1、NSO1234567PenamNSO1234567PenemNO1234567CarbapenemNSONO123456781234CefmMonobactam青霉烷 青霉烯 碳青霉烯 头孢烯 单环-内酰胺NSO1234567CH3CH3COOHHHRCOHNNO1234567COOHHHRCOHNSRPenicillinsCarbapenemsNSO12345678CephalosporinsHHRCOHNCH2A青霉素类 头孢菌素类 碳青霉烯类NSO12345678OxacephemsHH3CORCOHNCH2ANO1234MonobactamR3R2R1COHN头霉素类 单环-内酰胺类O
2、ONNROOOONNOOS粘肽D-丙氨酸-D-丙氨酸的末端构像青霉素构像NAGNAMnRGGGGGGGGAEKAANAGNAMnGAEKADDDDDGGGR转肽酶OOHNHAcOHCH2OHOHOOHNHAcOCH2OHOHCH3CHCOOHNAGNAMNAG=NAM=N-acetyglucosamine,N-乙酰葡萄糖胺N-acetylmuramic acid,N-乙酰壁氨酸A=ala;E=glu;K=lys;G=gly;CH3NCH3RHNCO2OHPBPCH2OHNH3NHHRCO2OHHRCO2HNOPBPCH2ONH3H2NCO2CH3+PBPCH2ONH3+CH3RHNO+_RHN
3、CH3NHNHROOPBPCH2OHNH3+H2NCH2CORPentaglycyl unit细胞壁片断(D-ala-D-ala)转肽酶-lactam细胞壁转氨酶水解细胞壁片断(D-ala-D-ala)细胞壁转氨酶水解-内酰胺环NSOCH3CH3COOHHHHNORCH2OH-lactamaseHNSOCH3CH3COOHHHHNORCH2O-lactamaseH2OHNSOCH3CH3COOHHHHNOROHCH2OH-lactamase+NSOCH3CH3COOHHHHNRONSCH3COOHNHROHOCH3OHNSCH3COOHNHROCH3OnNSOCH3CH3COOHHHHNONS
4、OCH3CH3COOHHHHNOHONSOCH3CH3COOHHHHNOONSOCH3CH3COOHHHHNOH3CNSOCH3COOHHHHNOH3C NSOCH3COOHHHHNOH3CNSOCH3COOHHHHNOHONH2ONSOCH3CH3COOHHHHNONSOCH3CH3COOHHHHNRONSOCH3CH3COOHHHHNROHHNSCH3CH3COOHHHNOOHRNHSCH3CH3COOHNOORHNHSCH3CH3COOHNOORHNSOCH3CH3COOHHHHNROHO-CO2HNSCH3CH3COOHHHNROH2NHSCH3CH3COOHHNROCHOH2OH2O
5、青霉酸青霉噻唑酸青霉醛D-青霉胺CO2HHNROCHO青霉醛酸-CO2NSCH3CH3COOHNHOOCR青霉二酸H2O-CO2 NSOCH3CH3COOHHHHNRONS-OCH3CH3COOHHHHNRO-lactamaseOH-OHHNSOCH3CH3COOHHHHNROHO青霉酸NHSOCH3CH3COOHHHNROOH-CO2HSCH3CH3COOHNHRCOHNHNSCH3CH3COOHHHNRO青霉噻唑酸H2NHSCH3CH3COOHHNROCHO青霉醛D-青霉胺+NSOCH3CH3COOHHHHNOONCH2CH3H2NOCH2CH3普鲁卡因青霉素NHNHNSOCH3CH3CO
6、OHHHHNO苄星西林 NSOCH3CH3COOHHHHNONSOCH3COOHHHHNON3OCH3CH3NSOCH3COOHHHHNOOCH3H3C 阿度西林 非奈西林 丙匹西林 CO NHNSOCH3H3CCOOHNSOCH3CH3COOHHHHNOOCH3H3CONSOCH3CH3COOHHHHNOOCH2CH3甲氧西林甲氧西林 萘夫西林萘夫西林NSOCH3CH3COOHHHHNOOCH3H3CONSOCH3CH3COOHHHHNOOCH2CH3-lactamase resistantNSOCH3CH3COOHHHHNOOCH3H3CONSOCH3COOHHHHNOOCH3NSOCH3
