Agrochemical Discovery Research Articles

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives.

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 °C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Protocol for the Synthesis of <em>Ortho</em>-trifluoromethoxylated Aniline Derivatives

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of trifluoromethoxylated aromatic compounds remains a formidable challenge in organic synthesis. Conventional approaches often suffer from poor substrate scope, or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Herein, we report a user-friendly protocol for the synthesis of methyl 4-acetamido-3-(trifluoromethoxy)benzoate using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (Togni reagent II). Treating methyl 4-(N-hydroxyacetamido)benzoate (1a) with Togni reagent II in the presence of a catalytic amount of cesium carbonate (Cs2CO3) in chloroform at RT afforded methyl 4-(N-(trifluoromethoxy)acetamido)benzoate (2a). This intermediate was then converted to the final product methyl 4-acetamido-3-(trifluoromethoxy)benzoate (3a) in nitromethane at 120 °C. This procedure is general and can be applied to the synthesis of a broad spectrum of ortho-trifluoromethoxylated aniline derivatives, which could serve as useful synthetic building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and functional materials.

Synthesis and Biological Activity of Novel Furan/Thiophene and Piperazine‐Containing (Bis)1,2,4‐triazole Mannich Bases

AbstractSeries of novel furan/thiophene and piperazine‐containing 1,2,4‐triazole Mannich bases and bis(1,2,4‐triazole) Mannich bases have been conveniently synthesized via Mannich reaction with triazole Schiff bases, various piperazine derivatives, and formaldehyde as intermediates in good yields. Their structures were characterized by melting points, 1H NMR, 13C NMR, IR and elemental analysis. The preliminary bioassay showed that most compounds exhibited significant in vitro and in vivo fungicidal activity against several test plant fungi. Among 32 new compounds, the trifluoromethyl‐containing compounds showed superior activity than the methyl‐containing ones. Several compounds, such as F8, F9, F10, G5, H7, H8, I3 and I4, were comparable with some commercial fungicides against different fungi during the present study and could be further structurally optimized. Meanwhile, several compounds showed good herbicidal activity against Brassica campestris at 100 µg/mL and KARI inhibitory activity at 200 µg/mL. However, compounds exhibited poor insecticidal activity against oriental armyworm at 200 µg/mL in the preliminary studies. The research results will provide useful information for the design and discovery of new agrochemicals with novel heterocyclic structures.

Discovery of pyridine-based agrochemicals by using Intermediate Derivatization Methods

Pyridine-based compounds have been playing a crucial role as agrochemicals or pesticides including fungicides, insecticides/acaricides and herbicides, etc. Since most of the agrochemicals listed in the Pesticide Manual were discovered through screening programs that relied on trial-and-error testing and new agrochemical discovery is not benefiting as much from the in silico new chemical compound identification/discovery techniques used in pharmaceutical research, it has become more important to find new methods to enhance the efficiency of discovering novel lead compounds in the agrochemical field to shorten the time of research phases in order to meet changing market requirements. In this review, we selected 18 representative known agrochemicals containing a pyridine moiety and extrapolate their discovery from the perspective of Intermediate Derivatization Methods in the hope that this approach will have greater appeal to researchers engaged in the discovery of agrochemicals and/or pharmaceuticals.

Rational Design of Highly Potent and Slow-Binding Cytochrome bc1 Inhibitor as Fungicide by Computational Substitution Optimization

Hit to lead (H2L) optimization is a key step for drug and agrochemical discovery. A critical challenge for H2L optimization is the low efficiency due to the lack of predictive method with high accuracy. We described a new computational method called Computational Substitution Optimization (CSO) that has allowed us to rapidly identify compounds with cytochrome bc1 complex inhibitory activity in the nanomolar and subnanomolar range. The comprehensively optimized candidate has proved to be a slow binding inhibitor of bc1 complex, ~73-fold more potent (Ki = 4.1 nM) than the best commercial fungicide azoxystrobin (AZ; Ki = 297.6 nM) and shows excellent in vivo fungicidal activity against downy mildew and powdery mildew disease. The excellent correlation between experimental and calculated binding free-energy shifts together with further crystallographic analysis confirmed the prediction accuracy of CSO method. To the best of our knowledge, CSO is a new computational approach to substitution-scanning mutagenesis of ligand and could be used as a general strategy of H2L optimisation in drug and agrochemical design.

Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method.

Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate "what is the IDM" and "why to use" and "how to use" it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years.

Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis

Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods. The azabicyclic compounds synthesized in this study reside in attractive regions of heterocyclic chemical space that are underexploited in current drug and agrochemical discovery efforts.

ChemInform Abstract: Recent Advances in C—H Fluorination

AbstractReview: 52 refs.

Quantitative estimation of pesticide-likeness for agrochemical discovery.

BackgroundThe design of chemical libraries, an early step in agrochemical discovery programs, is frequently addressed by means of qualitative physicochemical and/or topological rule-based methods. The aim of this study is to develop quantitative estimates of herbicide- (QEH), insecticide- (QEI), fungicide- (QEF), and, finally, pesticide-likeness (QEP).In the assessment of these definitions, we relied on the concept of desirability functions.ResultsWe found a simple function, shared by the three classes of pesticides, parameterized particularly, for six, easy to compute, independent and interpretable, molecular properties: molecular weight, logP, number of hydrogen bond acceptors, number of hydrogen bond donors, number of rotatable bounds and number of aromatic rings. Subsequently, we describe the scoring of each pesticide class by the corresponding quantitative estimate. In a comparative study, we assessed the performance of the scoring functions using extensive datasets of patented pesticides.ConclusionsThe hereby-established quantitative assessment has the ability to rank compounds whether they fail well-established pesticide-likeness rules or not, and offer an efficient way to prioritize (class-specific) pesticides. These findings are valuable for the efficient estimation of pesticide-likeness of vast chemical libraries in the field of agrochemical discovery.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-014-0042-6) contains supplementary material, which is available to authorized users.

Application of the intermediate derivatization approach in agrochemical discovery.

ADVERTISEMENT RETURN TO ISSUEPREVReviewNEXTApplication of the Intermediate Derivatization Approach in Agrochemical DiscoveryAiying Guan†, Changling Liu*†, Xiaoping Yang‡, and Mark Dekeyser§View Author Information† State Key Laboratory of the Discovery and Development of Novel Pesticide, Shenyang Research Institute of Chemical Industry, Shenyang 110021, China‡ Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado Denver Anschutz Medical Center, Aurora, Colorado 80045, United States§ Chemtura Canada, Guelph, ON N1H 6N3, Canada (retired)*Tel.: 86-24-85869078. Fax: 86-24-85869137. E-mail: [email protected]Cite this: Chem. Rev. 2014, 114, 14, 7079–7107Publication Date (Web):May 29, 2014Publication History Received8 October 2013Published online29 May 2014Published inissue 23 July 2014https://doi.org/10.1021/cr4005605Copyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views3496Altmetric-Citations127LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (7 MB) Get e-AlertsSUBJECTS:Agrochemicals,Modification,Pest control,Phenyls,Plant derived food Get e-Alerts

Current Challenges and Trends in the Discovery of Agrochemicals

Crop protection chemistry has come a long way from its "alchemic" beginnings in the late 19th century to a high-tech science that supports the sustainable production of food, feed, and fiber for a rapidly growing population. Cutting-edge developments in the design and synthesis of agrochemicals help to tackle today's challenges of weed and pest resistance, higher regulatory safety margins, and higher cost of goods with the invention of selective, environmentally benign, low use rate, and cost-effective active ingredients.

Bioassay-guided Isolation and Identification of Fungitoxic Coumarins from Angelica dahurica

Bio-prospecting of natural products allows for the discovery of new agrochemicals for pest management and chemistry found from plants used in traditional medicines have often not been evaluated as bio-pesticides. TCM Bai Zhi is the root of Angelica dahurica which has been used as early as 400 BC in Ancient China for the treatment of illnesses such as headaches, nasal obstruction, detoxification of the blood, swollen gums, toothaches, anti-inflammatory, a laxative, sedative, and an anti-fungal cream for skin. The root of A. dahurica is also widely known to contain furanocoumarins. Our preliminary evaluations of several Angelica species were completed in 2012 for antifungal and mosquito deterrent activity. Several species of Angelica were shown to be active. TLC-bioautography with Colletotrichum species as the antifungal detection agents demonstrated that the ethyl acetate extract of A. dahurica showed strong antifungal activity. Current mosquito testing with new plant material failed to show significant biting deterence, or toxicant activity. In order to isolate and identify the antifungal constituents in the root of A. dahurica, a systematic bioassay-guided fractionation of the ethyl acetate extract was performed. Several active fractions were obtained by combining biotage with direct-bioautography. Two coumarins “bergapten (1)” and “suberosin (2)” were isolated from active fractions using biotage and HPLC and the structures were confirmed by 1H and 13C NMR spectroscopic analyses. Other active antifungal fractions are being purified. Our current goal is to test all pure compounds in a micro-dilution broth assay in comparison to bergapten, suberosin and commercial fungicide standards. Development of natural fungicides with low mammalian and environmental toxicity will help guarantee food safety and sustainability of the U.S. and Chinese agricultures.

