1、第一節 概述l-內酰胺類l四環素類l氨基糖苷類l大環內酯類l多肽多烯類l其它類抗生素是某些細菌、放線菌、真菌等微生物的次級代謝產物，或用化學方法合成的與這些次級代謝物具有相同結構或對次級代謝產物進行結構修飾得到的產物，是一種在低濃度下對各種病原性微生物或腫瘤細胞有選擇性殺滅、抑制作用的藥物。抗生素殺菌作用的4種主要機制第二節 -內酰胺類抗生素NSCH3CH3RCOHNOCOOHHH1234567NSO1234567青霉烷基本母核1234567HHNRCOHNOSCOOHCH2A81234567NOS8頭孢烯基本母核12345678HNRCOHNOSCOOHCH2ACH3O1234567NCCO

2、SRCH3COOHHHHHO1234NOR2R3R1CONH-內酰胺類抗生素的結構特點青霉素類NSCH3CH3OCOOHCH2COHN青霉素 G青霉素G的特點1. 不耐酸 （1）在稀酸、室溫條件下，發生分子內重排生成青霉二酸，后者進一步分解成青霉胺和青霉醛 （2）在強酸條件下降解為青霉酸和青霉醛酸，后者再降解為青霉醛2.不耐酶耐藥性產生的機制NSCH3CH3NHOCOPhCOOHH+CH3CH3CCH COOHNH2SH+青霉胺青霉醛H+H+NNSPhCOOHCOOH青霉二酸PhONHCHONSCH3CH3NHOCOPhCOOHH+CH2CHONHOPh青霉醛ONHOOHHNSCOOH+ONH

3、OOOH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氨芐西林NSCH3CH3OHNCOCHNH2HOCOOHHH阿莫西林NSCH3CH3OHNCOCHCOOHHHCOOH羧芐西林NSCH3CH3OHNCOCHCOOHHH

4、磺芐西林SO3HNSCH3CH3OHNCOCHHH匹氨西林NH2COOCH2OCOC(CH3)3HH替卡西林NSCH3CH3OHNCOCHCOOHSCOOHNSHNOOHHCOONa青霉素鈉（2S，5R，6R）-3，3-二甲基-6-（2-苯乙酰氨基）-7-氧代-4-硫雜-1-氮雜雙環3.2.0庚烷-2-甲酸鈉NSHNOONOHHCOONa苯唑西林鈉（2S，5R，6R）-3，3-二甲基-6-（5-甲基-3-苯基-4-異惡唑甲酰氨基）-7-氧代-4-硫雜-1-氮雜雙環3.2.0庚烷-2-甲酸鈉NSHNOONOH HCOOHPH3.8Cu+NOONONHOHOSHHNSHNOONOHHClCOOH氯

5、唑西林NSHNOONOHHClClCOOH雙氯西林HHCOONaHONSHNOONH2H2O3.阿莫西林（2S，5R，6R）-3，3-二甲基-6-（R）-（-）-2-氨基-（4-羥基苯基）乙酰氨基-7-氧代-4-硫雜-1-氮雜雙環3.2.0庚烷-2-甲酸三水合物構效關系NSCH3CH3NHOCORCOOHHHIIIIIIIVV半合成青霉素類藥物的合成基本母核6-APA的合成RCOCl+NSCH3CH3COOHH2NOPH 6.57.0室溫(C2H5)3NNSCH3CH3COOHNHOCOR+HClR COCROO+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+RCOOH

6、RCOOH+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+NCNNHCNHO具體藥物的合成CHOCN-H2OCHCNOHCHCNNH2CHCNNHCOOH環合CHNHCCNHOO(1)OH-(2)H+CHCOOHNH2(-)-樟腦磺酸CHNH2COOH.XD（ ）-a-氨基苯乙酸樟腦磺酸鹽PCl5CHCOOHNH2.HCl6-APACHNH2CONHNOSCH3CH3COOHCH3（CH2）3CHCOONaC2H5C4H9OHCHNH2CONHNOSCH3CH3COONaCH3OCHONaCN，NH4HCO3CH3ONHHNOONaOHCH3OCHCOOHNH2HBrH

7、OCHCOOHNH2CH3OHHOCHCOOCH3NH2酒石酸HOCHCOOCH3NH2.HOOC（CHOH）2COOHNaOHHOCHCOOHNH2CH3COCH2COOC2H5NaOHHOCHCOONaNCH3CHCHCOOC2H56-APAHOCHNH2CONHNSOCH3CH3COOH頭孢菌素類NSOCOOHCH2OCOCH3H2N7-ACACH（CH2）3CONHH3NOOCNSOCOOHCH2OCOCH3+-頭孢菌素C結構改造NSHOONHROOOOHH在7位進行結構改造HH頭孢噻吩NSCOOHCH2CONHOOOSHHNSCOOHCH2OCONH2CONHOCO頭孢呋辛NOCH3