7、COOHHHHNOH3COOCH3-lactamase sensitiveNSOCH3CH3COOHHHHNOONCH3R1R2苯唑西林 R1=H R2=H氯唑西林 R1=H R2=Cl氟氯西林 R1=F R2=Cl双氯西林 R1=Cl R2=ClNSOCH3CH3COOHHHNN NSOCH3CH3COOCH2OCOC(CH3)3HHNN NSOCH3CH3COOHHHNHOHOHNH2NSOCH3COOHHHNHONSOCH3CH3COOHHHNHOHNH2HONH2OCH3青霉素青霉素N 氨苄西林氨苄西林 阿莫西林阿莫西林NSOCH3CH3COOHHHNHONSOCH3CH3COOHHH
8、NHOHO2CHO3S羧苄西林羧苄西林 磺苄西林磺苄西林NSOCH3CH3COOHHHNHOHNHNSOCH3COOHHHNHOHNHNNOOH3CH2COCH3NNOOHNSOCH3CH3COOHHHNHOHNHNNOH3CO2SO 哌拉西林 阿帕西林 美洛西林 NSOCH3COOHNHCHONHOHNHNNOOH3CH2COCH3NSOCH3CH3COOHOCH3NHOHO2CNSOCH3CH3CO2CH2OCOC(CH3)3HHNHOHNH2SHOHO替莫西林 福米西林匹氨西林 NSOCH3CH3COOHHHHNO,3H2OHH2NHONSOCH3CH3COOHHHNHOHOHNH2NS
9、OCH3CH3COOHHHHNOHOHNH2HNSCH3CH3COOHHHNSOCH3CH3COOHHHOHOHNH2HNOHOHOHNNHHOHHNONSOCH3CH3COOHHHnNSOCH3CH3COOHHHNHOHNH2HOHNSOCH3COOHHHHNOHOHH2NHOCH3HNSCH3COOHCH3NHHNHOOO各种糖类各种糖类(葡萄糖和葡聚糖葡萄糖和葡聚糖)和多元醇在碱性条件下均能加速其分解，发生和多元醇在碱性条件下均能加速其分解，发生分子内成环反应，生成分子内成环反应，生成2，5-吡嗪二酮。因此不宜采用葡萄糖溶液作为稀释吡嗪二酮。因此不宜采用葡萄糖溶液作为稀释剂剂 NSOCH
10、3CH3COOHHHH2N6-氨基青霉烷酸氨基青霉烷酸ClNH2.HClO6-APANSOCH3CH3COOHHHNHOHNH2NSOCH3CH3COONaHHNHOHNH2H3CONaCH3O2.酸酐法 NSOCH3COOHHHNHOHNHNNOOH3CH2COCH3OHNHNNOOH3CH2COOHOHNHNNOOH3CH2COOOCH3OClCOOCH2CH3N(CH2CH3)36-APANaOHNSOCH3COONaHHNHOHNHNNOOH3CH2COCH3OHNH2ODCC6-APANSOCH3CH3COOHHHNHOHNH24.固相酶法固相酶法用具有催化活性的酶，将其固定在一定的
11、空间内，催化侧用具有催化活性的酶，将其固定在一定的空间内，催化侧链与链与6-APA直接缩合，此法工艺简单，收率高。但保证酶直接缩合，此法工艺简单，收率高。但保证酶的催化活性是关键问题的催化活性是关键问题 NSHHOHN-OOOCH3OOHONH3+O12354678NSHHOHNROOCH3OOHOHO-NSHHOHNROCH2OOHHONSHHOHNROOCH3OOHONSHHOHNROOHOOHNSHHOHNROOO3-HydroxycephalosporinCephalosporin LactoneNSHHOH2NCH3OOHNSHHOH2NOOHOCH3ONSHHOH2NOOHCH2N
12、SHHOH2NClOOH7-ACA7-ADCANSHHOHNSOCO2HNNNNSNNCH3NSHHOHNOOCO2HSN头孢唑林头孢唑林(Cefazolin)头孢噻啶头孢噻啶(Cefaloridine)NSHHOHNOOCO2HSNCH3ONSHHOHNOOCO2HCH3OSNSHHOHNOOCO2HCH3OCN头孢匹林头孢匹林(Cephapirin)头孢噻吩头孢噻吩(Cefalothin)头孢乙腈头孢乙腈(Cefacetrile)NSHHOHNCH3OCO2HNH2HClNSHHOHNCH3OCO2HNH2HONSHHOHNCH3OCO2HNH2头孢氨苄头孢氨苄(Cefalexin)头孢羟
13、氨苄头孢羟氨苄(Cefadroxil)头孢拉定头孢拉定(Cefradinel)NSHHOHNSOCO2HNNNNCH2SO3HHONSHHOHNOCO2HNH2CH3HONSHHOHNOOCO2HNH2OOH3CON头孢尼西头孢尼西(Cefonicid)头孢呋辛头孢呋辛(Cefuroxime)头孢丙烯头孢丙烯(Cefprozil)NSHOCH3OHNSOCO2HNNNNCH3CONH2HOOCNHHOHNClOCO2HNH2NSHHOHNSOCO2HNNNNCH2NH2CH2COOH 头孢雷特头孢雷特(Ceforanide)头孢替坦头孢替坦(Cefotatan)氯碳头孢氯碳头孢(Loracar
