EditedbyPeterJeschke,WolfgangKra¨mer, UlrichSchirmer,andMatthiasWitschel ModernMethodsinCropProtection Research RelatedTitles Kra¨mer,W.,Schirmer,U.,Jeschke,P., Walters,D. Witschel,M.(eds.) PlantDefense Modern CropProtection Wardingoffattackbypathogens, Compounds herbivoresandparasiticplants 2012 2010 ISBN:978-3-527-32965-6 ISBN:978-1-4051-7589-0 Filho,V.C. Tadros,T.F.(ed.) PlantBioactives andDrug Colloids inAgrochemicals Discovery ColloidsandInterfaceScience Principles,Practice,andPerspectives Volume5oftheColloidsandInterfaceScience Series 2012 2009 ISBN:978-0-470-58226-8 ISBN:978-3-527-31465-2 Edited by Peter Jeschke, Wolfgang Kra¨mer, Ulrich Schirmer, and Matthias Witschel Modern Methods in Crop Protection Research TheEditors AllbookspublishedbyWiley-VCHare carefullyproduced.Nevertheless,authors, Dr.PeterJeschke editors,andpublisherdonotwarrantthe BayerCropScienceAG informationcontainedinthesebooks, BCSAG-R&D-CPR-PC-PCC-Chemistry2 includingthisbook,tobefreeoferrors. Bldg.6510 Readersareadvisedtokeepinmindthat Alfred-Nobel-Str.50 statements,data,illustrations,procedural 40789Monheim detailsorotheritemsmayinadvertentlybe Germany inaccurate. Dr.WolfgangKra¨mer LibraryofCongressCardNo.:appliedfor Rosenkranz25 51399Burscheid BritishLibraryCataloguing-in-Publication Germany Data Acataloguerecordforthisbookisavailable Dr.UlrichSchirmer fromtheBritishLibrary. Berghalde79 69126Heidelberg Bibliographicinformationpublishedbythe Germany DeutscheNationalbibliothek TheDeutscheNationalbibliothek Dr.MatthiasWitschel liststhispublicationintheDeutsche BASFSE Nationalbibliografie;detailedbibliographic GVA/HC-B009 dataareavailableontheInternetat 67056Ludwigshafen <http://dnb.d-nb.de>. Germany 2012Wiley-VCHVerlag&Co.KGaA, Boschstr.12,69469Weinheim,Germany Allrightsreserved(includingthoseof translationintootherlanguages).Nopart ofthisbookmaybereproducedinany form–byphotoprinting,microfilm,orany othermeans–nortransmittedortranslated intoamachinelanguagewithoutwritten permissionfromthepublishers.Registered names,trademarks,etc.usedinthisbook, evenwhennotspecificallymarkedassuch, arenottobeconsideredunprotectedbylaw. Composition LaserwordsPrivateLtd., Chennai,India PrintingandBinding MarkonoPrintMedia PteLtd,Singapore CoverDesign Formgeber,Eppelheim PrintISBN:978-3-527-33175-8 ePDFISBN:978-3-527-65593-9 ePubISBN:978-3-527-65592-2 mobiISBN:978-3-527-65591-5 oBookISBN:978-3-527-65590-8 PrintedinSingapore Printedonacid-freepaper V Contents Preface XV ListofContributors XIX PartI MethodsfortheDesignandOptimization ofNewActiveIngredients 1 1 High-ThroughputScreeninginAgrochemicalResearch 3 MarkDrewes,KlausTietjen,andThomasC.Sparks 1.1 Introduction 3 1.2 Target-BasedHigh-ThroughputScreening 6 1.2.1 Targets 6 1.2.2 High-ThroughputScreeningTechniques 9 1.3 OtherScreeningApproaches 13 1.3.1 High-ThroughputVirtualScreening 13 1.4 InVivoHigh-ThroughputScreening 13 1.4.1 CompoundSourcingandIn-SilicoScreening 15 1.5 Conclusions 17 Acknowledgments 18 References 18 2 ComputationalApproachesinAgriculturalResearch 21 Klaus-Ju¨rgenSchleifer 2.1 Introduction 21 2.2 ResearchStrategies 21 2.3 Ligand-BasedApproaches 22 2.4 Structure-BasedApproaches 26 2.5 EstimationofAdverseEffects 33 2.6 