药物化学课件第八章抗生素

1、药物化学课件第八章抗生素第一节 概述1.-内酰胺类2.四环素类3.氨基糖苷类4.大环内酯类5.多肽多烯类6.其它类抗生素是某些细菌、放线菌、真菌等微生物的次级代谢产物，或用化学方法合成的与这些次级代谢物具有相同结构或对次级代谢产物进行结构修饰得到的产物，是一种在低浓度下对各种病原性微生物或肿瘤细胞有选择性杀灭、抑制作用的药物。抗生素杀菌作用的4种主要机制第二节 -内酰胺类抗生素NSCH3CH3RCOHNOCOOHHH1234567NSO1234567青霉烷基本母核1234567HHNRCOHNOSCOOHCH2A81234567NOS8头孢烯基本母核12345678HNRCOHNOSCOOHC

2、H2ACH3O1234567NCCOSRCH3COOHHHHHO1234NOR2R3R1CONH-内酰胺类抗生素的结构特点青霉素类NSCH3CH3OCOOHCH2COHN青霉素 G青霉素G的特点1. 不耐酸 （1）在稀酸、室温条件下，发生分子内重排生成青霉二酸，后者进一步分解成青霉胺和青霉醛 （2）在强酸条件下降解为青霉酸和青霉醛酸，后者再降解为青霉醛2.不耐酶耐药性产生的机制NSCH3CH3NHOCOPhCOOHH+CH3CH3CCH COOHNH2SH+青霉胺青霉醛H+H+NNSPhCOOHCOOH青霉二酸PhONHCHONSCH3CH3NHOCOPhCOOHH+CH2CHONHOPh青霉

3、醛ONHOOHHNSCOOH+ONHOOOH青霉酸青霉醛酸半合成青霉素NSCH3CH3OHNCOCH2OCOOHHH青霉素VNSCH3CH3OHNCOC6H5OCHCH3COOHHH非那西林NSCH3CH3OHNCOC6H5OCHCOOHHHCH2CH3丙匹西林NSCH3CH3OHNCOCCOOHHHNSCH3CH3OHNCOOCH3OCH3COOHHH甲氧西林COOHHHNSCH3CH3OHNCOONCH3苯唑西林NSCH3CH3OHNCOCHNH2COOHHH氨苄西林NSCH3CH3OHNCOCHNH2HOCOOHHH阿莫西林NSCH3CH3OHNCOCHCOOHHHCOOH羧苄西林NSC

4、H3CH3OHNCOCHCOOHHH磺苄西林SO3HNSCH3CH3OHNCOCHHH匹氨西林NH2COOCH2OCOC(CH3)3HH替卡西林NSCH3CH3OHNCOCHCOOHSCOOHNSHNOOHHCOONa青霉素钠（2S，5R，6R）-3，3-二甲基-6-（2-苯乙酰氨基）-7-氧代-4-硫杂-1-氮杂双环3.2.0庚烷-2-甲酸钠NSHNOONOHHCOONa苯唑西林钠（2S，5R，6R）-3，3-二甲基-6-（5-甲基-3-苯基-4-异恶唑甲酰氨基）-7-氧代-4-硫杂-1-氮杂双环3.2.0庚烷-2-甲酸钠NSHNOONOH HCOOHPH3.8Cu+NOONONHOHOSH

5、HNSHNOONOHHClCOOH氯唑西林NSHNOONOHHClClCOOH双氯西林HHCOONaHONSHNOONH2H2O3.阿莫西林（2S，5R，6R）-3，3-二甲基-6-（R）-（-）-2-氨基-（4-羟基苯基）乙酰氨基-7-氧代-4-硫杂-1-氮杂双环3.2.0庚烷-2-甲酸三水合物构效关系NSCH3CH3NHOCORCOOHHHIIIIIIIVV半合成青霉素类药物的合成基本母核6-APA的合成RCOCl+NSCH3CH3COOHH2NOPH 6.57.0室温(C2H5)3NNSCH3CH3COOHNHOCOR+HClR COCROO+NSCH3CH3COOHH2NONSCH3C

6、H3COOHNHOCOR+RCOOHRCOOH+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+NCNNHCNHO具体药物的合成CHOCN-H2OCHCNOHCHCNNH2CHCNNHCOOH环合CHNHCCNHOO(1)OH-(2)H+CHCOOHNH2(-)-樟脑磺酸CHNH2COOH.XD（ ）-a-氨基苯乙酸樟脑磺酸盐PCl5CHCOOHNH2.HCl6-APACHNH2CONHNOSCH3CH3COOHCH3（CH2）3CHCOONaC2H5C4H9OHCHNH2CONHNOSCH3CH3COONaCH3OCHONaCN，NH4HCO3CH3ONHHNOONaO

7、HCH3OCHCOOHNH2HBrHOCHCOOHNH2CH3OHHOCHCOOCH3NH2酒石酸HOCHCOOCH3NH2.HOOC（CHOH）2COOHNaOHHOCHCOOHNH2CH3COCH2COOC2H5NaOHHOCHCOONaNCH3CHCHCOOC2H56-APAHOCHNH2CONHNSOCH3CH3COOH头孢菌素类NSOCOOHCH2OCOCH3H2N7-ACACH（CH2）3CONHH3NOOCNSOCOOHCH2OCOCH3+-头孢菌素C结构改造NSHOONHROOOOHH在7位进行结构改造HH头孢噻吩NSCOOHCH2CONHOOOSHHNSCOOHCH2OCON

