MCQ Quiz: Medicinal Chemistry – Drug Classes: ACE Inhibitors

Angiotensin-Converting Enzyme (ACE) inhibitors are pivotal in contemporary cardiovascular pharmacotherapy, widely prescribed for conditions such as hypertension, heart failure, and post-myocardial infarction management. For PharmD students, a deep understanding of the medicinal chemistry of ACE inhibitors is crucial. This encompasses their mechanism of action at a molecular level, the structural features dictating their efficacy and pharmacokinetic profiles, and the evolution of different chemical classes within this group. This MCQ quiz will challenge your knowledge of the essential medicinal chemistry principles underlying ACE inhibitors, including their structure-activity relationships (SAR), classification, prodrug strategies, and interaction with the ACE enzyme.

1. ACE inhibitors primarily exert their therapeutic effect by blocking the conversion of:

• A. Angiotensinogen to Angiotensin I
• B. Angiotensin I to Angiotensin II
• C. Angiotensin II to Angiotensin III
• D. Bradykinin to inactive peptides

Answer: B. Angiotensin I to Angiotensin II

2. The ACE enzyme contains a critical metal ion in its active site that is essential for its catalytic activity. This ion is:

• A. Magnesium (Mg2+)
• B. Iron (Fe2+)
• C. Zinc (Zn2+)
• D. Copper (Cu2+)

Answer: C. Zinc (Zn2+)

3. Captopril was the first orally active ACE inhibitor. Which functional group in Captopril is primarily responsible for binding to the zinc ion in the ACE active site?

• A. Carboxylate group
• B. Sulfhydryl (-SH) group
• C. Amide carbonyl
• D. Methyl group

Answer: B. Sulfhydryl (-SH) group

4. Enalapril is an example of which class of ACE inhibitor based on its zinc-binding moiety?

• A. Sulfhydryl-containing
• B. Dicarboxylate-containing
• C. Phosphonate-containing
• D. Natural product-derived

Answer: B. Dicarboxylate-containing

5. Many dicarboxylate-containing ACE inhibitors, like enalapril and ramipril, are administered as prodrugs. This is primarily to:

• A. Increase their water solubility for IV administration
• B. Improve their oral bioavailability by masking polar groups
• C. Reduce their interaction with food
• D. Decrease their binding to plasma proteins

Answer: B. Improve their oral bioavailability by masking polar groups

6. The active metabolite of enalapril is:

• A. Enalaprilat
• B. Lisinopril
• C. Ramiprilat
• D. Captopril

Answer: A. Enalaprilat

7. Lisinopril is unique among many dicarboxylate ACE inhibitors because it:

• A. Contains a sulfhydryl group
• B. Is not a prodrug and is active as administered
• C. Is primarily eliminated unchanged through the biliary route
• D. Has a very short duration of action

Answer: B. Is not a prodrug and is active as administered

8. Fosinopril is a phosphonate-containing ACE inhibitor. The phosphinate group (-PO(O-)R) in fosinoprilat (active form) mimics which part of the natural substrate of ACE?

• A. The C-terminal carboxylate
• B. The scissile peptide bond’s transition state (tetrahedral intermediate)
• C. A hydrophobic amino acid side chain
• D. The N-terminal amino group

Answer: B. The scissile peptide bond’s transition state (tetrahedral intermediate)

9. The development of ACE inhibitors was significantly influenced by the discovery of peptides from the venom of which snake?

• A. Cobra (Naja species)
• B. Rattlesnake (Crotalus species)
• C. Brazilian pit viper (Bothrops jararaca)
• D. Black mamba (Dendroaspis polylepis)

Answer: C. Brazilian pit viper (Bothrops jararaca)

10. Teprotide, a nonapeptide from snake venom, served as a lead compound for ACE inhibitor development. A major disadvantage of teprotide was its:

• A. Lack of potency
• B. Poor oral bioavailability and short duration of action
• C. Pro-arrhythmic effects
• D. Inability to bind to the zinc ion

Answer: B. Poor oral bioavailability and short duration of action

11. In the structure-activity relationship (SAR) of dicarboxylate ACE inhibitors, what is the role of the N-ring (often a proline or proline-like moiety)?

• A. It acts as the primary zinc-binding group.
• B. It mimics the C-terminal carboxylate of Angiotensin I.
• C. It interacts with a hydrophobic pocket (S1′ pocket) in the ACE active site.
• D. It is responsible for prodrug hydrolysis.

Answer: C. It interacts with a hydrophobic pocket (S1′ pocket) in the ACE active site.