14、bef)NSOCOOHCOHNCH2OCOCH3NSH2NN OCH3H HNSOCOOHCOHNHHNSHNN OCH3H H头孢噻肟头孢噻肟(Cefotaxime)头孢唑肟头孢唑肟(Ceftizoxime)NSOCOOHCOHNNSH2NN OCH3H HCH2SNNNHOOCH3NSOCOOHCOHNNSH2NNOH HCCOOHCH3CH3N+头孢曲松头孢曲松(Ceftriaxone)头孢他啶头孢他啶(Ceftazidime)NSOCOOHCOHNNSH2NN OCH2COOHH HNSOCOOHCOHNCH2H HNHHONONOOC2H5SN NNNH3CCH2头孢哌酮头孢哌酮(C
15、efoperazone)头孢克肟头孢克肟(Cefixime)NSOCOOHCOHNNSH2NH HCH2COOHNSOCOHNNSH2NN OHH HCH2OHONSOCOHNNSH2NN OCH3H HOOOCH3OCH3OCH3OCH3头孢泊肟酯头孢泊肟酯(Cefpodoxime proxetil)Ar(7-ACA/7-ADCA)NOORAr(7-ACA/7-ADCA)NORO顺式体反式体NHHONHOSCOONNOCH3SNH2NNHHONHOSCOONSNH2NCH3NOCH3头孢匹罗(Cefpirom)头孢吡肟(Cefepime)NHHONHOSCOONNNNSNH2NOCH3NNH
16、HONHOSCOONNNH2NOCH3SNH2NCH2OH头孢唑兰(Cefozopran)头孢瑟利(Cefoselis)NSOCOOHCOHNCH2OCOCH3H HR抗菌谱的决定基团抗菌活性药物代谢-内酰胺 酶稳定性抗菌活性NSHHOHNOOCH3OOHOH3+NCOO-NSHHOHNOOCH3OOHO+N2COOHNSHHONOOCH3OOHOCOOHNSHHOH2NOCH3OOHONOClHCOOHH2O-N2NSHHOHNOOCH3OOHOH3+NCOO-(CH3)3SiClNSHHOHNOOCH3OOSi(CH3)3OH2NCOOSi(CH3)3PCl5NSHHOH2NOCH3OOH
17、OH2ONSHHONClOCH3OOSi(CH3)3OH2NCOOSi(CH3)3NSHHONC4H9OOCH3OOSi(CH3)3OH2NCOOSi(CH3)3C4H9OHNSOCH3CH3COOKHHHNOClCOOCH2CCl3NSOCH3CH3COOCH2CCl3HHHNOH2O2NSOCH3CH3COOCH2CCl3HHHNOONSOCOOCH2CCl3HHHNOOHCH3CH2H3PO4NSHHOHNOCOOCH2CCl3CH3NSHHOH2NCOOHCH3PCl5CH3OHH2O7-ADCANH HOCOOHSNH2H3CHONH HOCOOHSNH2H3CHONHHH3COCO
18、OHHO HSNHNH沙纳霉素沙纳霉素 亚安培南亚安培南NH3COH HCH3COOHSOHNHONH3CCH3CH3H3CNHOHCOOHSCOOHHNH2美洛培南 西司他丁 NOHOOHCOOHHNOHOOHCOOHHEnz-SerOHHNOHOHCOOHHEnz-SerOONOOHCOOHHEnz-SerOOH2+NOOHCOO-HEnz-SerOOH2+NOOHCOO-HEnz-SerOONuEnzEnz-SerOONuEnzNSHCOOHOCH3CH3OONSHCOOHOCH3CH3OONSHCOOHOCH3CH3H2NHNaNO2HBrNSHCOOHOCH3CH3BrBr10%Pd
19、-CNSHCOOHOCH3CH3BrBrOOKMnO4NSHHONHOCH3CH3NH2NSHOH3CH3COOOOOO舒它西林 NSNNNCH3HOOOCOOH他唑巴坦他唑巴坦NONHOSO3HNOHOOCCH3CH3SNH2NH CH3NHONHOSO3HNOCOOHSNH2NCH3CH3NHHONHOSO3HNOCOOHSNH2NONH2O氨曲南 替吉莫南 卡芦莫南 OHOHN(CH3)2OHCONH2OOH3COHHHOHN(CH3)2OHCONH2OOHHN(CH3)2OHCONH2OHON(CH3)2OHCONH2OOHHH+H+BaseBase4-epitetracyclineT
20、etracyclineOHOHN(CH3)2OHCONH2OOH3COHHHOHOHON(CH3)2OHCONH2OOHCH3OHOHOHN(CH3)2OHCONH2OOH3COHHHOHOHON(CH3)2OHCONH2OOHCH3OHTetracycline(active)Anhydrotetracycline4-epianhydrotetracycline4-epitetracycline(inactive)(inactive)(inactive)H+H+OOH3CHHOHOOH3CHOisotetracyclineOOH3CHHOHHMOOH3CHHOHMM=di or trivale
21、nt metal ionOHOHN(CH3)2OHCONH2OOCH3OHHHOH,HCl,1/2H2O,1/2CH3CH2OHOHOHN(CH3)2OHCONH2OOH3COHHHOH OHNOOClCH3OH-NH3OHOHN(CH3)2OHCONH2OOH3COHOOHClHF,pH12H3CSO3HOHON(CH3)2OHCONH2OOCH2OHOHClCH3SO3HOHOHN(CH3)2OHCONH2OOCH3OHHHOH,HCl,1/2H2O,1/2CH3CH2OHHO3SCO2HOHH2/Pd-COHOHN(CH3)2OHCONH2OOCH3OHOHOHSO3HCO2HCH3CH
22、2OHHClHNH2NNHHOHOOHOHHNNH2HNStreptamineH2NHOHOOHNH22-DeoxystreptamineHNHOHOOHHNCH3CH3OHSpectinamineHNH2NNHHOHOOOHHNNH2HNCH3OHOOOHHNCH3HOHOHOOHC链霉素CH3OO红霉素 A R=OH R1=CH3CH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OR1R2ONCH3CH3CH3O12356789101112132313红霉素 B R=H R1=CH3红霉素 C R=OH R1=H红霉内酯克拉定糖脱氧氨基糖CH3OOCH3H3COHOH
23、CH3OHH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OOCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3O2.-H2OCH3OCH3H3COHOCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OCH3H3CHOOCH3OH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OCH3H3CHOOCH3OH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OH+HO1.H+CH3OOCH3H3COHOHCH3H
24、OH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCO2HOHHHHOHOHOHCH2OHOHOCH2OHOHOH红霉素乳糖醛酸盐CH3OOCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3RONCH3CH3CH3O红霉素碳酸乙酯红霉素硬脂酸酯依托红霉素琥乙红霉素R=COOCH2CH3R=CO(CH2)16CH3R=CO(CH2)2OCOCH2CH3R=CO2CH2CH3.C12H25SO3HCH3ONOCH2OCH2CH2OCH3CH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3O
25、CH3ONOHCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OOCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3ONH2OH.HClKOHCH3ONOCH2OCH2CH2OCH3CH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OClCH2OCH2OCH2CH2OCH3CH3OOCH3H3COHOCH3CH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OOCH3H3COHOHCH