In-SilicoToxicology 34 2.7 ProgramsandDatabases 34 2.7.1 In-SilicoToxicologyModels 36 VI Contents 2.8 Conclusion 39 References 40 3 QuantumChemicalMethodsintheDesignofAgrochemicals 43 MichaelSchindler 3.1 Introduction 43 3.2 ComputationalQuantumChemistry:Basics,Challenges, andNewDevelopments 44 3.3 MinimumEnergyStructuresandPotentialEnergySurfaces 47 3.4 Physico-ChemicalProperties 51 3.4.1 ElectrostaticPotential,FukuiFunctions,andFrontierOrbitals 53 3.4.2 MagneticProperties 55 3.4.3 pKaValues 57 3.4.4 SolvationFreeEnergies 59 3.4.5 AbsoluteConfigurationofChiralMolecules 60 3.5 QuantitativeStructure-ActivityRelationships 60 3.5.1 PropertyFields,Wavelets,andMulti-ResolutionAnalysis 61 3.5.2 TheCoMFASteroidDataset 63 3.5.3 ANeonicotinoidDataset 64 3.6 Outlook 66 References 67 4 TheUniqueRoleofHalogenSubstituentsintheDesign ofModernCropProtectionCompounds 73 PeterJeschke 4.1 Introduction 73 4.2 TheHalogenSubstituentEffect 75 4.2.1 TheStericEffect 76 4.2.2 TheElectronicEffect 78 4.2.2.1 ElectronegativitiesofHalogensandSelectedElements/Groups onthePaulingScale 78 4.2.2.2 EffectofHalogenPolarityoftheC–HalogenBond 79 4.2.2.3 EffectofHalogensonpK Value 79 a 4.2.2.4 ImprovingMetabolic,Oxidative,andThermalStability withHalogens 80 4.2.3 EffectofHalogensonPhysico-ChemicalProperties 82 4.2.3.1 EffectofHalogensonMolecularLipophilicity 82 4.2.3.2 ClassificationintheDisjointPrincipleSpace 84 4.2.4 EffectofHalogensonShiftofBiologicalActivity 84 4.3 InsecticidesandAcaricidesContainingHalogens 86 4.3.1 Voltage-GatedSodiumChannel(vgSCh)Modulators 86 4.3.1.1 Pyrethroidsof TypeA 86 4.3.1.2 Pyrethroidsof TypeB 89 Contents VII 4.3.1.3 Pyrethroidsof TypeC 90 4.3.2 Voltage-GatedSodiumChannel(vgSCh)Blockers 90 4.3.3 Inhibitorsoftheγ-AminobutyricAcid(GABA)Receptor/Chloride IonophoreComplex 91 4.3.4 InsectGrowthRegulators(IGRs) 93 4.3.5 MitochondrialRespiratoryChain 96 4.3.5.1 InhibitorsofMitochondrialElectronTransportatComplexI 96 4.3.5.2 InhibitorsofQ SiteofCytochromebc1– ComplexIII 97 o 4.3.5.3 InhibitorsofMitochondrialOxidativePhosphorylation 97 4.3.6 RyanodineReceptor(RyR)Effectors 98 4.4 FungicidesContainingHalogens 99 4.4.1 SterolBiosynthesisInhibitors(SBIs)andDemethylationInhibitors (DMIs) 99 4.4.2 MitochondrialRespiratoryChain 101 4.4.2.1 InhibitorsofSuccinateDehydrogenase(SDH)– ComplexII 101 4.4.2.2 InhibitorsofQ SiteofCytochromebc1– ComplexIII 104 o 4.4.2.3 NADHInhibitors – ComplexI 107 4.4.3 FungicidesActingonSignalTransduction 107 4.5 PlantGrowthRegulators(PGRs)ContainingHalogens 108 4.5.1 ReductionofInternodeElongation:InhibitionofGibberellin Biosynthesis 108 4.6 HerbicidesContainingHalogens 109 4.6.1 InhibitorsofCarotenoidBiosynthesis:PhytoeneDesaturase(PDS) Inhibitors 109 4.6.2 InhibitorsofAcetolactateSynthase(ALS) 111 4.6.2.1 SulfonylureaHerbicides 111 4.6.2.2 Sulfonylaminocarbonyl-TriazoloneHerbicides(SACTs) 115 4.6.2.3 TriazolopyrimidineHerbicides 116 4.6.3 ProtoporphyrinogenIXOxidase(PPO) 117 4.7 SummaryandOutlook 119 References 119 PartII NewMethodstoIdentifytheModeofAction ofActiveIngredients 129 5 RNAInterference(RNAi)forFunctionalGenomicsStudies andasaToolforCropProtection 131 BerndEssigmann,EricPaget,andFre´de´ricSchmitt 5.1 Introduction 131 5.2 