Identification and Characterization of Herbicide from Pileostegia viburnoides var.glabrescens

Increasing resistance to agrochemicals by insects and plant pathogens and the loss of weed and disease control agents are factors that drive the need to search for new natural product derived plant protestants and agrochemicals. Bio-prospecting natural products allows discovery of new agrochemicals for pest management and chemistry found from plants used worldwide in traditional medicines have not been evaluated as potential bio-pesticides or new plant growth regulators. Pileostegia viburnoides var. glabrescens is a traditional Chinese medicine plant used for treating traumatic injury and fractures. Preliminary evaluations of P. viburnoides var. glabrescens was completed in 2012 for antifungal and herbicidal activity. N-Butanol extract from P. viburnoides var. glabrescens was shown to be active at higher concentrations to Agrostis (monocot) and less active against lettuce (dicots). Several pure compounds were separated by chromatography from n-butanol extract of P. viburnoides var. glabrescens. The pure compound skimmin in the active fractions obtained from n-butanol extract was identified. These fractions and skimmin showed phytotoxic activity against Iceberg lettuce and Agrostis seeds in primary research. Skimmin possessed high seed germination inhibition of monocot species and moderate seed germination inhibition against the dicot species. Therefore, we began a more in-depth evaluation of 8 pure compounds obtained from the active n-butanol extract of P. viburnoides and skimmin. Following natural product leads offers an efficient approach to discovering and optimizing new herbicides for weed management. Due to the continuing development of chemical resistance in agriculture, discovery of new herbicides is an important research objective. Natural product based herbicides with low mammalian and environmental toxicity will help guarantee food safety and sustainability of U.S. and Chinese agriculture.

PTID: an integrated web resource and computational tool for agrochemical discovery

Although in silico drug discovery approaches are crucial for the development of pharmaceuticals, their potential advantages in agrochemical industry have not been realized. The challenge for computer-aided methods in agrochemical arena is a lack of sufficient information for both pesticides and their targets. Therefore, it is important to establish such knowledge repertoire that contains comprehensive pesticides' profiles, which include physicochemical properties, environmental fates, toxicities and mode of actions. Here, we present an integrated platform called Pesticide-Target interaction database (PTID), which comprises a total of 1347 pesticides with rich annotation of ecotoxicological and toxicological data as well as 13 738 interactions of pesticide-target and 4245 protein terms via text mining. Additionally, through the integration of ChemMapper, an in-house computational approach to polypharmacology, PTID can be used as a computational platform to identify pesticides targets and design novel agrochemical products. http://lilab.ecust.edu.cn/ptid/. hlli@ecust.edu.cn; xhqian@ecust.edu.cn Supplementary data are available at Bioinformatics online.

Computational Prediction of Metabolism: Sites, Products, SAR, P450 Enzyme Dynamics, and Mechanisms