12. The presence of a carboxylate group at the C-terminus (or analogous position) of most ACE inhibitors is crucial because it:

• A. Interacts with a positively charged residue (e.g., Arginine) in the ACE active site
• B. Binds to the zinc ion
• C. Facilitates crossing the blood-brain barrier
• D. Undergoes rapid metabolic inactivation

Answer: A. Interacts with a positively charged residue (e.g., Arginine) in the ACE active site

13. ACE also inactivates bradykinin. Inhibition of bradykinin degradation by ACE inhibitors can lead to which common side effect?

• A. Hypokalemia
• B. Tachycardia
• C. Dry cough and angioedema
• D. Hyperglycemia

Answer: C. Dry cough and angioedema

14. The stereochemistry of ACE inhibitors is critical for their activity. For most dicarboxylate inhibitors, which configuration is generally more potent?

• A. The (R,R,R) configuration at the three chiral centers
• B. The (S,S,S) configuration at the three chiral centers (e.g., in enalaprilat)
• C. Racemic mixtures are always preferred
• D. Stereochemistry is not important for dicarboxylate ACE inhibitors

Answer: B. The (S,S,S) configuration at the three chiral centers (e.g., in enalaprilat)

15. Compared to captopril, dicarboxylate ACE inhibitors like enalapril generally have:

• A. A higher incidence of taste disturbances and rash
• B. A shorter duration of action
• C. A lower potency
• D. A longer duration of action and potentially fewer sulfhydryl-related side effects

Answer: D. A longer duration of action and potentially fewer sulfhydryl-related side effects

16. The conversion of enalapril (prodrug) to enalaprilat (active drug) involves which metabolic reaction?

• A. Oxidation
• B. Reduction
• C. Hydrolysis of an ethyl ester
• D. N-dealkylation

Answer: C. Hydrolysis of an ethyl ester

17. Which ACE inhibitor contains a lysine side chain, making it more hydrophilic and not requiring prodrug modification for oral absorption?

• A. Ramipril
• B. Perindopril
• C. Lisinopril
• D. Quinapril

Answer: C. Lisinopril

18. The “S1 pocket” of the ACE enzyme active site typically accommodates which type of amino acid residue from the substrate?

• A. Acidic residues (e.g., Asp, Glu)
• B. Basic residues (e.g., Lys, Arg)
• C. Bulky hydrophobic residues (e.g., Phe, Tyr)
• D. Small, polar residues (e.g., Ser, Thr)

Answer: C. Bulky hydrophobic residues (e.g., Phe, Tyr)

19. What is a common structural feature of the N-ring in many dicarboxylate ACE inhibitors that enhances binding to the S1′ pocket?

• A. A primary amine
• B. A fused heterocyclic ring system (e.g., tetrahydroisoquinoline in quinapril, perindopril)
• C. A sulfhydryl group
• D. A nitro group

Answer: B. A fused heterocyclic ring system (e.g., tetrahydroisoquinoline in quinapril, perindopril)

20. Fosinoprilat, the active metabolite of fosinopril, has a unique elimination profile due to its phosphinate group, which involves:

• A. Exclusively renal excretion
• B. Exclusively hepatic metabolism
• C. Dual elimination pathways (renal and hepatic)
• D. Rapid degradation in plasma

Answer: C. Dual elimination pathways (renal and hepatic)

21. The term “transition-state analog” in the context of ACE inhibitor design refers to compounds that:

• A. Mimic the structure of Angiotensin I
• B. Mimic the structure of Angiotensin II
• C. Mimic the tetrahedral intermediate formed during peptide bond hydrolysis by ACE
• D. Bind irreversibly to the ACE enzyme

Answer: C. Mimic the tetrahedral intermediate formed during peptide bond hydrolysis by ACE

22. One of the key interactions between ACE inhibitors and the ACE active site involves the terminal carboxylate of the inhibitor mimicking the C-terminal carboxylate of:

• A. Bradykinin
• B. Angiotensin I
• C. Renin substrate
• D. Angiotensinogen

Answer: B. Angiotensin I

23. Ramipril is a prodrug that is converted to its active form, ramiprilat. Ramiprilat has a high affinity for ACE due in part to:

• A. Its sulfhydryl group
• B. Its phosphinate group
• C. Its bicyclic N-ring structure effectively fitting the S1′ pocket and optimal stereochemistry
• D. Its rapid conversion to an even more potent metabolite

Answer: C. Its bicyclic N-ring structure effectively fitting the S1′ pocket and optimal stereochemistry

