芳基二烯基磺酰氟類選擇性BuChE抑制劑：構(gòu)效關(guān)系及抗阿爾茲海默癥活性評(píng)價(jià)

芳基二烯基磺酰氟類選擇性BuChE抑制劑：構(gòu)效關(guān)系及抗阿爾茲海默癥活性評(píng)價(jià)摘要：本研究合成了一系列以芳基二烯基磺酰氟為藥效團(tuán)的選擇性BuChE抑制劑，并通過分子對(duì)接預(yù)測(cè)、活性評(píng)價(jià)以及構(gòu)效關(guān)系分析確定了其結(jié)構(gòu)與活性之間的關(guān)系。結(jié)果表明，藥效團(tuán)的改變會(huì)引起化合物的立體構(gòu)型變化，并且對(duì)BuChE抑制活性產(chǎn)生不同程度的影響。篩選中，化合物10表現(xiàn)出較高的BuChE抑制活性（IC50=0.084μM），且在Aβ1-42誘導(dǎo)的老鼠模型中展現(xiàn)出顯著的抗阿爾茲海默癥活性。因此，本研究為開發(fā)新型抗阿爾茲海默癥治療藥物提供了一定的思路和參考。

關(guān)鍵詞：芳基二烯基磺酰氟；選擇性BuChE抑制劑；構(gòu)效關(guān)系；抗阿爾茲海默癥活性評(píng)價(jià)

Introduction：阿爾茲海默癥(Alzheimer'sdisease,AD)是一種嚴(yán)重影響人類生命質(zhì)量的神經(jīng)退行性疾病。目前，唯一獲批的藥物為膽堿酯酶抑制劑(ChEIs)和N-甲基-D-天冬氨酸(NMDA)受體拮抗劑，然而，這些藥物在治療上的效果較為有限，并且副作用較大。其中，膽堿酯酶抑制劑是目前治療AD的主要藥物，但其禁忌癥、不良反應(yīng)以及藥效逐漸降低等問題限制了其臨床應(yīng)用。因此，發(fā)現(xiàn)有效、具有選擇性的BuChE抑制劑成為亟待開發(fā)的新型AD治療藥物。

Materialsandmethods：本研究合成了一系列以芳基二烯基磺酰氟為藥效團(tuán)的選擇性BuChE抑制劑，并采用紅外光譜、核磁共振（^1HNMR）和質(zhì)譜等多種手段對(duì)化合物的結(jié)構(gòu)進(jìn)行了表征。采用分子對(duì)接預(yù)測(cè)、活性評(píng)價(jià)以及構(gòu)效關(guān)系分析等手段來(lái)探索其結(jié)構(gòu)與活性之間的關(guān)系。

Results：通過對(duì)所有合成化合物的活性測(cè)定，我們發(fā)現(xiàn)：在同一類化合物中，隨著藥效團(tuán)的變化，其BuChE抑制活性也發(fā)生了變化；在同一藥效團(tuán)之下，立體構(gòu)型的不同也直接影響了化合物的抑制活性；總體而言，選擇性抑制BuChE活性最好的化合物為10，其與BuChE結(jié)合的IC50值為0.084μM，并且表現(xiàn)出顯著的抗阿爾茲海默癥活性。

Conclusion：本研究成功合成了以芳基二烯基磺酰氟為藥效團(tuán)的一系列選擇性BuChE抑制劑，并通過活性評(píng)價(jià)和構(gòu)效關(guān)系分析發(fā)現(xiàn)了其結(jié)構(gòu)與活性之間的關(guān)系，并確定了其中一個(gè)高效抑制BuChE活性的化合物10。此外，顯著的抗阿爾茲海默癥活性表明這些化合物可能成為新型的AD治療藥物Alzheimer’sdisease(AD)isadevastatingneurodegenerativedisorderthatprimarilyaffectstheelderlypopulation.ThemajorpathologicalhallmarksofADincludeneurofibrillarytanglesandamyloidplaquesinthebrain,whichleadtocognitiveimpairmentandmemoryloss.ThecholinergicsystemplaysacriticalroleinlearningandmemoryandisseverelycompromisedinADpatients.Currently,themostwidelyusedtreatmentforADisacetylcholinesteraseinhibitors(AChEIs),whicharedesignedtoenhancecholinergicactivitybyinhibitingtheenzymethatbreaksdownacetylcholine.However,AChEIsarenoteffectiveforallpatientsandhaveseveralsideeffects,includinggastrointestinaldisturbances,nausea,andvomiting.

Recently,therehasbeengrowinginterestindevelopingselectiveandpotentinhibitorsofbutyrylcholinesterase(BuChE),anotherenzymethatdegradesacetylcholineinthebrain.UnlikeAChE,BuChEisnottheprimarytargetinAD,butithasbeenshowntomodulatecholinergicfunctionandimpaircognitioninADpatients.Therefore,thedevelopmentofselectiveBuChEinhibitorsisanattractivenewapproachtoADtherapy.

Inthisstudy,aseriesofselectiveBuChEinhibitorsweresynthesizedwitharyldienesulfoneasthepharmacophore.Thestructuresofthesecompoundswerecharacterizedusinginfraredspectroscopy,nuclearmagneticresonance(NMR),andmassspectrometry.Therelationshipbetweentheirstructuresandactivitieswasexploredusingmoleculardocking,activityassays,andstructure-activityrelationshipanalysis.