8、HHNSCOOHCH2OCOCH3CONHOC頭孢噻肟NOCH3NSH2N在7位和3位同時進行改造NSCOOHCH2CH2CONHSONHH+頭孢噻啶HHNSCOOHCH2CH2CONHOSNNNNNNSCH3頭孢唑啉HHNSCOOHClCHCONHO頭孢克洛NH2HHNSCOOHCH3CHCONHOHONH2頭孢羥胺芐NSCOOHCH3CHCONHONH2HH頭孢胺芐HHNSCOOHCH2SCHCONHONNNNCH3OH頭孢孟多利用前藥原理將COOH做成前藥NSCH2OCONH2CONHOCNOCH3OH HCOOCHOCOCH3CH3頭孢呋辛酯5位S原子用生物電子等排體取代NCOOHCH

9、2CH2SCONHOCHCOOHHONNNNCH3CH3OH拉他頭孢合成NSOH2NCOOCH2CH3CH37-ADCANSOH2NCOOHCH2OCOCH37-ACA7-ACA的合成NSOH2NCOOHCH2OCOCH37-ACA7-ADCA的合成NSOCH2CONHCH3CH3COOKClCOOCH2CCl3NSOCH2CONHCH3CH3COOCH2CCl3H2O2NSOCH2CONHCH3CH3COOCH2CCl3OH3PO4NSOCH2CONHCH3OHCH2COOCH2CCl3擴環COOKNOCH2CONHSCH3PCl5CH3OHH2OADCA7-頭孢胺芐的合成NSH2NOCOO

10、CH2CCl3CH3CHNHCOOCH2CCl3COClCHNHCOOCH2CCl3CONHNSOCOOCH2CCl3CH3ZnHCOOHCHCONHNSOCOOCH2CCl3CH3NH2非經典的-內酰胺抗生素碳青霉烯類NOCOOHSCHH3COHNHHHNH硫霉素NOCOOHSCHH3COHNH2HH亞胺培南NOCOOHSCHH3COHNHCN（CH3）2OHH美洛培南單環-內酰胺類OHOOHNH2NOHNHONOOHHOOHH諾卡霉素HOONOSNNH2NHONOSOHOOHH氨曲南-內酰胺酶抑制劑氧青霉素NOOOHOOKH克拉維酸NOOOHHCOOHEnz-SerOHOHNOOHHCOO

11、HEnz-SerOONOOHEnz-SerOCOOH克拉維酸異構體OH2N+OOHEnz-SerOCOO-OH2N+OOHNuEnzEnz-SerOCOO-ONuEnZEnz-SerO亞胺青霉烷砜類NSOCH3CH3OCOOH舒巴坦亞硝酰氯法NSOH2NCOOHCH2OCOCH3NSOHNCOOHCH2OCOCH3OH3NOOC+-NOClNSOHNCOOHCH2OCOCH3ON2HOOC+_N2NSONCOOHCH2OCOCH3OH2O硅酯法NSORCONHCOOHCH2OCOCH3(CH3)3SiClNSOR1CONHCOOSi(CH3)3CH2OCOCH3PCl5NSONCOOSi(CH

12、3)3CH2OCOCH3CR1Cln_C4H9OHNSONCOOSi(CH3)3CH2OCOCH3CR1OCH9CH3OH/H2O7-ACAR=(CH2)3CHCOOHNH2R1=(CH2)3CHCOOSi(CH3)3NH2第二節 四環素類抗生素DCBA12345678910111211a12aOHOOHOOHCONH2ClOHN(CH3)2HOCH3金霉素OHOOHOOHCONH2OHHOOHN(CH3)2CH3土霉素OHOOHOOHCONH2HON(CH3)2CH3四環素OHOHOOHOOHCONH2OHOHN(CH3)2CH3多西環素OHOOHOOHCONH2N(CH3)2OHN(CH3

13、)2米諾環素結構通式OHOOHOOHCONHR5R4R1DCBA12345678910111211a12aOHN(CH3)2R2R3不穩定性酸性條件下OHOOHOOHCONH2OHRN(CH3)2OHCH3HHOHOOHCONH2OHOHRN(CH3)2OHOCH3HHH+H+H2OOHOOHCONH2OOHCH3RN(CH3)2OHH堿性條件下OOO-OHCH3-OHOOOCH3HHOH差向異構化OCONH2N(CH3)HOHH+OOHCONH2N(CH3)HOHOH與金屬螯合OOHCa+OOCa+OHOH構效關系OHOOHOOHCONH2N(CH3)2OH山環素第四節 氨基糖苷類抗生素OO

14、OOHOHOHOH2CNHCH3HOOHCH3CNHCNH2NHHOOHOHNHCNH2NHN-甲基葡萄糖胺鏈霉糖氨基環乙醇鏈霉素OOHOHOH2CHOH2NOH2NHONH2OHOOHOHCH2NH2卡那霉素AOOHOHOH2CHOH2NONHONH2OHOOHOHCH2NH2OH2NH阿米卡星OOH2NNH2HOOR1CHNHR2OHOCH3HNOHCH3慶大霉素C第五節 大環內酯類OOOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689紅霉素A不穩定性OCH3H3COHCH396H+HOCH3H3COCH3H+脫水

15、CH3H3COHOCH3H3CHO689CH3H3COOH3C689HOCH3H3COHOH3C689CH3CH3加成脫水水解紅霉胺6，9-9，12-螺縮酮8，9-脫水-6，9-半縮酮+OHOH3COCH3OH克拉定糖結構改造OOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689NOCH2O（CH2）2OCH3羅紅霉素CH3CH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH3OCH3CH31356OONCH3HO阿奇霉素OOOCH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHC