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1、Chapter 8 AntibioticsSection 2.TetracyclinesSection 3.AminoglycosideSection 4.MacrolidesSection 5.ChloramphenicolAntibiotics as disturber with the biosynthesis of protein lTheseantibioticsalltargetthebacterialribosomeandinterfereintheprocessoftranslationofthemessengerRNAintoproteinandthusblockafunda
2、mentalprocessinbacterialmetabolism.lInhibitorsof30sRibosomalsubunit:AminoglycosidesandTetracyclineslInhibitorsofthe50sRibosomalsubunit:MacrolidesandChloramphenicolTetracycline Antibiotics Tetracyclines are produced by actinomyces(放线菌放线菌),which have broad-antibacterial spectrum.The basic skeleton of
3、tetracyclines is naphthacene ring.Tetracyclines differing from each other chemically only by substituent variation at positions 5,6 and 7.Mechanism of Action:Tetracyclines inhibit bacterial protein synthesis by blocking the attachment of the t-RNA-amino acid to the ribosome.Tetracyclines can also in
4、hibit protein synthesis in the host,but are less likely to reach the concentration required because eukaryotic(真核状态的真核状态的)cells do not have a tetracycline uptake mechanism.Tetracyclinel6-Methyl-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2-naphthacenecarboxamideFormat
5、ion of 4-EpitetracyclinelAt C-4 in acidic medium(pH 2-6),epimerization of the“natural”C-4-dimethylamino group to the C-4-epimer occurs.Under acidic conditions,a 1:2 equilibrium is established in solution within a day.Stability under base conditionlIn basic medium,ring C of tetracycline is opened to
6、form isotetracycline.Aminoglycoside Antibiotics Chemistry lAminoglycosides are so named because their structures consist of amino sugars linked glycosidically.All have at least one aminohexose,and some have a pentose lacking an amino group.（L-Streptose）（Streptide）（N-Methyl-L-Glucosmine）Caution!lIt s
7、hould be remember that penicillin and aminoglycoside antibiotics must never be physically mixted,because both are chemically inactivated to a significant degree on mixting.Spectrum of activity lAminoglycosides are used for treatment of serious systemic infections caused by aerobic Gram-negative baci
8、lli.Aerobic G-N and G-P cocci tend to be less sensitive;thus the lactams and other antibiotics tend to be preferred for the treatment of infections caused by these organisms.Anaerobic bacteria are invariably resistant to the aminoglycosides.lStreptomycin is the most effective of the group for the ch
9、emotherapy of tuberculosis.lUnder certain circumstances,aminoglycoside and lactams antibiotics exert a synergistic action in vivo against some bacterial strains when the two are administered jointly.Mechanism of Action lThe mechanism of action of these antibiotics believed that they can inhibit the
10、biosynthesis of protein of bacteria.lAt less than toxic doses,they bind to the protein portion of the 30S ribosomal subunit leading to mistranslation of RNA templates and the consequent insertion and wrong amino acids and formation so-called nonsense proteins.ToxicitylTheir undesirable side effects:
11、severe ototoxicity and nephrotoxicity.l18 of 21 actress showing“qianshou guanyin”were caused deafness by aminoglycosides.Streptomycin(链霉素)Streptomycin is the first aminoglycosides isolated from Streptomyces griseus.There are three basic centers in the structure.Clinical Use lStreptomycin was the fir
12、st aminoglycoside isolated and the first antibiotic with potent activity against Mycobacterium tuberculosis and this antibiotic continues to be used to treat tuberculosis,but as a result of the development of resistance,now in combination therapy with other antibiotics.lStreptomycin can also be used
13、 for the treatment of tularemia（野兔病）,plague（瘟疫）and leprosy(麻风病).lThe aminoglycosides are highly water soluble and poorly absorbed orally.These antibiotics are therefore primarily delivered by intramuscular injection or intravenously.Macrolide AntibioticsMechanism of actionlThe mechanism of action of
14、 macrolides is that:it inhibits bacteria by interfering with programmed ribosomal protein biosynthesis by inhibiting translocation of amino acid m-RNA following binding to the 50s subunit.ErythromycinlA and B A C-12=-OHB C-12=-HA and CA C-3=OCH3C C-3=-OHExtremely unstable under acid conditionSimply
15、modification of erythromycin-Ester Pro-drugStrategy for erythromycin modificationErythromycin derivativesTelithromycinlTelithromycin is the first ketolide(3-keto macrolide derivatives).It is prepared by removing the cladinose sugar from the C-3 position of the erythronolide skeleton and oxidizing th
16、e remaining hydroxyl group to a keto group.lIn addition to the C-3 ketone,telithromycin has an aromatic N-substituted carbamate extension at position C-11 and C-12.This ring has an imidazo-pyridyl group attachment.lTelithromycin possesses a 6-OCH3 group(like clarithromycin),avoiding internal kemiket
17、alization with the 3-keto function and giving the ketolide molecule excellent acid stability.lThe ketolides are very active against respiratory pathogens,including erythromycin-resistant strains Chloramphenicol AntibioticsChloramphenicol(氯霉素氯霉素)lChemical name:lD-(-)-threo-1-p-nitrophenyl-2-dichloroa
18、cetamido-1,3-propanediolA molecule,with two chiral centers,has four isomers(diastereomers).Chloramphenicol is an antibiotic produced by Streptomyces venezuelae and other soil bacteria that was first discovered in 1947 and is now exclusively produced synthetically.With two chiral centers it is one of
19、 four diastereomers only one of which(1R,2R)is active.Chemical propertiesChloramphenicol is bacteriostatic by inhibition of protein biosynthesis.Its toxicities prevent Chloramphenicol from being more widely used.The major adverse effect of chloramphenicol is a risk of fatal irreversible aplastic ane
20、mia that occurs after therapy and does not appear to be related to dose or administration route.Reversible bone marrow suppression and several other adverse effects including gastrointestinal problems,headache,and mild depression have also been noted.Usage Despite potentially serious limitations,Chl
21、oramphenicol is an excellent drug when used carefully.Its special value is in typhoid(伤寒伤寒)and paratyphoid fever（副（副伤寒）伤寒）,Haemophilus infection,pneumococcal(肺炎球菌肺炎球菌)and meningococcal meningitis(脑膜炎脑膜炎)in-lactam allergic patients,anaerobic(厌氧菌厌氧菌)infection,rickettsial infections,and so on.Synthesis
22、 Chloramphenicol Palmitate is the palmitic acid ester of chloramphenicol.It is a tasteless prodrug of chloramphenicol intended for pediatric use.The ester must hydrolyze in vivo following oral absorption to provide the active form.Chloramphenicol Palmitate(棕榈氯霉素棕榈氯霉素)Chloramphenicol Sodium Succinate
23、(琥珀氯霉素钠琥珀氯霉素钠)Chloramphenicol sodium succinate is the water-soluble sodium salt of the hemisuccinate ester of chloramphenicol.Because of the low solubility of chloramphenicol,the sodium succinate is preferred for intravenous administration.The availability of chloramphenicol from the ester following
24、 intravenous administration is estimated to be 70 to 75%.SummarylTetracyclineslAminoglycosideslMacrolideslErythromycinlStructure modification of semi-synthetic erythromycinlChloramphenicollMechanism of actionlQuestion:l1.Why is the erythromycin A unstable in acidic condition?l2.What is the difference of the action mechanism of antibiotics?lAssignment:l1.Read textbook pp334-355,360-361l2.Do homework Exercises of medicinal chemistry p96 Type A and药物化学学习指导,第八章