8、H2CONHOCO头孢呋辛NOCH3HHNSCOOHCH2OCOCH3CONHOC头孢噻肟NOCH3NSH2N在7位和3位同时进行改造NSCOOHCH2CH2CONHSONHH+头孢噻啶HHNSCOOHCH2CH2CONHOSNNNNNNSCH3头孢唑啉HHNSCOOHClCHCONHO头孢克洛NH2HHNSCOOHCH3CHCONHOHONH2头孢羟胺苄NSCOOHCH3CHCONHONH2HH头孢胺苄HHNSCOOHCH2SCHCONHONNNNCH3OH头孢孟多利用前药原理将COOH做成前药NSCH2OCONH2CONHOCNOCH3OH HCOOCHOCOCH3CH3头孢呋辛酯5位S原

9、子用生物电子等排体取代NCOOHCH2CH2SCONHOCHCOOHHONNNNCH3CH3OH拉他头孢合成NSOH2NCOOCH2CH3CH37-ADCANSOH2NCOOHCH2OCOCH37-ACA7-ACA的合成NSOH2NCOOHCH2OCOCH37-ACA7-ADCA的合成NSOCH2CONHCH3CH3COOKClCOOCH2CCl3NSOCH2CONHCH3CH3COOCH2CCl3H2O2NSOCH2CONHCH3CH3COOCH2CCl3OH3PO4NSOCH2CONHCH3OHCH2COOCH2CCl3扩环COOKNOCH2CONHSCH3PCl5CH3OHH2OADCA

10、7-头孢胺苄的合成NSH2NOCOOCH2CCl3CH3CHNHCOOCH2CCl3COClCHNHCOOCH2CCl3CONHNSOCOOCH2CCl3CH3ZnHCOOHCHCONHNSOCOOCH2CCl3CH3NH2非经典的-内酰胺抗生素碳青霉烯类NOCOOHSCHH3COHNHHHNH硫霉素NOCOOHSCHH3COHNH2HH亚胺培南NOCOOHSCHH3COHNHCN（CH3）2OHH美洛培南单环-内酰胺类OHOOHNH2NOHNHONOOHHOOHH诺卡霉素HOONOSNNH2NHONOSOHOOHH氨曲南-内酰胺酶抑制剂氧青霉素NOOOHOOKH克拉维酸NOOOHHCOOHE

11、nz-SerOHOHNOOHHCOOHEnz-SerOONOOHEnz-SerOCOOH克拉维酸异构体OH2N+OOHEnz-SerOCOO-OH2N+OOHNuEnzEnz-SerOCOO-ONuEnZEnz-SerO亚胺青霉烷砜类NSOCH3CH3OCOOH舒巴坦亚硝酰氯法NSOH2NCOOHCH2OCOCH3NSOHNCOOHCH2OCOCH3OH3NOOC+-NOClNSOHNCOOHCH2OCOCH3ON2HOOC+_N2NSONCOOHCH2OCOCH3OH2O硅酯法NSORCONHCOOHCH2OCOCH3(CH3)3SiClNSOR1CONHCOOSi(CH3)3CH2OCOC

12、H3PCl5NSONCOOSi(CH3)3CH2OCOCH3CR1Cln_C4H9OHNSONCOOSi(CH3)3CH2OCOCH3CR1OCH9CH3OH/H2O7-ACAR=(CH2)3CHCOOHNH2R1=(CH2)3CHCOOSi(CH3)3NH2第二节 四环素类抗生素DCBA12345678910111211a12aOHOOHOOHCONH2ClOHN(CH3)2HOCH3金霉素OHOOHOOHCONH2OHHOOHN(CH3)2CH3土霉素OHOOHOOHCONH2HON(CH3)2CH3四环素OHOHOOHOOHCONH2OHOHN(CH3)2CH3多西环素OHOOHOOHC

13、ONH2N(CH3)2OHN(CH3)2米诺环素结构通式OHOOHOOHCONHR5R4R1DCBA12345678910111211a12aOHN(CH3)2R2R3不稳定性酸性条件下OHOOHOOHCONH2OHRN(CH3)2OHCH3HHOHOOHCONH2OHOHRN(CH3)2OHOCH3HHH+H+H2OOHOOHCONH2OOHCH3RN(CH3)2OHH碱性条件下OOO-OHCH3-OHOOOCH3HHOH差向异构化OCONH2N(CH3)HOHH+OOHCONH2N(CH3)HOHOH与金属螯合OOHCa+OOCa+OHOH构效关系OHOOHOOHCONH2N(CH3)2O

14、H山环素第四节 氨基糖苷类抗生素OOOOHOHOHOH2CNHCH3HOOHCH3CNHCNH2NHHOOHOHNHCNH2NHN-甲基葡萄糖胺链霉糖氨基环乙醇链霉素OOHOHOH2CHOH2NOH2NHONH2OHOOHOHCH2NH2卡那霉素AOOHOHOH2CHOH2NONHONH2OHOOHOHCH2NH2OH2NH阿米卡星OOH2NNH2HOOR1CHNHR2OHOCH3HNOHCH3庆大霉素C第五节 大环内酯类OOOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689红霉素A不稳定性OCH3H3COHCH396H+HOCH3H3COCH3H+脱水CH3H3COHOCH3H3CHO689CH3H3COOH3C689HOCH3H3COHOH3C689CH3CH3加成脱水水解红霉胺6，9-9，12-螺缩酮8，9-脱水-6，9-半缩酮+OHOH3COCH3OH克拉定糖结构改造OOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689NOCH2O（CH2）2OCH3罗红霉素CH3CH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH3OCH3CH31356OONCH3HO阿奇霉素OOOCH3OCH3O