Sulfonamides – history, chemistry and SAR MCQs With Answer

Sulfonamides – history, chemistry and SAR MCQs With Answer

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Sulfonamides – history, chemistry and SAR MCQs With Answer

Sulfonamides, the first widely used synthetic antibacterial agents, revolutionized therapy after Gerhard Domagk’s discovery of Prontosil in the 1930s. For B. Pharm students, understanding sulfonamide chemistry, mechanism as PABA analogues that inhibit dihydropteroate synthase, and key SAR (para‑amino benzene sulfonamide scaffold, N‑substitutions, pKa effects) is essential. Clinical uses, resistance mechanisms, pharmacokinetics, adverse effects (hypersensitivity, crystalluria, kernicterus) and combinations like trimethoprim–sulfamethoxazole illustrate therapeutic principles. This concise, keyword‑rich overview prepares you for applied questions and exam-style MCQs. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. Which discovery marked the clinical beginning of sulfonamide therapy?

  • Discovery of penicillin by Alexander Fleming
  • Development of trimethoprim
  • Discovery of Prontosil by Gerhard Domagk
  • Synthesis of sulfadiazine

Correct Answer: Discovery of Prontosil by Gerhard Domagk

Q2. What is the primary antibacterial mechanism of sulfonamides?

  • Inhibition of dihydrofolate reductase
  • Inhibition of dihydropteroate synthase by acting as PABA analogues
  • Disruption of bacterial cell wall synthesis
  • Inhibition of DNA gyrase

Correct Answer: Inhibition of dihydropteroate synthase by acting as PABA analogues

Q3. Which structural feature is most important in the classical SAR of antibacterial sulfonamides?

  • Ortho‑nitro group on the benzene ring
  • Para‑amino group on the benzene ring relative to the sulfonamide
  • Alkyl chain of at least six carbons on N
  • Replacement of sulfonyl with carbonyl

Correct Answer: Para‑amino group on the benzene ring relative to the sulfonamide

Q4. Sulfonamides are best described chemically as which functional class?

  • Weak bases (amine salts)
  • Neutral esters
  • Weak acids (sulfonamide derivatives)
  • Strong acids

Correct Answer: Weak acids (sulfonamide derivatives)

Q5. Which sulfonamide is a classic orally active example used in combination with trimethoprim?

  • Sulfapyridine
  • Sulfamethoxazole
  • Sulfadiazine
  • Sulfaguanidine

Correct Answer: Sulfamethoxazole

Q6. Why is the free sulfonamide NH generally important for activity?

  • It increases lipophilicity and tissue penetration
  • It forms a hydrogen bond to the active site of dihydropteroate synthase
  • It is required for prodrug activation by the liver
  • It provides fluorescence for tracking

Correct Answer: It forms a hydrogen bond to the active site of dihydropteroate synthase

Q7. Which factor increases the risk of sulfonamide crystalluria?

  • Alkaline urine
  • High drug ionization at urinary pH
  • Acidic urine leading to more unionized drug
  • Concomitant use of urinary alkalinizers

Correct Answer: Acidic urine leading to more unionized drug

Q8. Combining sulfonamides with trimethoprim is synergistic because:

  • Both drugs inhibit the same enzyme at different sites
  • Trimethoprim prevents bacterial uptake of sulfonamides
  • They sequentially block two steps in folate synthesis
  • Trimethoprim increases sulfonamide renal clearance

Correct Answer: They sequentially block two steps in folate synthesis

Q9. A common severe hypersensitivity associated with sulfonamides is:

  • Agranulocytosis only
  • Stevens–Johnson syndrome and toxic epidermal necrolysis
  • Immediate anaphylaxis in all patients
  • Purely gastrointestinal upset

Correct Answer: Stevens–Johnson syndrome and toxic epidermal necrolysis

Q10. Which resistance mechanism is NOT commonly associated with sulfonamides?

  • Mutations in dihydropteroate synthase (DHPS)
  • Increased production of PABA
  • Enzymatic degradation of sulfonamides by beta‑lactamases
  • Plasmid‑mediated resistant DHPS genes

Correct Answer: Enzymatic degradation of sulfonamides by beta‑lactamases

Q11. Prontosil is a prodrug that is metabolized in vivo to which active compound?

  • Sulfamethoxazole
  • Sulfanilamide
  • Sulfadiazine
  • Sulfisoxazole

Correct Answer: Sulfanilamide

Q12. Which sulfonamide is commonly used to treat neonatal toxoplasmosis in combination therapy?

  • Sulfadoxine
  • Sulfadiazine
  • Sulfacetamide
  • Sulfisoxazole

Correct Answer: Sulfadiazine

Q13. The pKa of many sulfonamides falls in which approximate range, affecting their ionization?

  • pKa 2–3
  • pKa 6–8
  • pKa 9–11
  • pKa >12

Correct Answer: pKa 6–8

Q14. Which modification typically improves water solubility and shortens duration of action?

