Environment-Friendly Antiviral Agents for Plants

　　Plant virus disease is a worldwide threat to agriculture.
Environment-
　　Friendly Antiviral Agents for Plants systematically describes the
basic
　　theory, new ideas, and new methods to discover novel antiviral
agents through research on plant immune activation. The
cutting-edge research methodology, technology and progress on novel
antiviral agent innovation are systematically described. With
abundant illustrations and figures, the book is intended for
researchers and practitioners in the fields of pesticide science,
plant protection, organic chemistry, fine chemicals, applied
chemistry, environment chemistry and agriculture science.
　　Dr. Baoan Song and Dr. Song Yang are professors at the Center for
R&D of Fine Chemicals, Guizhou University, China; Mr. Linhong
lin and Dr. Pinaki S. Bhadury are associate professors there.

Introduction
1 Studies on ?-Aminophosphonates with Antiviral Activity
1.1 Organocatalytic Synthesis and Antiviral Activity of Asymmetric
a-Aminophosphonates
1.1.1 Introduction
1.1.2 Materials and Methods
1.1.3 Results and Discussion
1.1.4 Conclusions
1.2 Synthesis & Bioactivity of ?-Aminophosphonates Containing
Amide Moiety
1.2.1 Introduction
1.2.2 Materials and Methods
1.2.3 Results and Discussion
1.2.4 Conclusions
1.3 Green Synthesis & Bioactivity of ?-Aminophosphonates
Containing an Alkoxyethyl Moiety
1.3.1 Introduction
1.3.2 Materials and Methods
1.3.3 Results and Discussion
1.3.4 Conclusions
1.4 Green Synthesis & Bioactivity of Brominated
?-Aminophosphonates
1.4.1 Introduction
1.4.2 Materials and Methods
1.4.3 Results and Discussion
1.4.4 Conclusions
1.5 Synthesis & Bioactivity of ?-Aminophosphonates
Containing
Trifluorinated Methyl Moiety
1.5.1 Introduction
1.5.2 Materials and Methods
1.5.3 Results and Discussion
1.5.4 Conclusions
1.6 Synthesis & Bioactivity of Chiral ?-Aminophosphonates
Containing Fluorine Moiety
1.6.1 Introduction
1.6.2 Materials and Methods
1.6.3 Results and Discussion
1.6.4 Conclusions
1.7 Green Synthesis of ?-Aminophosphonates Containing Bromine and
Fluorine under Ultrasonic Irradiation
1.7.1 Introduction
1.7.2 Materials and Methods
1.7.3 Results and Discussion
1.7.4 Conclusions
1.8 Synthesis & Bioactivity of ?-Aminophosphonates
Containing
Isoxazole Moiety
1.8.1 Introduction
1.8.2 Materials and Methods
1.8.3 Results and Discussion
1.8.4 Conclusions
1.9 Synthesis & Bioactivity of ?-Aminophosphonates Containing
Benzothiazole Moiety
1.9.1 Introduction
1.9.2 Materials and Methods
1.9.3 Results and Discussion
1.9.4 Conclusions
1.10 Chiral Separation & Bioactivity of ?-Aminophosphonates
Containing Benzothiazole Moiety
1.10.1 Introduction
1.10.2 Materials and Methods
1.10.3 Results and Discussion
1.10.4 Conclusions
1.11 Crystal Structure of O,O-Dipropyl-?-aminophosphonate
Containing Benzothiazole Moiety
1.11.1 Introduction
1.11.2 Materials and Methods
1.11.3 Results and Discussion
References
2 Synthesis, Characterization and Antiviral Activity of
Cyanoacrylates and Derivatives
2.1 Synthesis and Antivival Activity of Cyanoacrylates Containing
Phosphonyl Moiety
2.1.1 Introduction
2.1.2 Materials and Methods
2.1.3 Results and Discussion
2.1.4 Conclusions
2.2 Synthesis and Bioactivity of Cyanoacrylate Derivatives
Containing Pyridine Moiety
2.2.1 Introduction
2.2.2 Materials and Methods
2.2.3 Results and Discussion
2.2.4 Conclusions
2.3 Preparation of Chiral Cyanoarylate Derivatives under Microwave
Irradiation
2.3.1 Introduction
2.3.2 Materials and Methods
2.3.3 Results and Discussion
2.3.4 Conclusions
2.4 Preparation of Chiral Cyanoacylate Derivatives from
Phenylethanamine
2.4.1 Introduction
2.4.2 Materials and Methods
2.4.3 Results and Discussion
2.4.4 Conclusions
2.5 Preparation and Antiviral Activity of Chiral Cyanoacylate
Derivatives from Aryl (Heterocyclic) Amine
2.5.1 Introduction
2.5.2 Materials and Methods
2.5.3 Chemistry
2.5.4 Antiviral Activity
2.5.5 Discussion
2.5.6 Conclusions
2.6 Preparation and Antiviral Activity of Chiral Cyanoacylate
Derivatives Containing ?-Aminophosphonate Moiety
2.6.1 Introduction
2.6.2 Materials and Methods
2.6.3 Results and Discussion
2.6.4 Conclusions
2.7 Crystal Structure elucidation of Cyanoacrylates
2.7.1 Crystal Structure of
(E)-Ethyl-3-[(S)-1-phenylethylamino]-3-[4-(trifluoromethyl)-
phenylamino]-2-cyanoacrylate
2.7.2 Characterization of Two Chiral Isomers of (E)-Ethyl-3-[(R) or
(S)-1-phenylethyl
amino]-3-[4-nitrophenylamino]-2-cyanoacrylate
References
3 Synthesis and Antiviral Activity of Chiral Thiourea
Derivatives
3.1 Chiral Thiourea Deravatives from Primary Amine and
Isocyanate
3.1.1 Introduction
3.1.2 Materials and Methods
3.1.3 Results and Discussion
3.1.4 Conclusions
3.2 Chiral Thiourea Derivatives Containing ?-Aminophosphonate
Moiety
3.2.1 Introduction
3.2.2 Materials and Methods
3.2.3 Results and Discussion
3.2.4 Conclusions
References
4 The Heterocyclic Antiviral Agents
4.1 Pyrazole Derivatives Containing Oxime Ester Moiety
4.1.1 Introduction
4.1.2 Materials and Methods
4.1.3 Chemistry
4.1.4 Antiviral Activity
4.1.5 Discussion
4.1.6 Conclusions
4.2 Pyrazole Derivatives Containing Oxime Ether Moiety
4.2.1 Introduction
4.2.2 Materials and Methods
4.2.3 Results and Discussion
4.2.4 Conclusions
4.3 Quinazolinone Derivatives
4.3.1 Introduction
4.3.2 Materials and Methods
4.3.3 Results and Discussion
4.3.4 Conclusions
References
5 Innovation and Application of Environment-Friendly Antiviral
Agents for Plants
5.1 Innovation of New Antiviral Agent Dufulin[N-[2-(4-methyl-
benzothiazol)]-2-ylamino-2-fluophenyl-O,O-diethyl
phosphonate]
5.1.1 Product Chemistry
5.1.2 Formulation of Dufulin
5.1.3 Optimization of Synthetic Conditions in Lab Scale and Pilot
Scale
5.1.4 Toxicology Test
5.1.5 Field Trials
5.1.6 Pesticide Residue
5.1.7 Environmental toxicology
5.1.8 Mode of Action
References
5.1.9 Photolysis and Hydrolysis
5.1.10 Systemic Behaviors
References
5.2 GU188, 2-Cyanoacrylate Derivative, Candidate Antiviral
Agent
5.2.1 Synthesis
5.2.2 Analytical Method
5.2.3 Bioassays and Field Trials
5.2.4 Toxicological Test
5.2.5 Action Mechanism
5.3 Studies on the Development of Novel Amino-oligosaccharide
5.3.1 Introduction
5.3.2 Anti-TMV and Mechanism of Action
5.3.3 Industrialization
Index

