【文档说明】药物化学课件第八章抗生素-.ppt，共(94)页，1022.515 KB，由小橙橙上传

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第一节概述◼定义◼抗生素的来源◼分类◼作用机制1.ß-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

种在低浓度下对抗生素杀菌作用的4种主要机制◼抑制细菌细胞壁的合成，如青霉素类和头孢菌素类◼与细胞膜相互作用，如多粘菌素和短杆菌素◼干扰蛋白质的合成，如氨基糖苷类和四环素类◼抑制核酸的转录和复制第二节ß-内酰胺类抗生素基本结构及结构特点◼青霉素类◼头孢菌素类◼头霉素类◼碳青霉烯类◼单环ß-内酰胺类N

SCH3CH3RCOHNOCOOHHH1234567NSO1234567青霉烷基本母核1234567HHNRCOHNOSCOOHCH2A81234567NOS8头孢烯基本母核12345678HNRCOHNOSC

OOHCH2ACH3O1234567NCCOSRCH3COOHHHHHO1234NOR2R3R1CONHß-内酰胺类抗生素的结构特点◼都有一个四元的ß-内酰胺环◼与N相邻的C上连有一个羧基（除单环ß-内酰胺外）◼ß-内酰

胺环N的3位有酰胺基侧链（除碳青霉烯外）◼立体结构特点：两个稠合环非共平面◼ß-内酰胺环上取代基的构型有a和ß◼青霉素2S，5R，6R有活性，头孢菌素6R，7R有活性。◼含有链-C-CO-NH-C-CO-N-C-COO-青霉素类◼天然青霉素◼半

合成青霉素NSCH3CH3OCOOHCH2COHN青霉素G青霉素G的特点◼不稳定性◼容易产生耐药性◼抗菌谱窄◼过敏反应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◼使抗生素分解或失去活性◼使抗菌药物作用的靶点发生改变◼细胞特性的改变◼细菌产生的药泵将进入细胞的抗生素泵出细胞NSCH3CH3NHOCOPhCOOHH+CH3CH3CCHCOOHNH2SH+青霉胺青霉醛H+H

+NNSPhCOOHCOOH青霉二酸PhONHCHONSCH3CH3NHOCOPhCOOHH+CH2CHONHOPh青霉醛ONHOOHHNSCOOH+ONHOOOH青霉酸青霉醛酸半合成青霉素◼耐酸青霉素◼耐酶青霉素◼既耐酸又耐酶的青霉素◼广谱青霉素NSCH3

CH3OHNCOCH2OCOOHHH青霉素VNSCH3CH3OHNCOC6H5OCHCH3COOHHH非那西林NSCH3CH3OHNCOC6H5OCHCOOHHHCH2CH3丙匹西林NSCH3CH3OHNCOCCOOHHHNSCH3CH3OHNCOOCH3OCH3COOHHH甲氧西林C

OOHHHNSCH3CH3OHNCOONCH3苯唑西林NSCH3CH3OHNCOCHNH2COOHHH氨苄西林NSCH3CH3OHNCOCHNH2HOCOOHHH阿莫西林NSCH3CH3OHNCOCHCOOHH

HCOOH羧苄西林NSCH3CH3OHNCOCHCOOHHH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NSHNOONO

HHCOOHPH3.8Cu++NOONONHOHOSHHNSHNOONOHHClCOOH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◼I6位侧链是结构修饰的主要部位，能产生各种各样的作用。◼II羧基是活性必须基团，不能被取代，可

以利用前药原理做成脂◼III6a-位引入-OCH3或甲酰氨基，可增加药物的稳定性得到耐酶抗生素◼IV3位的两个-CH3不是活性所必需的◼V四元环并五元环的结构是活性所必需的◼在青霉素芳环侧链的a-位引入极性亲水性基团可扩大抗菌谱，基团的亲水性越强，药物对革兰氏阴性菌作用越强。

◼耐酶青霉素的侧链往往有较大的取代基，占用较大的空间。◼在分子的适当部位引入立体障碍的基团可以克服耐药性，引入杂环，可得到耐酶和耐酸的抗生素，在杂环部位引入甲氧基、卤素得到耐酶药物。半合成青霉素类药物的合成◼基本母核6-

