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kyleannkelsey
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 What is this molecule?
6-aminopenicillinic acid, the penicillin pharmacophore
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The 2 methyls off the thiazolidine ring have what significance?
Essential for activity and are present on all marketed products
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The nature of the R group will determine What characteristic?
Spectrum of activity, Stability against hydrolysis by beta-lactamases, Acid stability, GI absorption, Side effects, DDIs and protein binding
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 What action is occurring in this picture?
In vitro hydrolysis of a penicillin by a base
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The rare of this hydrolysis reaction will increase with increasing _________.
pH
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 What reaction is occurring in the picture?
In vitro or in vivo penicillin decomposition by acid
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At what pH must the media be for this reaction to occur?
< 3
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 Preventing nucleophilic attack by the side chain acyl O at the lactam carbonyl C will have what effect on the Penicillin molecule?
Increase acid stability
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Is the C3-COOH essential, why or why not?
Yes, it mimics the glutamate in the bacterial cell wall
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In what form does the C3-COOH exist at physiological pH?
COO-
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If you create an inorganic salt (e.g. sodium or potassium) from the C3-COOH group, would it be water soluble or insoluble?
Water-Soluble
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If you create an organic salt from the C3-COOH group, would it be water soluble or insoluble?
Water-Insoluble
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If you wanted to formulate a penicillin to be administered by IV, how would you alter this molecule?
Make the C3-COOH an inorganic salt with K or Na
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What is this structure?
Pen G
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Why is this structure acid liable?
Because there is negligible electronic influence on side-chain acyl carbonyl, so the acyl carbonyl oxygen has good δ- character
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Why is Pen G susceptible to penicillinases?
The benzyl group is not bulky enough to protect the structure from attack
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What characteristic of the R group on Pen G promotes activity against G+ organisms?
Lipophilicity of the Benzyl group
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What characteristic of the R group on Pen G prevents activity against G- organisms?
Lipophilicity of the Benzyl group
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The lipophilic nature of the benzyl group on Pen G has what effect on the molecule?
Promotes activity against G+, prevents activity against G-, promotes protein binding and promote CNS distribution
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Why is Pen G not good for systemic infections?
Lipophilicty of the benzyl group promotes protein binding and reduces percent free drug
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What structure of Pen G allows it to be used in the treatment of meningitis caused by strep pneumoniae?
The lipophilic benzyl group, which allows it to cross the BBB and attack G+ organisms
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What aspect of Pen G allows it to cause side effects like nervousness, dizziness and convulsions?
The lipophilic benzyl group that allows penetration of the BBB
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What enhancement of activity occurs when you add substituents on the benzene group of Pen G?
None
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 What is this structure?
Ticarcillin
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 What is this structure?
Thienyl group
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What is the R group called on Ticarcillin?
Thienyl group
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How does the Thienyl group on Ticarcillin compare to a benzene?
More polar than benzene and may be responsible for increased anaerobic activity
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 What is the name of the R side chain on this molecule?
Phenoxymethyl group
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What is this R group called?
Phenoxymethyl
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How does the side chain of Pen V inhibit nucleophilic attack at the lactam carbonyl carbon in acidic medium?
The O atom on the side chain is negative inducing, which decreases the nucleophilic character of the side chain acyl Oxygen, inhibiting nucleophilic attack
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How can you change this molecule to provide protection against B-lactamase hydrolysis?
Incorporate the on the side chain into a ring, providing sufficient steric hindrance
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What is the benefit of having an R group of one of these structures on your penicillin?
Sterically hinders attack by B-lactamases
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The ortho substituents on the rings (R1, R2) have what significance?
Important for maximum beta-lactamase inhibiting activity (increase steric hindrance) AND for oral activity
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What should R1 and R2 be in order for the molecule to have oral activity?
Electron withdrawing (e.g. Cl)
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Cloxacillin has string B-lactamase inhibition and good oral activity, why?
Isoxazole ring blocks B-lactamases and electron withdrawing Cl group enhances this and adds oral activity
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