24. Side effects like rash and taste disturbances are more commonly associated with which class of ACE inhibitors?

• A. Dicarboxylate-containing
• B. Phosphonate-containing
• C. Sulfhydryl-containing (e.g., captopril)
• D. Natural product ACE inhibitors

Answer: C. Sulfhydryl-containing (e.g., captopril)

25. What is the primary functional group in lisinopril responsible for binding to the zinc ion in the ACE active site?

• A. Sulfhydryl group
• B. One of its two carboxylate groups (specifically the N-carboxymethyl group)
• C. The amino group of the lysine side chain
• D. The amide carbonyl

Answer: B. One of its two carboxylate groups (specifically the N-carboxymethyl group)

26. The increased lipophilicity of some ACE inhibitor prodrugs compared to their active forms leads to:

• A. Decreased oral absorption
• B. Enhanced penetration into tissues and improved oral absorption
• C. Increased renal excretion
• D. Higher incidence of cough

Answer: B. Enhanced penetration into tissues and improved oral absorption

27. Which of the following best describes the role of the methyl group typically found adjacent to the zinc-binding group in many dicarboxylate ACE inhibitors (e.g., in enalaprilat)?

• A. It increases water solubility.
• B. It interacts with the S1 hydrophobic pocket.
• C. It orients the zinc-binding carboxylate for optimal interaction.
• D. It is the site of metabolic hydroxylation.

Answer: C. It orients the zinc-binding carboxylate for optimal interaction.

28. Perindopril is a prodrug ester that is hydrolyzed to the active diacid perindoprilat. What is a characteristic structural feature of perindoprilat’s N-ring?

• A. A simple proline ring
• B. A perhydroindole ring system
• C. A tetrahydroisoquinoline ring system
• D. A thiazolidine ring

Answer: B. A perhydroindole ring system

29. The design of ACE inhibitors often involves mimicking the dipeptide unit at the C-terminus of Angiotensin I, which is:

• A. Pro-Phe
• B. Phe-Arg
• C. His-Leu
• D. Pro-Lys

Answer: C. His-Leu

30. Moexipril is a prodrug that is converted to moexiprilat. A distinguishing feature of moexiprilat’s N-ring contributing to its potency is:

• A. A sulfhydryl group
• B. A phosphinate group
• C. A tetrahydroisoquinoline-3-carboxylic acid derivative
• D. A simple alanine residue

Answer: C. A tetrahydroisoquinoline-3-carboxylic acid derivative

31. The zinc ion in the ACE active site polarizes which bond of the substrate during catalysis?

• A. The N-H bond of an amide
• B. The C=O bond of the scissile peptide
• C. The C-N bond of the scissile peptide
• D. The S-H bond in cysteine residues

Answer: B. The C=O bond of the scissile peptide

32. Why are ACE inhibitors generally contraindicated during pregnancy?

• A. They cause severe maternal hepatotoxicity.
• B. They can cause fetal injury and death, particularly in the second and third trimesters.
• C. They are potent teratogens causing neural tube defects in the first trimester.
• D. They rapidly cross the placenta and cause neonatal hypoglycemia.

Answer: B. They can cause fetal injury and death, particularly in the second and third trimesters.

33. The duration of action of an ACE inhibitor is influenced by:

• A. Its affinity for the ACE enzyme and its pharmacokinetic half-life
• B. The rate of bradykinin degradation
• C. Its ability to also inhibit renin
• D. Its selectivity for tissue ACE vs. plasma ACE

Answer: A. Its affinity for the ACE enzyme and its pharmacokinetic half-life

34. Benazepril is a prodrug that is metabolized to benazeprilat. Which functional group in benazepril is hydrolyzed?

• A. An amide group
• B. An ethyl ester group
• C. A methyl ether group
• D. A thioester group

Answer: B. An ethyl ester group

35. What is the general strategy behind designing phosphonate-containing ACE inhibitors like fosinopril?

• A. To improve water solubility
• B. To create a more stable and potent zinc-binding group mimicking the transition state
• C. To reduce interaction with food
• D. To target a different binding site on the ACE enzyme

Answer: B. To create a more stable and potent zinc-binding group mimicking the transition state

36. The peptide -Pro-Phe-Arg-Gln- from snake venom was found to potentiate bradykinin. This observation was key because:

• A. It directly led to the structure of captopril.
• B. It suggested that inhibiting the enzyme responsible for bradykinin degradation (ACE) could be beneficial.
• C. It identified a new target for antihypertensive drugs distinct from ACE.
• D. It showed that bradykinin itself was an ACE inhibitor.

Answer: B. It suggested that inhibiting the enzyme responsible for bradykinin degradation (ACE) could be beneficial.