APA的合成◼具体药物的合成基本母核6-APA的合成◼酰氯法◼酸酐法◼DCC法RCOCl+NSCH3CH3COOHH2NOPH6.5~7.0室温(C2H5)3NNSCH3CH3COOHNHOCOR+HClR

COCR'OO+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+R'COOHRCOOH+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+NCNNHCNHO具体药物的合成◼用酰氯法合成安苄西林钠◼阿莫西林的合成CHOCN-H2OCHCNOH

CHCNNH2CHCNNHCOOH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.HC

l6-APACHNH2CONHNOSCH3CH3COOHCH3（CH2）3CHCOONaC2H5C4H9OHCHNH2CONHNOSCH3CH3COONaCH3OCHONaCN，NH4HCO3CH3O

NHHNOONaOHCH3OCHCOOHNH2HBrHOCHCOOHNH2CH3OHHOCHCOOCH3NH2酒石酸HOCHCOOCH3NH2.HOOC（CHOH）2COOHNaOHHOCHCOOHNH2CH3COCH2COOC2H5NaOHHOCHCOONaNCH3C

HCHCOOC2H56-APAHOCHNH2CONHNSOCH3CH3COOH头孢菌素类NSOCOOHCH2OCOCH3H2N7-ACACH（CH2）3CONHH3NOOCNSOCOOHCH2OCOCH3

+-头孢菌素C◼优点：a、稳定性较青霉素类好b、过敏反应发生率较青霉素类低，且彼此不发生交叉过敏反应。◼缺点：a、3位乙酰氧基的存在使其不耐酶，抗菌活性较弱。b、头孢菌素C口服不吸收结构改造NSHOONHROOOOHH在7位进行结构改造◼7位侧链引入亲脂性

基团(eg：头孢噻吩）◼7位引入肟（eg：头孢噻肟）HH头孢噻吩NSCOOHCH2CONHOOOSHHNSCOOHCH2OCONH2CONHOCO头孢呋辛NOCH3HHNSCOOHCH2OCOCH3CONHOC头孢噻肟NOCH3NSH2N在7位和3位同时进行改造1.7位侧

链引入亲脂性基团，同时在3位引入杂环（eg：头孢噻啶、头孢唑啉）2.7位酰胺的a-位引入亲水性基团，同时改变3位上的取代基（eg：头孢氨苄、头孢羟胺苄、头孢克洛、头孢孟多）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NSCH2OCONH2CO

NHOCNOCH3OHHCOOCHOCOCH3CH3头孢呋辛酯5位S原子用生物电子等排体取代NCOOHCH2CH2SCONHOCHCOOHHONNNNCH3CH3OH拉他头孢合成◼中间体7-ACA和7-ADCA的合成◼头孢胺苄的合成NSOH2NCOOCH2CH3CH37-ADCA

NSOH2NCOOHCH2OCOCH37-ACA7-ACA的合成◼亚硝酰氯法◼硅酯法NSOH2NCOOHCH2OCOCH37-ACA亚硝酰氯法硅酯法7-ADCA的合成NSOCH2CONHCH3CH3COOKClCOOCH2CCl3NSOCH2CONHCH3CH3COOCH2CCl3H

2O2NSOCH2CONHCH3CH3COOCH2CCl3OH3PO4NSOCH2CONHCH3OHCH2COOCH2CCl3扩环COOKNOCH2CONHSCH3PCl5CH3OHH2OADCA7-头孢胺苄的合成NSH2NOCOOCH2CCl3CH3CHNH

COOCH2CCl3COClCHNHCOOCH2CCl3CONHNSOCOOCH2CCl3CH3ZnHCOOHCHCONHNSOCOOCH2CCl3CH3NH2非经典的ß-内酰胺抗生素◼碳青霉烯类◼单环ß-内酰胺类碳青霉