Plantviruses,generallyknownas“cancerofplant”,areresponsibleforthemostcommondiseasesoccurringinthemainagriculturecropsaswellasvegetableandtobaccothatleadtoseriousdamageandenormouseconomicloss.Inordertoprotecttheplantfromthevirusdisease,variousmethodshavebeendeveloped,includingcroprotation,viruseradication,mildstraincrossprotection(MSCP),virustransmissioncontrol,applicationofantivirusagentsandnewlyemerginggeneticallyantivirusmodifiedcrops.However,damagefromplantviruscannotbeavoidedeffectivelydespitetakingreasonablemeasures.Theuseoftraditionalchemicalpesticides,ontheotherhand,maybringaboutadisastrousimpactonourenvironment.Thus,thecontinuousresearchanddevelopmentofenvironment-friendlyantivirusagentsforfieldapplicationhavebecomeanimportantendeavorforthescientistsengagedinplantprotection.Theauthorscarriedouttenyearsofresearchaimingatdiscoveringnovelgreenantiviralagentsforplantsandsuccessfullyfoundsomenewcompoundswithexcellentantivirusbioactivity.AftercompletingsystematicR&Dwork,onebrandofnewcompoundwasindustrializedandappliedinthefieldwithexcellentprotectioneffectthusavoidinghugeeconomiclossduetothegreatdamagecausedbyplantvirus.Interestinglyenough,itwasfoundtoexertitsfunctionthroughnewmechanismofactivatingplantimmunesystem.

