Chem167_L18_Jun4_final

Some gram ve bacteria less likely to cause allergic

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Unformatted text preview: Presence of β- lactamases 5) Transfer of β- lactamases between strains 6) Efflux mechanisms Strategy • The number of factors involved make a single strategy impossible • Use trial and error by varying R groups on the side chain • Successful in producing broad spectrum an#bio#cs • Results demonstrate general rules for broad spectrum ac#vity. Problem 3 - Range of Ac#vity O C Examples of Broad Spectrum Penicillins NH2 H H S N Me O CO2H H NH2 C C H N H HO C C H N H O O O O Ampicillin (Penbri#n) 2nd most used penicillin Me R Class 1 - NH2 at the α- posi#on Ampicillin and amoxicillin (Beechams, 1964) H H N Amoxicillin (Amoxil) • Ac#ve vs Gram +ve bacteria and Gram - ve bacteria which do not produce β- lactamases • Acid resistant and orally ac#ve • Non toxic • Sensi#ve to β- lactamases • Increased polarity due to extra amino group • Poor absorp#on through the gut wall • Disrup#on of gut flora leading to diarrhoea • Inac#ve vs. Pseudomonas aeruginosa Problem 3 - Range of Ac#vity Prodrugs of Ampicillin (Leo Pharmaceu#cals - 1969) O H R= NH2 C CH2O CMe3 PIVAMPICILLIN C C H N O H H S O Me TALAMPICILLIN O R= Me N O O CO2R R= CH O C O Me Proper#es • Increased cell membrane permeability • Polar carboxylic acid group is masked by the ester • Ester is metabolised in the body by esterases to give the free drug CH2Me BACAMPICILLIN Cephalosporin C 7- Aminoadipic side chain HH N H2N H CO2H 7 8 O H 6 5 N S 1 4 2 3 O O Dihydrothiazine ring β- Lactam ring H H Me O CO2H H2N C S N O O CO2H C Me O 7- Aminocephalosporinic acid (7- ACA) more evenly directed against gram- posi#ve and - nega#ve bacteria lower hydrolysis suscep#bility by beta- lactamase Proper*es of Cephalosporin C HH N H2N H CO2H 7 8 O H 6 5 N S 1 4 2 3 O CO2H O C Me O Disadvantages • Polar due to the side chain - difficult to isolate and purify • Low potency - limited to the treatment of urinary tract infec*ons where it is concentrated in the urine • Not abso...
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