Metabolism of xenobiotics remains a central challenge for the discovery and development of drugs, cosmetics, nutritional supplements, and agrochemicals. Metabolic transformations are frequently related to the incidence of toxic effects that may result from the emergence of reactive species, the systemic accumulation of metabolites, or by induction of metabolic pathways. Experimental investigation of the metabolism of small organic molecules is particularly resource demanding; hence, computational methods are of considerable interest to complement experimental approaches. This review provides a broad overview of structure- and ligand-based computational methods for the prediction of xenobiotic metabolism. Current computational approaches to address xenobiotic metabolism are discussed from three major perspectives: (i) prediction of sites of metabolism (SOMs), (ii) elucidation of potential metabolites and their chemical structures, and (iii) prediction of direct and indirect effects of xenobiotics on metabolizing enzymes, where the focus is on the cytochrome P450 (CYP) superfamily of enzymes, the cardinal xenobiotics metabolizing enzymes. For each of these domains, a variety of approaches and their applications are systematically reviewed, including expert systems, data mining approaches, quantitative structure–activity relationships (QSARs), and machine learning-based methods, pharmacophore-based algorithms, shape-focused techniques, molecular interaction fields (MIFs), reactivity-focused techniques, protein–ligand docking, molecular dynamics (MD) simulations, and combinations of methods. Predictive metabolism is a developing area, and there is still enormous potential for improvement. However, it is clear that the combination of rapidly increasing amounts of available ligand- and structure-related experimental data (in particular, quantitative data) with novel and diverse simulation and modeling approaches is accelerating the development of effective tools for prediction of in vivo metabolism, which is reflected by the diverse and comprehensive data sources and methods for metabolism prediction reviewed here. This review attempts to survey the range and scope of computational methods applied to metabolism prediction and also to compare and contrast their applicability and performance.

Immunosuppressive Polyketides from Mantis-Associated Daldinia eschscholzii

Polyketides with unknown architectures are highly desired for the discovery of new drugs and agrochemicals. Here, the mantis-associated Daldinia eschscholzii, a fungus known to produce immunosuppressants dalesconols A and B, was found to simultaneously generate four novel skeletons capable of shaping the unusual chemistry of the fungal polyketides, of which seven were structurally unique and substantially immunosuppressive. In particular, the scaled-up fermentation of the microbe enabled the structural characterization of minor or "transitional" intermediate polyketides that allowed the reasonable recognition of the four biosynthetic pathways initiated by condensations of four, five, six and eight acetate units, respectively. Furthermore, the decarbonylation reaction of triketone, as in the case of daeschol A, was described for the first time, in addition to the structural correction of sporothrin C and nodulone. The work provided a set of novel immunosuppressive molecules that are of significance to drug discovery.

10th international symposium on the synthesis and applications of isotopes and isotopically labelled compounds—applications of isotopes in agriculture, nutrition and environmental research Session 11, Wednesday, June 17, 2009

AbstractThe preparation of carbon‐14 labeled compounds and their use in discovery and development of agrochemicals was discussed. Copyright © 2010 John Wiley & Sons, Ltd.

ChemInform Abstract: Synthetic Development for the Discovery of Novel Heterocyclic Agrochemicals

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Temporally resolved GC-MS-based metabolic profiling of herbicide treated plants treated reveals that changes in polar primary metabolites alone can distinguish herbicides of differing mode of action

We conducted a comprehensive metabolic phenotyping of primary metabolism of photosynthetic tissue of Arabidopsis thaliana following spray treatment with a number of commercially used herbicides using a well established gas-chromatography mass-spectrometry profiling method. Applying this technique we were able to identify and quantify in excess of 80 polar metabolites and based on a combination of co-elution with standards and prediction from the mass spectra a similar number of lipophillic components within two chromatographic runs. The herbicides selected were glufosinate, sulcotrione, AE944 [N2-(1-ethyl-3-phenylpropyl)-6-(1-fluoro-1-methylethyl)-1,3,5-triazine-2,4-diamine], foramsulfuron, benfuresate and glyphosate. We determined causal changes in the metabolite profiles by following their time-dependent changes using a serial sampling strategy. The resultant profiles were compared both by looking at the largest changes in a metabolite by metabolite manner and by performance of statistical analyses. These data revealed that analysis of the polar metabolites allows clear separation of the compounds under test. This finding is discussed in the context of current strategies for agrochemical discovery.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-008-0149-8) contains supplementary material, which is available to authorized users.

Studies on the synthetic development for the discovery of novel heterocyclic agrochemicals

Various heterocyclic compounds have significantly contributed to current commercial agrochemicals. We focused our attention on these heterocycles as screening targets to create novel bioactive compounds. Although recent progress in agrochemical research has enabled us to discover drugs directly, we selected a chemical approach to N- and N,S-heterocyclic compounds in an expectation of new chemical classes with biological activity. In consequence, this method led to the generation of four heterocycles which had either herbicidal or fungicidal activity. These heterocycles were extended to optimized compounds, resulting in the discovery of three herbicides (2,4-diphenylpyrimidine, 2-acylimino-1,3-thiazoline and 5-trifluoromethylpyridazinone) and one fungicide (2-pyridylpyrimidine).