Chem167_L18_Jun4_final

Building block vancomycin binds to the tail of the

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Unformatted text preview: rbed orally Advantages • Non toxic • Lower risk of allergic reac*ons compared to penicillins • More stable to acid condi*ons • More stable to β- lactamases • Ra*o of ac*vity vs Gram - ve and Gram +ve bacteria is beUer Conclusion • Useful as a lead compound SAR of Cephalosporins HH N R 7 8 O O H 6 5 N S 1 4 2 3 O C Me O CO2H • Similar to penicillins • The β- lactam ring is crucial to the mechanism • The carboxylic acid at posi*on 4 is important to binding • The bicyclic system is important in increasing ring strain • Stereochemistry is important • The acetoxy subs*tuent is important to the mechanism Possible modifica*ons • 7- Acylamino side chain • 3- Acetoxymethyl side chain • Subs*tu*on at C- 7 Mechanism of Ac*on HH N 7 R O H S N O O CO2H C O Me H S -CH3CO2- O N O O CO2H Ser OH Ser HH N R Enzyme Enzyme Note The acetoxy group acts as a good leaving group and aids the mechanism First Genera*on Cephalosporins Cephalothin HH N 7 S O H S 3 N OAc O CO2H • More ac*ve than penicillin G vs. some Gram - ve bacteria • Less likely to cause allergic reac*ons • Useful vs. penicillinase producing strains of S. aureus • Not ac*ve vs. Pseudonomas aeruginosa • Poorly absorbed from GIT • Administered by injec*on • Metabolised to give a free 3- hydroxymethyl group (deacetyla*on) • Metabolite is less ac*ve β- Lactamase Inhibitors Clavulanic acid (Beechams 1976) Sulphur replaced by O No acylamino side chain H 9 O 6 7 5 N 1 OH 4 3 2 Secreted when antibiotics are present in the environment H O H CO2H β-Lactam Oxazolidine ring • Isolated from Streptomyces clavuligerus • Weak, unimportant an#bacterial ac#vity • Powerful irreversible inhibitor of β- lactamases - suicide substrate • Used as a sentry drug for ampicillin • Augmen#n = ampicillin + clavulanic acid • Allows less ampicillin per dose and an increased ac#vity spectrum • Timen#n = #carcillin + clavulanic acid • used in combina#on with penicillins to shut down cell wall synthesis and drug resistance β- Lactamase Inhibitors Clavulanic acid - mechanism of ac#on 1 N H 2 N H 2 O 2 CH2OH O N O H CH2OH HN O H Base CO2H O O H 3 CO2H 4 O 5 CH2OH H2N NH NH NH CO2H H O HN O O H CH CH2OH HC O CO2H O O O Irreversibly blocked Vancomycin and vancomycin analogues β- Lactams Growing cell wall ....... ...... . . . . .. . . . . . . . . . .. . . ....
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