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Chapter13AntifungalAgents抗真菌药AntifungalAgentsFungiareplant-like,nonphotosyntheticeukaryotesgrowingeitheroncoloniesofsinglecells(yeasts)orinfilamentous(纤维)multicellularaggregetes(molds).Mostfungiliveassaprophytes(腐生菌)insoilorondeadplantmaterialsandareimportantinthemineralizationoforganicmatter.Thereare300,000kindsoffungi,butonly270ofwhichproducediseaseinhumansandanimals.Thesefungiaredividedintotwosectionsaccordingmycoticillnessesinhuamnstheyproduced.Thatis:shallowfungi,producesskinandhairinfections,systemfungi,producesvisceralinfetions.Inrecentyear,theincidenceoffungalinfectionshasreachedalarmingproportions.Thisduotoanumberoffactorssuchasintensiveusesofchemotherapiesforbacterialinfectionandcancers.Thenumberofsystemicinfectionshaveespeciallyincreased,thishasbeentrueforlargepopulationsofimmunocompromizedpatientsaswellasthoseSufferingfromvarioushematologicalmalignancies,acquiredimmunedeficiencysyndrome(AIDS)andpatientsundergoingorgantransplantation.So,todevelopanewantifungalagentsisaveryimportantwork.5.1Theclassificationofantifungalagents:Antimycoticantibiotics:抗真菌抗生素SyntheticantifungalAgents:Polyenes(Amphotericin)B多烯类化合物Others(Griseofulvin)灰黄霉素Fluorinatedpyrimidines(Fluorocytosine)AzolesImidazoles(ketoconazole)Triazoles(Fluoconazole)Allyamines(Terbinafine)Thioureas(Tolnafate)Others(Ciclopirox)AcetylCoASqualeneEpoxidaseAllyamines(Thiocarbamates)Lanosterol14DemethyllanosterolCellmembranesErgosterolCytochromeP450AzolesPolyenes(Morphilines)CellnuclesGrisofulvinFlucytosineDNANucleicacidTheclassificationaccordingtotheactionsofdrugs5.2Antimycoticantibiotics5.2.1AmpotericinB(AMB)(两性霉素B)OOOOHHHOOCOHOHOHOHOHOHOHOOCH3OHNH2OHAMBwasmarkedin1951’s,ismostcommonlyantibioticsusedtotreatmentsystemicfungalinfectionsandistheonlyPolyeneantibioticantifungalagentsforinjectionuse.MechanismofActionof(AMB)Thiskindofantifungalagentsactagainstsensitivefungalbycombiningwithmembraneergosterolswithsubsequentalerationinpermeabilityandlossofessentialorganicandinorganiccellconstituents.Inmammaliancellmembranes,theprincipalsterolischloesterol(胆甾醇),AMBbindsapproximatelytimesmoretightlytovesicles(醇囊)containingergoesterolratherthantothosecontainingchloesterol.Side-effectsThemostseriousarehypokalemiaanddistaltubularacidosis.theNephrotoxicityhasbeenlessenedtosomeextentbylipid-complexedformulations.Somelipid-complexedformulationofAMBinmarketandR&D(1)两性霉素B脂质体剂型(AmBisome),是用脂质体将两性霉素B包裹而成.已在欧洲和美国上市多年.(2)两性霉素B脂质体复合物(ABLC),商品名Abelcet是脂质体与两性霉素B交织而成,近来已在美国上市.