RNASilencingPathways 131 5.2.1 TheMicroRNA(miRNA)Pathway 133 5.2.2 TheSmallInterferingPathway(siRNA) 134 5.3 RNAiasaToolforFunctionalGenomicsinPlants 134 VIII Contents 5.4 RNAiasaToolforEngineeringResistanceagainstFungi andOomycetes 138 5.5 RNAiasaToolforEngineeringInsectResistance 140 5.6 RNAiasaToolforEngineeringNematodesResistance 142 5.7 RNAiasaToolforEngineeringVirusResistance 144 5.8 RNAiasaToolforEngineeringBacteriaResistance 149 5.9 RNAiasaToolforEngineeringParasiticWeedResistance 150 5.10 RNAiSafetyinCropPlants 153 5.11 SummaryandOutlook 153 References 153 6 FastIdentificationoftheModeofActionofHerbicides byDNAChips 161 PeterEckesandMarcoBusch 6.1 Introduction 161 6.2 GeneExpressionProfiling:AMethodtoMeasureChanges oftheCompleteTranscriptome 162 6.3 ClassificationoftheModeofActionofanHerbicide 164 6.4 IdentificationofProdrugsbyGeneExpressionProfiling 165 6.5 AnalyzingtheAffectedMetabolicPathways 169 6.6 GeneExpressionProfiling:PartofaToolboxforModeofAction Determination 171 References 172 7 ModernApproachesforElucidatingtheModeofAction ofNeuromuscularInsecticides 175 DanielCordova 7.1 Introduction 175 7.2 BiochemicalandElectrophysiologicalApproaches 176 7.2.1 BiochemicalStudies 176 7.2.2 ElectrophysiologicalStudiesonNativeandExpressedTargets 179 7.2.2.1 Whole-CellVoltageClampStudies 179 7.2.2.2 OocyteExpressionStudies 180 7.2.3 AutomatedTwo-ElectrodeVoltage-ClampTEVCRecording Platforms 182 7.3 Fluorescence-BasedApproachesforModeofActionElucidation 183 7.3.1 Calcium-SensitiveProbes 183 7.3.2 Voltage-SensitiveProbes 186 7.4 GenomicApproachesforTargetSiteElucidation 187 7.4.1 Chemical-to-GeneScreening 187 7.4.2 Double-StrandedRNAInterference 190 7.4.3 Metabolomics 191 Contents IX 7.5 Conclusion 191 References 192 8 NewTargetsforFungicides 197 KlausTietjenandPeterH.Schreier 8.1 Introduction:CurrentFungicideTargets 197 8.2 ARetrospectiveLookattheDiscoveryofTargetsforFungicides 199 8.3 NewSourcesforNewFungicideTargetsintheFuture? 199 8.4 MethodstoIdentifyaNovelTargetforaGivenCompound 200 8.4.1 MicroscopyandCellularImaging 200 8.4.2 CultivationonSelectiveMedia 200 8.4.3 IncorporationofIsotopicallyLabeledPrecursors andMetabolomics 201 8.4.4 AffinityMethods 201 8.4.5 ResistanceMutantScreening 201 8.4.6 GeneExpressionProfilingandProteomics 202 8.5 MethodsofIdentifyingNovelTargetswithoutPre-Existing Inhibitors 202 8.5.1 BiochemicalIdeastoGenerateNovelFungicideTargets 203 8.5.2 GenomicsandProteomics 203 8.6 Non-ProteinTargets 213 8.7 ResistanceInducers 213 8.8 BeneficialSideEffectsofCommercialFungicides 214 8.9 ConcludingRemarks 214 References 214 PartIII NewMethodstoImprovetheBioavailability ofActiveIngredients 217 9 NewFormulationDevelopments 219 RolfPontzenandArnoldusW.P.Vermeer 9.1 Introduction 219 9.2 DriversforFormulationTypeDecisions 223 9.3 DescriptionofFormulationTypes,TheirProperties,andProblems duringDevelopment 225 9.3.1 PesticidesDissolvedinaLiquidContinuousPhase 225 9.3.2 CrystallinePesticidesinaLiquidContinuousPhase 228 9.3.3 PesticidesinaSolidMatrix 232 9.4 BioavailabilityOptimization 235 9.4.1 SprayFormationandRetention 236 9.4.2 SprayDepositFormationandProperties 238 9.4.3 CuticularPenetration 240 9.4.3.1 CuticularPenetrationTest 242