藥物化學(xué)課件_第八章_抗生素

1、第一節(jié) 概述1.-內(nèi)酰胺類2.四環(huán)素類3.氨基糖苷類4.大環(huán)內(nèi)酯類5.多肽多烯類6.其它類抗生素是某些細(xì)菌、放線菌、真菌等微生物的次級代謝產(chǎn)物，或用化學(xué)方法合成的與這些次級代謝物具有相同結(jié)構(gòu)或?qū)Υ渭壌x產(chǎn)物進(jìn)行結(jié)構(gòu)修飾得到的產(chǎn)物，是一種在低濃度下對各種病原性微生物或腫瘤細(xì)胞有選擇性殺滅、抑制作用的藥物?？股貧⒕饔玫?種主要機制第二節(jié) -內(nèi)酰胺類抗生素NSCH3CH3RCOHNOCOOHHH1234567NSO1234567青霉烷基本母核1234567HHNRCOHNOSCOOHCH2A81234567NOS8頭孢烯基本母核12345678HNRCOHNOSCOOHCH2ACH3O12345

2、67NCCOSRCH3COOHHHHHO1234NOR2R3R1CONH-內(nèi)酰胺類抗生素的結(jié)構(gòu)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(fā)生分子內(nèi)重排生成青霉二酸，后者進(jìn)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(chǎn)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ONHOOHHNSCO

3、OH+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氨芐西林NSCH3CH3OHNCOCHNH2HOCOOHHH阿莫西林NSCH3CH3OHNCOCHCOOHHHCOOH羧芐西林NSCH3CH3OHNCOCH

4、COOHHH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(huán)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(huán)3.2.0庚烷-2-甲酸鈉NSHNOONOH HCOOHPH3.8Cu+NOONONHOHOSHHNSHNOONOHHC

5、lCOOH氯唑西林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(huán)3.2.0庚烷-2-甲酸三水合物構(gòu)效關(guān)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

6、+RCOOHRCOOH+NSCH3CH3COOHH2NONSCH3CH3COOHNHOCOR+NCNNHCNHO具體藥物的合成CHOCN-H2OCHCNOHCHCNNH2CHCNNHCOOH環(huán)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，NH4HCO3CH3ONHHNOONaOHCH3OCHCOOHN

7、H2HBrHOCHCOOHNH2CH3OHHOCHCOOCH3NH2酒石酸HOCHCOOCH3NH2.HOOC（CHOH）2COOHNaOHHOCHCOOHNH2CH3COCH2COOC2H5NaOHHOCHCOONaNCH3CHCHCOOC2H56-APAHOCHNH2CONHNSOCH3CH3COOH頭孢菌素類NSOCOOHCH2OCOCH3H2N7-ACACH（CH2）3CONHH3NOOCNSOCOOHCH2OCOCH3+-頭孢菌素C結(jié)構(gòu)改造NSHOONHROOOOHH在7位進(jìn)行結(jié)構(gòu)改造HH頭孢噻吩NSCOOHCH2CONHOOOSHHNSCOOHCH2OCONH2CONHOCO頭孢呋

8、辛NOCH3HHNSCOOHCH2OCOCH3CONHOC頭孢噻肟NOCH3NSH2N在7位和3位同時進(jìn)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N

9、COOHCH2CH2SCONHOCHCOOHHONNNNCH3CH3OH拉他頭孢合成NSOH2NCOOCH2CH3CH37-ADCANSOH2NCOOHCH2OCOCH37-ACA7-ACA的合成NSOH2NCOOHCH2OCOCH37-ACA7-ADCA的合成NSOCH2CONHCH3CH3COOKClCOOCH2CCl3NSOCH2CONHCH3CH3COOCH2CCl3H2O2NSOCH2CONHCH3CH3COOCH2CCl3OH3PO4NSOCH2CONHCH3OHCH2COOCH2CCl3擴環(huán)COOKNOCH2CONHSCH3PCl5CH3OHH2OADCA7-頭孢胺芐的合成NSH

10、2NOCOOCH2CCl3CH3CHNHCOOCH2CCl3COClCHNHCOOCH2CCl3CONHNSOCOOCH2CCl3CH3ZnHCOOHCHCONHNSOCOOCH2CCl3CH3NH2非經(jīng)典的-內(nèi)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(huán)-內(nèi)酰胺類OHOOHNH2NOHNHONOOHHOOHH諾卡霉素HOONOSNNH2NHONOSOHOOHH氨曲南-內(nèi)酰胺酶抑制劑氧青霉素NOOOHOOKH克拉維酸NOOOHHCOOHEnz-SerOHOHNO

11、OHHCOOHEnz-SerOONOOHEnz-SerOCOOH克拉維酸異構(gòu)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)3CH2OCOCH3PCl5NSONCO

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

13、HN(CH3)2米諾環(huán)素結(jié)構(gòu)通式OHOOHOOHCONHR5R4R1DCBA12345678910111211a12aOHN(CH3)2R2R3不穩(wěn)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(gòu)化OCONH2N(CH3)HOHH+OOHCONH2N(CH3)HOHOH與金屬螯合OOHCa+OOCa+OHOH構(gòu)效關(guān)系OHOOHOOHCONH2N(CH3)2OH山環(huán)素第四節(jié) 氨基糖苷

14、類抗生素OOOOHOHOHOH2CNHCH3HOOHCH3CNHCNH2NHHOOHOHNHCNH2NHN-甲基葡萄糖胺鏈霉糖氨基環(huán)乙醇鏈霉素OOHOHOH2CHOH2NOH2NHONH2OHOOHOHCH2NH2卡那霉素AOOHOHOH2CHOH2NONHONH2OHOOHOHCH2NH2OH2NH阿米卡星OOH2NNH2HOOR1CHNHR2OHOCH3HNOHCH3慶大霉素C第五節(jié) 大環(huán)內(nèi)酯類OOOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689紅霉素A不穩(wěn)定性O(shè)CH3H3COHCH396H+HOCH3H3COC

15、H3H+脫水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(jié)構(gòu)改造OOCH3CH3OCH3OCH3H5C2CH3HOH3COHOHOHOCH3NCH3CH3OOHCH3OCH3CH3135689NOCH2O（CH2）2OCH3羅紅霉素CH3CH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH3OCH3CH31356OONCH3HO阿奇霉素OOOCH3OCH3OCH3H5C2CH3HOH3COHOHOCH3NCH3CH3OOHCH