Chem Basis - Structures - Penicillins 1

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  1. Image Upload 1What is this molecule?
    6-aminopenicillinic acid, the penicillin pharmacophore
  2. Image Upload 2The 2 methyls off the thiazolidine ring have what significance?
    Essential for activity and are present on all marketed products
  3. Image Upload 3The 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
  4. Image Upload 4What action is occurring in this picture?
    In vitro hydrolysis of a penicillin by a base
  5. Image Upload 5 The rare of this hydrolysis reaction will increase with increasing _________.
    pH
  6. Image Upload 6 What reaction is occurring in the picture?
    In vitro or in vivo penicillin decomposition by acid
  7. Image Upload 7 At what pH must the media be for this reaction to occur?
    < 3
  8. Image Upload 8Preventing 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
  13. Image Upload 13
     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
  14. Image Upload 14
    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
  22. Image Upload 22
    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
  23. Image Upload 23
    What enhancement of activity occurs when you add substituents on the benzene group of Pen G?
    None
  24. Image Upload 24 What is this structure?
    Ticarcillin
  25. Image Upload 25What 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
  28. Image Upload 28What is the name of the R side chain on this molecule?
    Phenoxymethyl group
  29. Image Upload 29
     What is this R group called?
    Phenoxymethyl
  30. Image Upload 30
    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
  31. Image Upload 31 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
  32. Image Upload 32
     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
  34. Image Upload 34 What should R1 and R2 be in order for the molecule to have oral activity?
    Electron withdrawing (e.g. Cl)
  35. Image Upload 35
    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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Chem Basis - Structures - Penicillins 1
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Chem Basis - Structures - Penicillins 1
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