烯类NOCOOHSCHH3COHNHHHNH硫霉素NOCOOHSCHH3COHNH2HH亚胺培南NOCOOHSCHH3COHNHCN（CH3）2OHH美洛培南单环ß-内酰胺类OHOOHNH2NOHNHONOOHHOOHH诺卡霉素HOONOSNNH2NHONOSOHOOHH氨曲

南ß-内酰胺酶抑制剂◼氧青霉素◼青霉烷砜类氧青霉素NOOOHOOKH克拉维酸NOOOHHCOOHEnz-SerOHOHNOOHHCOOHEnz-SerOONOOHEnz-SerOCOOH克拉维酸异OH2N+OEnz-SerOCOOOH2

N+OOHNuEnzEnz-SerOONuEnZEnz-SerO亚胺青霉烷砜类NSOCH3CH3OCOOH舒巴坦亚硝酰氯法NSOH2NCOOHCH2OCOCH3NSOHNCOOHCH2OCOCH3OH3NOOC+-NOClNSOHNCOOHCH2OCOCH

3ON2HOOC+_N2NSONCOOHCH2OCOCH3OH2O硅酯法NSORCONHCOOHCH2OCOCH3(CH3)3SiClNSOR1CONHCOOSi(CH3)3CH2OCOCH3PCl5NSONCOOSi(CH3)

3CH2OCOCH3CR1Cln_C4H9OHNSONCOOSi(CH3)3CH2OCOCH3CR1OCH9CH3OH/H2O7-ACAR=(CH2)3CHCOOHNH2R1=(CH2)3CHCOOSi(CH3)3NH2第二节四环素类抗生素D

CBA12345678910111211a12aOHOOHOOHCONH2ClOHN(CH3)2HOCH3金霉素OHOOHOOHCONH2OHHOOHN(CH3)2CH3土霉素OHOOHOOHCONH2HON(CH3)2CH3四环素OHOHOOHOOHCONH2OHOHN(CH3)2CH3多西环素

OHOOHOOHCONH2N(CH3)2OHN(CH3)2米诺环素结构通式OHOOHOOHCONHR5R4R1DCBA12345678910111211a12aOHN(CH3)2R2R3不稳定性◼4-二甲氨基显碱性，3-烯醇基显酸性◼6-OH的存在使药物对酸

碱不稳定（eg：土霉素、金霉素、四环素不稳定，米诺环素、多西环素稳定性好）◼4-二甲氨基易发生差向异构化，若在5位引入-OH位阻基团，则稳定性相对提高。◼10-酚羟基和12-位烯醇基的存在可与金属离子螯合成有色络合物。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◼四个环是生物活性所必需的结构，山环素是四环素类药物的药效团。◼C11~C12a的双酮系统结构对抗菌活性很重要。◼6-去羟基可使药物稳定性增加，作用增强。OHOOHOOHCONH2N(CH3)2OH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AOOHOHOH2CHOH2NONHON

H2OHOOHOHCH2NH2OH2NH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+OHOH3C

OCH3OH克拉定糖结构改造◼主要在9-酮、6-OH、8-H上进行（与红霉素A的环合水解机制有关）◼9-羰基与羟胺成肟再与甲氧基乙氧基甲基缩合得到罗红霉素。◼9a-位杂入甲氨基得到阿奇霉素◼6位羟基甲基化得到克拉霉素◼8-位引入F得到氟红霉素OOCH

3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689NOCH2O（CH2）2OCH3罗红霉素CH3CH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH3OCH3CH3135

6OONCH3HO阿奇霉素OOOCH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH3OCH3CH3135689克拉霉素OCH3OOOCH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH

3NCH3CH3OOHCH3OCH3CH3135689氟红霉素F第六节其它抗生素O2NCCCH2OHOHHHNHCOCHCl2氯霉素O2NCCCH2OCOCH2CH2COOHOHHHNHCOCHCl2

琥珀氯霉素O2NCCCH2OCOC15H31OHHHNHCOCHCl2棕榈氯霉素鉴别◼1.◼2.CaCl2/ZnPhCOClFe3+HCl/ZnNaNO2HCl萘酚