  • Adding a long alkyl chain to N
  • Introducing a heterocyclic substituent that increases polarity
  • Converting the sulfonamide to a nitro group
  • Replacing the para‑amino group with methyl

Correct Answer: Introducing a heterocyclic substituent that increases polarity

Q15. Which adverse effect is a major neonatal concern with maternal sulfonamide use near term?

  • Ototoxicity
  • Kernicterus due to displacement of bilirubin
  • Congenital limb defects
  • Excessive fetal growth

Correct Answer: Kernicterus due to displacement of bilirubin

Q16. Sulfonamides are bacteriostatic alone because:

  • They rapidly lyse bacterial cells
  • They inhibit protein synthesis irreversibly
  • They inhibit folate synthesis leading to slowed growth
  • They destroy the bacterial membrane

Correct Answer: They inhibit folate synthesis leading to slowed growth

Q17. A structural change that often reduces antibacterial activity is:

  • Replacement of the aromatic ring with an aliphatic chain
  • Maintaining a para‑amino benzene ring
  • Keeping the sulfonamide NH unsubstituted when required
  • Adding small electron‑withdrawing groups on the ring

Correct Answer: Replacement of the aromatic ring with an aliphatic chain

Q18. Therapeutic use of sulfonamides declined after penicillin because:

  • They were never effective against any pathogens
  • Penicillins had broader spectrum and fewer serious side effects
  • Sulfonamides were too cheap to produce
  • Sulfonamides caused immediate resistance in all bacteria

Correct Answer: Penicillins had broader spectrum and fewer serious side effects

Q19. Which sulfonamide is commonly used topically for ocular infections?

  • Sulfacetamide
  • Sulfadoxine
  • Sulfapyridine
  • Sulfaguanidine

Correct Answer: Sulfacetamide

Q20. In SAR, what is the effect of bulky N‑substituents on sulfonamides?

  • Always increase antibacterial potency
  • Can alter distribution and decrease activity at the enzyme site
  • Convert the drug into an enzyme activator
  • Remove all adverse effects

Correct Answer: Can alter distribution and decrease activity at the enzyme site

Q21. Which laboratory test result would most directly indicate sulfonamide‑induced hemolysis in a patient with G6PD deficiency?

  • Elevated platelet count
  • Elevated indirect bilirubin and decreased hemoglobin
  • Decreased serum creatinine only
  • Isolated hypernatremia

Correct Answer: Elevated indirect bilirubin and decreased hemoglobin

Q22. Which of the following best describes the role of the para‑amino group in PABA mimicry?

  • It donates electrons to generate reactive oxygen species
  • It mimics PABA’s orientation allowing binding to DHPS active site
  • It is required for renal excretion
  • It prevents absorption from the GI tract

Correct Answer: It mimics PABA’s orientation allowing binding to DHPS active site

Q23. Which sulfonamide is known for a very long half‑life and used in malaria combination therapy historically?

  • Sulfamethoxazole
  • Sulfadoxine
  • Sulfanilamide
  • Sulfacetamide

Correct Answer: Sulfadoxine

Q24. Which pharmacokinetic property is influenced by the pKa of a sulfonamide?

  • Protein synthesis inhibition
  • Degree of ionization and tissue/urine distribution
  • DNA intercalation
  • Ability to chelate magnesium

Correct Answer: Degree of ionization and tissue/urine distribution

Q25. Which structural class does sulfanilamide belong to?

  • Para‑aminobenzenesulfonamide
  • Beta‑lactam
  • Macrolide
  • Quinolone

Correct Answer: Para‑aminobenzenesulfonamide

Q26. Which approach is appropriate to reduce risk of crystalluria during sulfonamide therapy?

  • Encourage dehydration
  • Acidify the urine with ammonium chloride
  • Hydrate well and alkalinize urine if needed
  • Combine with NSAIDs to increase clearance

Correct Answer: Hydrate well and alkalinize urine if needed

Q27. A change in bacterial sensitivity due to increased PABA synthesis is an example of which resistance type?

  • Target site mutation
  • Bypass or metabolic overproduction
  • Enzymatic drug inactivation
  • Efflux pump solely

Correct Answer: Bypass or metabolic overproduction

Q28. Which adverse hematologic effect can be caused by long‑term high‑dose sulfonamide therapy?

  • Leukocytosis
  • Aplastic anemia and bone marrow suppression
  • Thrombocytosis only
  • Polychythemia vera

Correct Answer: Aplastic anemia and bone marrow suppression

Q29. Which statement about topical sulfonamides is correct?

  • Topical sulfonamides are all prodrugs activated systemically
  • Topical formulations can avoid systemic hypersensitivity but still cause local reactions
  • Topical use guarantees no resistance development
  • Topical sulfonamides are the first line for systemic sepsis

Correct Answer: Topical formulations can avoid systemic hypersensitivity but still cause local reactions

Q30. In medicinal chemistry, adding electron‑withdrawing groups to the aromatic ring of a sulfonamide typically does what to acidity and antibacterial potency?

  • Decreases acidity and reduces potency
  • Increases acidity and may enhance potency depending on fit to DHPS
  • Has no effect on acidity or potency
  • Converts it into a base and eliminates activity

Correct Answer: Increases acidity and may enhance potency depending on fit to DHPS

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