to take advantage of this. Glyphosate is the only herbicide that targets 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSPS), so there are no competing herbicide analogs or classes. Since glyphosate became a generic compound, its cost has dropped dramatically. Perhaps the most important aspect of the success of glyphosate has been the introduction of transgenic, glyphosate-resistant crops in 1996. Almost 90% of all transgenic crops grown worldwide are glyphosate resistant, and the adoption of these crops is increasing at a steady pace. Glyphosate/glyphosate-resistant crop weed management offers significant environmental and other benefits over the technologies that it replaces. The use of this virtually ideal herbicide is now being threatened by the evolution of glyphosate-resistant weeds. Adoption of resistance management practices will be required to maintain the benefits of glyphosate technologies for future generations.     

Sulfur-based functional groups in agrochemistry

The element sulfur has an outstanding role in the crop protection chemistry because it is used in its elemental form as a multisite fungicide, but is also part of agrochemicals in the form of aromatic or aliphatic sulfur-containing rings or sulfur-based functional groups. This review gives an exhaustive overview over the latter category. Several fundamental agrochemical compound classes are named after a sulfur-based functionality, such as the dithiocarbamate fungicides and sulfonylurea herbicides. Altogether, 16 different sulfur-based functional groups are presented with their typical synthesis approaches and most important representatives in crop protection. © 2023 Society of Chemical Industry.