Wattle Pharmacy Prep

Structure-activity relationships
Practice questions with explanations

Structure-activity relationships belongs to Medicinal chemistry and biopharmaceutics, which makes up about 10% of the Overseas Pharmacist Readiness Assessment (OPRA®). Answer each question yourself before opening the explanation.

1. Which structural change explains why cefepime retains activity against organisms producing chromosomal AmpC beta-lactamase?

  1. Addition of a clavulanate moiety
  2. Loss of the beta-lactam ring
  3. A zwitterionic structure giving rapid penetration and poor affinity for the AmpC enzyme
  4. Conversion into a carbapenem
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C. A zwitterionic structure giving rapid penetration and poor affinity for the AmpC enzyme

Fourth-generation cephalosporins carry both a positive and a negative charge, which speeds passage through porins and reduces binding by AmpC enzymes that inactivate earlier cephalosporins. This illustrates how resistance is addressed by chemical design rather than only by adding an inhibitor, and why generational differences are structural.

2. Why is the beta-lactam ring essential to the activity of penicillins?

  1. It binds the bacterial ribosome
  2. Its strained four-membered ring is highly reactive and acylates the active site serine of penicillin-binding proteins
  3. It confers water solubility for renal excretion
  4. It protects the molecule from gastric acid
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B. Its strained four-membered ring is highly reactive and acylates the active site serine of penicillin-binding proteins

The four-membered beta-lactam is under considerable ring strain, so the carbonyl is unusually electrophilic and reacts with the serine hydroxyl in the transpeptidase active site, acylating it irreversibly. Anything that opens the ring — beta-lactamase, gastric acid, alkaline hydrolysis — destroys activity. The side chain at position 6 tunes spectrum, acid stability and beta-lactamase resistance, but the ring itself is the pharmacophore.

3. Why are aminoglycosides not absorbed after oral administration?

  1. They are destroyed by gastric acid
  2. They bind irreversibly to dietary protein
  3. They are metabolised entirely by gut flora
  4. They are highly polar polycations at physiological pH and cannot cross lipid membranes
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D. They are highly polar polycations at physiological pH and cannot cross lipid membranes

Aminoglycosides carry multiple amino sugar groups that are protonated at physiological pH, making them highly water soluble polycations with almost no passive membrane permeability. That is why they require parenteral administration for systemic infection, why they distribute poorly into fat and cells, and why they are cleared unchanged by glomerular filtration. The same polarity underlies their accumulation in renal tubular cells and the inner ear.

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More topics in Medicinal chemistry and biopharmaceutics

Dosage form design · Drug stability and degradation · Functional groups and drug classes · Pharmaceutical excipients · Solubility and partitioning · Sterile products