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1、CHEMMEDCHEMFULLPAPERSDOI:10.1002/cmdc.201300114SynthesisandinvitroEvaluationofWestNileVirusProteaseInhibitorsBasedonthe2-{6-[2-(5-Phenyl-4H-{1,2,4]triazol-3-ylsulfanyl)acetylamino]benzothiazol-2-ylsulfanyl}acetamideScaffold[a]SanjaySamanta,TingLiangLim,andYulinLam*Inre
2、centyears,clinicalsymptomsresultingfromWestNilebenzothiazol-2-ylsulfanyl}acetamidescaffoldwasidentifiedvirus(WNV)infectionhaveworsenedinseverity,withanin-duringscreening.Optimizationofthisinitialhitbysynthesiscreasedfrequencyinneuroinvasivediseasesamongtheelderly.andsc
3、reeningofafocusedcompoundlibrarywiththisscaffoldAstherearepresentlynosuccessfultherapiesagainstWNVforledtotheidentificationofanoveluncompetitiveinhibitoruseinhumans,continualeffortstodevelopnewchemothera-(1a24,IC50=3.40.2mm)oftheWNVNS2B-NS3protease.Mo-peuticsagainstth
4、isvirusarehighlydesired.TheviralNS2B-leculardockingof1a24intotheWNVproteaseshowedthatNS3proteaseisapromisingtargetforviralinhibitionduetothecompoundinterfereswithproductiveinteractionsoftheitsimportanceinviralreplicationanditsuniquesubstratepref-NS2BcofactorwiththeNS3p
5、roteaseandisanallostericinhibi-erence.Inthisstudy,aWNVNS2B-NS3proteaseinhibitorwithtoroftheWNVNS3protease.a2-{6-[2-(5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)acetylamino]-IntroductionTheWestNilevirus(WNV),aneurotropicFlavivirus,isamosqui-blycleavespeptidesubstratesattheC
6、-terminus,whichhasto-borne,reemergingpathogencausingoutbreaksonmultipleapairofbasicaminoacids(ArgandLys)attheP1andP2posi-[1][6]continents.TheclinicalmanifestationsofWNV-infectedtions.Site-directedmutagenesisstudieshaveshownthatmu-humansvarysignificantly,fromasymptomati
7、ctothedevelop-tationofessentialcatalyticresiduesontheNS3proteasecleav-mentofsevereneuroinvasivediseasessuchasmeningitis,flac-agesitesleadtoahaltinviralinfectivity.ThisdibasicP2/P1re-[2]cidparalysis,andencephalitis.Closefollow-upwithWNV-in-quirementforsubstraterecogniti
8、onindicatesthattheNS2B-fectedhumanshaveshownthatpatientswhomanifestsymp-NS3proteasecouldbeanattractivetherapeutictarg