Asmimicsofnaturalaminoacids,thesynthesisandbiologicalstudiesofaminophosphonicacidsandtheiresterderivativeshaveattractedwideattentioninrecentyears.Previousresearchdemonstratedthatsomeaminophosphonatesareassociatedwithantiviral,growth-regulatoryandantifungalactivities.Takingaminophosphonicacidastheleadcompoundforoptimizationstudies,morethanonethousandcompoundsweredesignedandsynthesizedbyusamongwhichDufulin(Bingduxing)wasidentifiedasoneofthepotentialstructureswithoutstandingantiviralactivity.Systematicresearcheswereconductedfrombasiclabresearchtofieldtrialaswellasfieldapplicationincludinglabbioassay,compoundsynthesisoptimization,fieldbioassaytrial,residualanalysis,toxicityevaluation,andenvironmentalbehaviorstudiesthatfinallypavedthewaytotheregistrationofnewpesticideDufulinasanewmolecularantivirusagentapprovedbytheMinistryofAgriculture.TheintellectualpropertyofDufulinaswellasitsusagewasapprovedbyStateIntellectualPropertyOfficeofChina(SIPO).Besidesstudyingitsapplication,basicresearchonthemodeofactionofDufulinwasalsocarriedoutanditwasfoundthatDufulinexertsitsfunctionthroughanewmechanismbyactivatingtheplantimmunesystem.Theobservationswere:(1)Itisassociatedwiththetobaccoresistanceenzymesandcouldcauseaggregationofthevirusparticletherebyreducingtheinfectingabilityofthevirus.(2)Thisantiviralagentcanalsoupregulatetheexpressionoftobaccopathogenesis-relatedproteinsPR-1andPR-5.(3)Theanti-TMVbioactivityofDufulinisassociatedwiththeinductionofcysteamineacidsynthaseinchloroplast,followedbyactivatingthesalicylicacidsignalingpathwayandthusconferringtheplantthesystematicallyacquiredresistance.

Cyanoacrylates,includedinourstudies,havebeentraditionallyconsideredas
herbicidesactingasPhotosystemⅡInhibitors.Ourresearchshowedthatthesecompoundsalsohavegoodanti-TMVactivitiesandareworthinvestigatingfor

theirpotentialtobeemployedasgreenantiviralagentsinfuture.Inaddition,somemorepromisingresultswereobtainedfromtheresearchofchiralthioureasandhetercycliccompoundscarriedoutinourcenter.

Althoughthereisnodearthwithregardtothescientificinformationoravailabilityintermsoftextbooksinthefieldofsyntheticpesticidesandtheirroleincropprotection,noneofthemdealswiththechemistryofgreenantiviralagentsforplants.

Inthecontextofthepresentinadequacyofprofessionalbookavailableontheanti-viralagents,wemadebestefforttoinvestigatethisrelativelyunexploredareaandsummarizeourfindingsintheformofacomprehensivetextbook.ThepresenteditionofEnvironment-FriendlyAntiviralAgentsforPlantshasbeenwrittenwithanideatokeepuppacewiththerecentprogressmadeinthefieldofenvironmentallybenignantiviralagentsforplantsandencompassesfivespecificdirectionsthatcouldopennewavenuesforthetreatmentofplantvirusdiseases.

Therearefivechaptersinthisbook.Chapter1describesthesynthesisandantiviralactivityof?-aminophosphonates.Chapter2introducesthesynthesisandantiviralactivityofcyanoacrylates.Chapter3talksaboutchiralthioureaantiviralagents.Chapter4discussestheheterocyclicantiviralagents,andChapter5introducestheinnovationandapplicationofenvironment-friendlyantiviralagentforplants,especiallythenovelantiviralchemicalforplantsentityDufulin,anewantiviralagentthatwasgrantedthetemporaryregistrationbytheMinistryofAgricultureofChina.Wemadebestpossibleefforttointroducetheresear