26、3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OFCH3OCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3ONH3CCH3ONOHCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OCH3OCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3OHNOH Beckmann RearrangementCH3OCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3
27、CH3OHNCH3OCH3H3COHOHCH3HOH3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3ONH3CHCHOHCOOHCH3OOCH3CH3OHCH3H3CCH3OH3COOOCH3OHCH3OCH3HONCH3CH3CH3ONOONNN泰利霉素泰利霉素麦 迪 霉 素 A1OROCH3H3COCH3CHOOOOHONCH3CH3CH3OOHCH3H3COR1OOH3C麦 迪 霉 素 A2R=O R1=COCH2CH3麦 迪 霉 素 A3麦 迪 霉 素 A4R=O R1=COCH2CH2CH3R=OH R1=COCH2CH3R=OH R1=COCH2CH2CH3
28、OOOCH3H3COR1CHOOOOHONCH3CH3CH3OOR2CH3H3COR3OH3CONCH3CH3CH3螺旋霉素 R1=H R2=H R3=H螺旋霉素 R1=COCH3 R2=H R3=H螺旋霉素 R1=COC2H5 R2=H R3=H乙酰螺旋霉素 R1=H R2=H R3=COCH3乙酰螺旋霉素 R1=COCH3 R2=H R3=COCH3乙酰螺旋霉素 R1=COC2H5 R2=COCH3 R3=COCH3CH2OHO2NHHOHNHCOCHCl2CH2OHH3CO2SHHOHNHCOCHCl2氯霉素 甲砜霉素CH2OCOCH2CH2CO2HO2NHHOHNHCOCHCl2CH2
29、OCOC15H31O2NHHOHNHCOCHCl2琥珀氯霉素 棕榈氯霉素CH2OHO2NHHOHNHCOCHCl2NO2CCCH2OHHOHHNHCOCHCl221NO2CCCH2OHHOHHNHCOCHCl221NO2CCCH2OHHOHCl2CHCOHNH21NO2CCCH2OHHOHCl2CHCOHNH1R,2R(-)1S,2S(+)1S.2R(+)1R,2S(-)D-(-)-ThreoL-(+)-ThreoD-(+)ErythroL-(-)-Erythro12O2NCH3OC6H5ClO2NCH2OBrC6H5ClO2NCH2OBr.C2H5OHHCl,H2OBr2(CH2)6N4(C
30、H2)6N4O2NCH2ONH2.HClAcONaO2NCH2ONHCOCH3HCHOO2NCHONHCOCH3OHAc2OO2NCHOHNHCOCH3OHthreo()HClH2OO2NCHOHNH2.HClOHthreo()NaOHO2NCHOHNH2OHthreo()AlOCH(CH3)23(CH3)2CHOHResolutionCH2OHO2NHHOHNH2D-(-)-threoCH3OHCH2OHO2NHHOHNHCOCHCl2Cl2CHCOOCH3O2NCH2OHOCH3OHAlOCH(CH3)23(CH3)2CHOHO2NCH2OCH3OHOAlOCH(CH3)2OH3CH3CH
31、-CH3COCH3O2NCH2OCH3OHOAlOCH(CH3)2HH2OO2NCH2OHOHCH3OHHNOCH3H3CNHCRCH3OOHCSCH3OHHOR1H林可霉素 A R=OH R1=H 克林霉素 R=H R1=ClOH3CPOOHOHHHH3COHCH3H3CPCl3(CH3CH2)3NH3COCH3H3CPOClCH3CH3CH3OHHCCH3OCH3CH3POOCH3H3CH3CHC重排 45CH3OCH3CH3POCH3H3CH3CCCH2Pt-C/H2HCl裂解OCH3OCH3CH3POH3CH3CCH3COCH3HHH3CPOHOHOHHNH2CH3（+）H2O2(CH3CH2)3NCH3CH2CH2OHH3CPO-OHOHHNH3CH3OOH3CPOONaONaHH强酸性阳离子交换树脂NaOH