37. Trandolapril is another prodrug ACE inhibitor. Its active metabolite, trandolaprilat, has a long duration of action which is partly due to:

• A. Its slow dissociation from the ACE enzyme
• B. Its extensive enterohepatic recirculation
• C. Its conversion to multiple active metabolites
• D. Its resistance to esterase hydrolysis

Answer: A. Its slow dissociation from the ACE enzyme

38. A key structural feature for interaction with the S2′ pocket of ACE (which accommodates the C-terminal residue of Angiotensin I) is mimicked in ACE inhibitors by:

• A. The zinc-binding group
• B. The N-ring (e.g., proline)
• C. The terminal carboxylate group
• D. The methyl group on the alpha-carbon

Answer: C. The terminal carboxylate group

39. Most orally administered ACE inhibitors are primarily eliminated via:

• A. Biliary excretion as unchanged drug
• B. Renal excretion, either as the active drug or its metabolites
• C. Pulmonary exhalation
• D. Degradation in the gastrointestinal tract

Answer: B. Renal excretion, either as the active drug or its metabolites

40. The rationale for designing ACE inhibitors with different N-ring structures (e.g., proline in captopril, perhydroindole in perindopril) is to:

• A. Change the zinc-binding affinity
• B. Modify the interaction with the S1′ hydrophobic pocket for improved potency or pharmacokinetics
• C. Alter the route of metabolism
• D. Increase water solubility significantly

Answer: B. Modify the interaction with the S1′ hydrophobic pocket for improved potency or pharmacokinetics

41. What is a potential chemical instability issue for captopril due to its sulfhydryl group?

• A. Hydrolysis of an ester linkage
• B. Oxidation to form disulfide dimers
• C. Racemization at its chiral center
• D. Decarboxylation

Answer: B. Oxidation to form disulfide dimers

42. The “mercaptoacyl” part of captopril refers to:

• A. The proline ring
• B. The sulfhydryl group and the adjacent acyl (carbonyl) group
• C. The methyl group
• D. The terminal carboxylate

Answer: B. The sulfhydryl group and the adjacent acyl (carbonyl) group

43. Which of the following ACE inhibitors has the simplest chemical structure, lacking a complex N-ring?

• A. Enalapril
• B. Lisinopril
• C. Captopril
• D. Ramipril

Answer: C. Captopril

44. The esterification of dicarboxylate ACE inhibitors to form prodrugs (e.g., enalapril from enalaprilat) primarily enhances:

• A. Binding to the ACE enzyme
• B. Lipophilicity and thus oral absorption
• C. Water solubility for injection
• D. Resistance to metabolism

Answer: B. Lipophilicity and thus oral absorption

45. The phosphinate group in fosinoprilat is considered a bioisostere of which group in other ACE inhibitors?

• A. A sulfhydryl group
• B. A carboxylate group involved in zinc binding
• C. A proline ring
• D. An amide bond

Answer: B. A carboxylate group involved in zinc binding

46. The design of potent ACE inhibitors often focuses on mimicking the last two amino acids of Angiotensin I, which are His-Leu. The leucine side chain is mimicked by groups interacting with which pocket of ACE?

• A. S1 pocket
• B. S1′ pocket
• C. S2 pocket
• D. S2′ pocket

Answer: A. S1 pocket

47. The proline moiety (or its analogues) in many ACE inhibitors is thought to mimic which amino acid of the natural substrate Angiotensin I at the S1′ position?

• A. Histidine
• B. Leucine
• C. Proline
• D. Phenylalanine

Answer: C. Proline

48. What functional group is common to enalaprilat, lisinopril, and ramiprilat that is responsible for chelating the zinc ion in ACE?

• A. A sulfhydryl group
• B. A carboxylate group (part of a N-carboxyalkyl dipeptide structure)
• C. A phosphinate group
• D. An amino group

Answer: B. A carboxylate group (part of a N-carboxyalkyl dipeptide structure)

49. The hydrophobic substituents on the N-ring of many ACE inhibitors (e.g., the phenyl ring in benazeprilat) are designed to:

• A. Increase water solubility
• B. Enhance interactions with the S1′ hydrophobic pocket of ACE
• C. Facilitate prodrug hydrolysis
• D. Bind directly to the zinc ion

Answer: B. Enhance interactions with the S1′ hydrophobic pocket of ACE

50. Drug design of ACE inhibitors evolved from understanding the enzyme’s mechanism and substrate specificity. This is an example of:

• A. Random screening
• B. Rational drug design
• C. Serendipitous discovery
• D. Natural product modification only

Answer: B. Rational drug design