(3)两性霉素B胶体分散剂(ABCD),商品名Amphocil和Amphotec,是用等量的硫酸胆固醇与等量的两性霉素混合包裹,现正在欧洲和美国使用.(4)聚乙二醇—AMB,AMB/polethelneglyco-phospholipid脂质,临床前研究.5.2.2Nystain(NYS)(制霉菌素)OOOOHHHOOCOHOHOHOHOHOHOHOOCH3OHNH2OHDerivingfromAMB,developedbyAronexandinpreclinicphase.NYSisrecommendedfortreatmentoforalthrushoresophagitiscausedbyCandidaalbicansinAIDS.5.2.3Griseofulvin(灰黄霉素)OCH3CH3OClOOOOCH3CH3Griseofulvinasmarkedin1958,theprimarysiteofactionofitinvolvesBindingtoRNA.Manifestationsincludeinhibitionofhyphalcell-wallsynthesisandcytoplasmicmicrotubules.Mainlyusedtotreattheskinfungalinfections.Thesideeffectsare:gastrointestinal,allergic,andmorefrequently,moderateincreaseinfecalprotoporphyrin.5.2.4OthersOHOHNHNHOHOOCH3HOONCH3HONHONOHOOHOHNHONHCH3CH3OO(CH2)4CH3脂肽类抗生素Echinocandin真菌细胞壁具有许多杀真局菌活性的靶位.参与真菌细胞壁的合成的许多合成酶是真菌特有的,如1,3-葡聚糖合成酶;聚乙酰氨基葡糖合成酶等.单酰甘油酯类抗生素:AKD-2A,B,C,DROOOOOCHCH2OROHCH2OHAKD-2AAKD-2B1AKD-2B2AKD-2CAKD-2D由日本科学家从Steptomycessp,OCU-42815菌株中分离纯化而得到的,通过对酵母细胞膜的作用而起抑制真菌作用NikkomycinZ(SP-920704)NOHCHOHCHCH3CHNH2CONHCHCOOHOOHOHNNHOO为基因工程菌Streptomycestendae的发酵代谢产物之一,单独使用时抗菌脯较窄,但当与唑类药物如氟康唑/伊曲康唑联用,则对多种真菌有效.由于扑如、哺乳动物细胞中不含合成乙酰氨基葡糖,因此本品几乎没有毒性,现已进入I/II期临床.5.3SyntheticantifungalAgents5.3.1AzolesBeginninginthelateof1960s,anextensiveseriesofazolecompoundshavebeensynthesizedandtestedforantifungalactivity.Currently,thetheR&Dforantifungalagentsarealsofocusedonthissacffold.Themechanismofactionofazole:InhibitionofcytochromeP-450thatcatalyzes14-apha-demethylationoflanosteroltoergosterol,accumulationof14-methylatedsterolacausepermeabilitydisrution.NXN(CH2)nCR1R2Arn=X=N,CH0,1SARofAzolesNXN(CH2)nCR1R2ArThetriazoleorimidazoleringareessentialfortheactivity,theN3bindstotheferricironatominthehemeprostheticgrouptoproventtheactivationofoxygenforinsertioninolanosterol.Theactivity:X=NX=CHatomofazolering1ThesubstitutionmustontheN,otherpositionwilllosetheactivityThe2,4positionofaromaticringareintruducedeletronwithdrawinggroup,suchas,F,Cl,willincreaseantifungalactivity.thevaryingofR1andR2canbe:R1=OH,orR,R2formeda1,3dioxapetane.(1)分子中的氮唑环(咪唑或三氮唑)是必须的,咪唑环的3位,三氮唑的4位氮原子与血红素铁原子形成配位键,竞争抑制酶的活性,当被其他基团取代时,活性丧失.比较咪唑和三氮唑类化合物可以发现三氮唑类化合物的治疗指数明显优于咪唑类化合物.(2)氮唑的取代基必须与氮杂环的1位上的氮原子相连.(3)Ar基团上取代基中苯环的4位取代基有一定的体积和电负性,苯环的2位有电负性取代基对抗真菌活性有利.R1、R2上取代基结构类型变化较大,其中活性最好的有两大类:R1、R2形成取代二氧戊环结构,成为芳乙基氮唑环状缩酮类化合物,代表性的药物有酮康唑、伊曲康唑.该类药物的抗真菌活性很强,但由于体内治疗是肝毒性较大,而成为目前临床上首选的外用药;R1为醇羟基,代表性药物为氟康唑,该类药物体外无活性,但体内活性非常强,是治疗深部真菌病的首选药.(5)该类化合物的立体化学:多相研究结果表明,氮唑类抗真菌药对立体化学要求十分严格.一般情况是3-三唑基-2-芳基-1-甲基-2-丙醇类化合物中,(1R,2R)立体异构与抗真菌活性有关.已有或正在研发的三氮唑类抗真菌药都存在一定的局限性，并且随着耐药菌株的出现，对新的三唑类药物的需求更为迫切。目前，科学家正从以下几方面进行深入的研究：a．作为P-450DM酶的抑制剂