作为FABP45抑制剂喹啉类化合物的设计合成与生物活性研究（英文）

作为FABP45抑制剂喹啉类化合物的设计合成与生物活性研究（英文）Title:Design,Synthesis,andBiologicalActivityStudyofQuinolineCompoundsasFABP4/5InhibitorsAbstract:Fattyacid-bindingproteins4and5(FABP4/5)haveemergedaspotentialtherapeutictargetsforvariousmetabolicdiseases,includingobesity,type2diabetes,andcardiovasculardiseases.Inthisstudy,weaimedtodesignandsynthesizeaseriesofquinolinecompoundsasFABP4/5inhibitorsandevaluatetheirbiologicalactivity.Introduction:FABP4/5arecytoplasmicproteinsthatplayacriticalroleinthetransportandmetabolismoffattyacids.InhibitionofFABP4/5hasshownpromisingresultsinpreclinicalstudies,indicatingtheirpotentialastherapeutictargetsformetabolicdiseases.Quinolinecompoundshavebeenreportedtopossessdiversebiologicalactivities,makingthemattractivescaffoldsfordrugdevelopment.Methods:Aseriesofquinolinederivativesweredesignedandsynthesizedusingestablishedsyntheticmethods.Thecompoundswerecharacterizedusingspectroscopictechniquessuchasnuclearmagneticresonance(NMR)andmassspectrometry(MS).TheinhibitoryactivityofthesynthesizedcompoundsagainstFABP4/5wasevaluatedusinginvitroandinvivoassays.Results:Alibraryofquinolinecompoundswassuccessfullysynthesized,andtheirstructureswereconfirmedbyNMRandMSanalysis.InvitroevaluationrevealedthatseveralcompoundsshowedpotentinhibitoryactivityagainstFABP4/5,withIC50valuesrangingfromnanomolartolowmicromolarconcentrations.Structure-activityrelationship(SAR)analysiswasconductedtoidentifykeystructuralfeaturesresponsiblefortheinhibitoryactivity.Furthermore,selectedcompoundswereevaluatedinananimalmodelofmetabolicdiseases.Treatmentwiththeleadcompoundresultedinsignificantimprovementsinmetabolicparameters,includingreducedbodyweight,improvedglucosetolerance,anddecreasedserumtriglyceridelevels.Conclusion:Inthisstudy,wesuccessfullydesignedandsynthesizedaseriesofquinolinederivativesasFABP4/5inhibitors.ThecompoundsexhibitedpotentinhibitoryactivityagainstFABP4/5andshowedpromisingtherapeuticpotentialforthetreatmentofmetabolicdiseases.OurfindingsprovidevaluableinsightsintothedesignanddevelopmentofnovelFABP4/5inhibitorsforfuturedrugdiscoveryefforts.Keywords:FABP4/5,quinolinecompounds,design,synthesis,biologicalactivityIntroduction(150words):Fattyacid-bindingproteins4and5(FABP4/5)areintracellularproteinsthatplayacrucialroleinthecellularuptakeandutilizationoffattyacids.AbnormalregulationofFABP4/5expressionandactivityhasbeenassociatedwithvariousmetabolicdisorders,includingobesity,insulinresistance,type2diabetes,andcardiovasculardiseases.Therefore,inhibitingFABP4/5activityhasgainedconsiderableattentionasapotentialtherapeuticstrategyforthetreatmentofthesediseases.Quinolinecompounds,characterizedbyabenzeneringfusedtoapyridinering,haveexhibiteddiversebiologicalactivities,includinganticancer,anti-inflammatory,andantibacterialproperties.SeveralquinolinederivativeshavebeenidentifiedaspotentialFABP4/5inhibitorsthroughvirtualscreeningandmoleculardockingstudies.However,furtherinvestigationandoptimizationofthesecompoundsarerequiredtoenhancetheirpotencyandselectivity.Methods(300words):Thedesignandsynthesisofaseriesofquinolinecompoundswerecarriedoutfollowingestablishedsyntheticroutes.Thestartingmaterialforthesynthesiswascommerciallyavailableandreadilyaccessible.Thedesiredmodificationswereachievedthroughwell-establishedsyntheticmethods,includingsubstitutionreactions,condensations,andcyclizations.Characterizationofthesynthesizedcompoundswasdoneusingnuclearmagneticresonance(NMR)spectroscopyandmassspectrometry(MS).NMRspectrawereobtainedonahigh-fieldNMRspectrometer,andthechemicalshiftswerereferencedtotheresidualsolventpeaks.MSanalysiswasperformedusingelectrosprayionizationtechnique,andthespectrawererecordedinthepositivemode.TheinhibitoryactivityofthesynthesizedcompoundsagainstFABP4/5wasevaluatedusinginvitroandinvivoassays.InvitroevaluationwasconductedusingrecombinantFABP4/5proteinsandafluorescentfattyaciddisplacementassay.Thecompoundswereincubatedwiththeproteins,andthedisplacementofafluorescentfattyacidprobewasmeasuredusingfluorescencespectroscopy.IC50valuesweredeterminedasameasureofinhibitoryactivity.Selectedcompoundsexhibitingpotentinhibitoryactivitywerefurtherevaluatedinananimalmodelofmetabolicdiseases.Theanimalstudywasconductedfollowingethicalguidelinesandwiththeapprovaloftherelevantauthorities.Animalsweretreatedwiththeleadcompound,andmetabolicparameterssuchasbodyweight,glucosetolerance,andserumlipidlevelsweremonitored.Results(500words):Alibraryofquinolinederivativeswassuccessfullysynthesizedusingastepwisesyntheticapproach.ThestructuresofthecompoundswereconfirmedbyNMRandMSanalysis.TheNMRspectradisplayedcharacteristicsignalscorrespondingtothequinolinescaffold,andMSanalysisprovidedmolecularweightconfirmationforeachcompound.ThesynthesizedcompoundswerescreenedfortheirinhibitoryactivityagainstFABP4/5usingthefluorescentfattyaciddisplacementassay.Initialscreeningrevealedthatseveralcompoundsexhibitedpotentinhibitoryactivity,withIC50valuesinthenanomolartolowmicromolarrange.Structure-activityrelationship(SAR)analysiswasconductedtoidentifykeystructuralfeaturesresponsiblefortheinhibitoryactivity.Thisanalysisrevealedthatthepositionandnatureofsubstituentsonthequinolinescaffoldplayedacrucialroleindeterminingthepotencyofinhibition.Compoundswithelectron-withdrawinggroupsatspecificpositionsshowedenhancedinhibitoryactivitycomparedtocompoundswithelectron-donatinggroups.Tofurtherevaluatethetherapeuticpotentialoftheleadcompound,ananimalstudywasconductedusingamousemodelofmetabolicdiseases.Treatmentwiththeleadcompoundresultedinasignificantdecreaseinbodyweightcomparedtothecontrolgroup.Glucosetolerancetestsshowedimprovedglucoseclearanceintreatedanimals,indicatinganenhancedinsulinsensitivity.Furthermore,treatedanimalsexhibiteddecreasedserumtriglyceridelevels,suggestingimprovedlipidmetabolism.Conclusion(150words):Inconclusion,wesuccessfullydesignedandsynthesizedaseriesofquinolinecompoundsasFABP4/5inhibitors.ThecompoundsexhibitedpotentinhibitoryactivityagainstFABP4/5,withIC50valuesrangingfromnanomolartolowmicromolarconcentrations.Structure-activityrelationshipanalysiside