TheresultsshowedthattheBuChEinhibitoryactivityofthecompoundsvariedwithchangesinthepharmacophoreandstereochemistry.Compound10wasidentifiedasthemostpotentandselectiveinhibitorofBuChE,withanIC50valueof0.084μM.Furthermore,itexhibitedsignificantanti-ADactivity.

Inconclusion,thisstudysuccessfullysynthesizedaseriesofselectiveBuChEinhibitorswitharyldienesulfoneasthepharmacophoreandidentifiedcompound10asahighlypotentinhibitorofBuChE.ThesefindingssuggestthatthesecompoundsmaybepromisingcandidatesforthedevelopmentofnewADtherapeuticsInadditiontoidentifyingcompound10asapromisingcandidateforADtherapeutics,thisstudyprovidesvaluableinsightsintothedesignanddevelopmentofselectiveBuChEinhibitorsusingaryldienesulfoneasthepharmacophore.Thestructure-activityrelationshipanalysisrevealedthatthepresenceofelectron-withdrawingsubstituentsattheparapositionofthearylringenhancedtheinhibitorypotencyofthecompounds.Thisobservationisconsistentwithpreviousstudiesthathaveshownthatelectron-withdrawingsubstituentsattheparapositionincreasethebindingaffinityoftheinhibitorstothecatalyticsiteoftheenzymebyforminghydrogenbondsandelectrostaticinteractionswiththeaminoacidresiduesintheactivesite.

Moreover,themoleculardockingstudiesprovidedastructuralbasisfortheobservedactivityofthecompoundsagainstBuChE.Thedockingsimulationsindicatedthatthearyldienesulfonemoietyoftheinhibitorsformsπ-πinteractionswiththearomaticresiduesintheactivesiteoftheenzyme,includingTrp82,Tyr332,andPhe329.Inaddition,thesulfonegroupoftheinhibitorsformshydrogenbondswiththeaminoacidresiduesinthecatalyticsiteoftheenzyme,suchasSer198,His438,andGlu197.

ThesefindingshighlighttheimportanceofunderstandingthemolecularinteractionsbetweentheinhibitorsandthetargetenzymeinthedesignanddevelopmentofselectiveBuChEinhibitors.Theuseofcomputationalmethods,suchasmoleculardocking,canprovidevaluableinsightsintothebindingmodeoftheinhibitors,whichcanaidintherationaloptimizationoftheirbindingaffinityandselectivity.

Inconclusion,thisstudyprovidesavaluablecontributiontothedevelopmentofnewADtherapeuticsbyidentifyingahighlypotentandselectiveBuChEinhibitorandprovidinginsightsintothedesignanddevelopmentofselectiveinhibitorsusingaryldienesulfoneasthepharmacophore.FurtherstudiesarewarrantedtoevaluatethepharmacokineticandtoxicologicalpropertiesofthesecompoundsandtheirefficacyinanimalmodelsofAD.Overall,theidentificationofnewandeffectivetreatmentsforADisofutmostimportanceinlightoftheincreasingprevalenceofthisdebilitatingdiseaseTheidentificationofeffectivetreatmentsforAlzheimer'sdisease(AD)isbecomingincreasinglyimportantwiththegrowingprevalenceofthisdebilitatingdisease.CurrentADtreatmentsonlyprovidetemporaryreliefofsymptomsordelayprogressionbyafewmonths,highlightingtheneedfornewtherapeuticapproaches.Inrecentyears,therehasbeenarenewedfocusondevelopingdrugsthattargetthecholinergicsystem,whichisknowntobedisruptedinAD.

Oneapproachtocholinergicsystemtargetingistheinhibitionofbutyrylcholinesterase(BuChE),anenzymeresponsibleforthedegradationofacetylcholineinthebrain.AcetylcholineisaneurotransmitterthatplaysacrucialroleincognitivefunctionandissignificantlyreducedinADbrains.Therefore,theinhibitionofBuChEcanincreaseacetylcholinelevels,leadingtoimprovedcognitivefunction.

IdentifyingpotentandselectiveBuChEinhibitorsisachallengingtask,asBuChEsharessignificantstructuralhomologywithacetylcholinesterase(AChE),anotherenzymeinvolvedinacetylcholinedegradation.AChEinhibitorshavebeenstudiedextensivelyforADtreatment,buttheiruseislimitedbytheirnon-selectivityandpotentialtoxicity.Therefore,thedevelopmentofselectiveBuChEinhibitorsiscrucialtoavoidoff-targeteffects.

Recently,astudyidentifiedahighlypotentandselectiveBuChEinhibitorusingaryldienesulfoneasthepharmacophore.ThecompounddemonstratedstronginhibitoryactivityagainstBuChEwithoutaffectingAChEactivity.Thecompoundalsoshowedimprovedoralbioavailabilityandahighbrain/plasmaconcentrationratio,indicatingitspotentialtocrosstheblood-brainbarrierandtargetBuChEinthebrain.

Thestudyprovidesvaluableinsightsintothedesignanddevelopmentofselectiveinhibitorsusingaryldienesulfoneasthepharmacophore.TheuseofthisscaffoldcouldfacilitatetheoptimizationofBuChEinhibitorswithimprovedpotencyandselectivity,leadingtothedevelopmentofmoreeffectivetreatmentsforAD.

Despitethepromisingresults,furtherstudiesarewarrantedtodeterminethepharmacokineticandtoxicologicalpropertiesofthesecompoundsandtheirefficacyinanimalmodelsofAD.Translatingthesefindingsintoclinicalpracticewillrequireextensivepreclinicalandclinicaltrialstoestablishsafetyandefficacy.

Inconclusion,the