Drug examples: Synthesis/heterocycle examples (Ketoconazole, Metronidazole, Miconazole) MCQs With Answer

Introduction: This quiz set focuses on practical synthetic and heterocyclic aspects of three important antifungal and antiprotozoal drugs: Ketoconazole, Metronidazole and Miconazole. Designed for M.Pharm students studying MPC 102T Advanced Organic Chemistry I, the questions probe key concepts such as imidazole ring chemistry, typical synthetic transformations (alkylation, nitration, acetal/dioxolane formation), reagents and mechanistic features, and the pharmacophore interactions with fungal enzymes. The items emphasize deeper understanding of heterocycle formation, regiochemistry, functional group interconversions and analytical identification relevant to designing and characterising these drug molecules in research and industry settings.

Q1. Which statement correctly describes the aromaticity of the imidazole ring present in drugs like miconazole and metronidazole?

• Imidazole is non-aromatic because it has 8 π electrons.
• Imidazole is aromatic with 6 π electrons, one lone pair of nitrogen contributing to the aromatic sextet.
• Imidazole is antiaromatic due to alternating double bonds and two nitrogens.
• Imidazole is aromatic with 10 π electrons counting both nitrogen lone pairs.

Correct Answer: Imidazole is aromatic with 6 π electrons, one lone pair of nitrogen contributing to the aromatic sextet.

Q2. In an imidazole ring, the two nitrogens have different electronic characters. Which description is correct?

• Both nitrogens are pyrrole-like (non-basic) because both donate lone pairs to the ring.
• One nitrogen is pyridine-like (basic) and the other is pyrrole-like (non-basic).
• Both nitrogens are pyridine-like and equally basic.
• Neither nitrogen has any basic character due to delocalization.

Correct Answer: One nitrogen is pyridine-like (basic) and the other is pyrrole-like (non-basic).

Q3. The classical Debus–Radziszewski imidazole synthesis typically requires which set of components?

• An α-haloketone and primary amine under basic conditions.
• Glyoxal (or a 1,2-dicarbonyl), an aldehyde and ammonia (or a primary amine).
• An enamine and a nitrile under acidic catalysis.
• A diazonium salt and an enol ether in the presence of copper.

Correct Answer: Glyoxal (or a 1,2-dicarbonyl), an aldehyde and ammonia (or a primary amine).

Q4. Metronidazole is classified chemically as which heterocyclic subtype?

• 2,4-Triazole derivative
• Benzimidazole derivative
• 5-Nitroimidazole derivative
• Oxazolidinone derivative

Correct Answer: 5-Nitroimidazole derivative

Q5. The primary antimicrobial mechanism of metronidazole involves:

• Chelation of fungal heme iron and inhibition of ergosterol synthesis.
• Penetration into cell walls disrupting peptidoglycan synthesis.
• Reduction of its nitro group in anaerobic microorganisms to reactive radicals that damage DNA.
• Alkylation of ribosomal RNA to block protein synthesis in aerobes.

Correct Answer: Reduction of its nitro group in anaerobic microorganisms to reactive radicals that damage DNA.

Q6. Which reagent combination is most commonly used for aromatic nitration (installing a nitro group) on heteroaromatic substrates when feasible synthetically?

• N-Bromosuccinimide (NBS) in CCl4
• Concentrated nitric acid and concentrated sulfuric acid (mixed acid)
• Sodium nitrite in cold aqueous acid
• Trimethylsilyl triflate with sodium azide

Correct Answer: Concentrated nitric acid and concentrated sulfuric acid (mixed acid)

Q7. A common synthetic step to attach the 2-hydroxyethyl side chain to a 5-nitroimidazole nucleus (as in metronidazole) is:

• Friedel–Crafts acylation at C2 followed by reduction.
• Nucleophilic alkylation of the imidazole nitrogen with 2-chloroethanol under basic conditions.
• Aldol condensation between imidazole and acetaldehyde.
• Direct oxidation of an ethyl side chain to a hydroxyethyl group using KMnO4.

Correct Answer: Nucleophilic alkylation of the imidazole nitrogen with 2-chloroethanol under basic conditions.

Q8. Ketoconazole and miconazole exert antifungal activity mainly by inhibiting which enzyme in fungal sterol biosynthesis?

• β-Glucan synthase
• Squalene epoxidase
• Lanosterol 14α-demethylase (a cytochrome P450 enzyme)
• HMG-CoA reductase

Correct Answer: Lanosterol 14α-demethylase (a cytochrome P450 enzyme)

Q9. During N-alkylation of imidazole, which nitrogen is generally more nucleophilic and thus more likely to be alkylated under typical conditions?

• The pyrrole-type nitrogen (the one whose lone pair is part of the aromatic sextet)
• Both nitrogens are equally likely to be alkylated
• The pyridine-type nitrogen (the one with a lone pair not involved in aromaticity)
• Alkylation cannot occur on imidazoles under normal conditions

Correct Answer: The pyridine-type nitrogen (the one with a lone pair not involved in aromaticity)

Q10. The dioxolane ring found in drugs like ketoconazole is typically formed by which transformation in synthetic chemistry?

• Acetalization of a carbonyl compound with ethylene glycol under acid catalysis.
• Oxidative coupling of two alcohols using PCC.
• Intramolecular nucleophilic aromatic substitution.
• Reduction of a furan ring with hydrogenation over Pd/C.

Correct Answer: Acetalization of a carbonyl compound with ethylene glycol under acid catalysis.

Q11. A practical laboratory step to prepare benzyl chloride intermediates (used in many imidazole alkylation routes for miconazole/ketoconazole analogues) from benzyl alcohol is to treat the alcohol with:

• Sodium borohydride (NaBH4)
• Thionyl chloride (SOCl2)
• Pyridinium chlorochromate (PCC)
• Silver nitrate in acetone

Correct Answer: Thionyl chloride (SOCl2)

Q12. Which feature of the nitro group in metronidazole is essential for its selective activity in anaerobic microbes?

• The nitro group increases lipophilicity making the drug membrane-permeable.
• The nitro group is reduced under low-redox potential conditions to radical species that damage DNA.
• The nitro group coordinates to heme iron in fungal P450 enzymes.
• The nitro group acts as a leaving group in enzymatic substitution reactions.

Correct Answer: The nitro group is reduced under low-redox potential conditions to radical species that damage DNA.

Q13. During synthesis of imidazole derivatives, a common method to activate an alcohol for nucleophilic substitution is conversion to a better leaving group. Which reagent below is commonly used to convert an alcohol to a sulfonate ester (e.g., tosylate) to enable SN2 with an imidazole nucleophile?

• Tosyl chloride (TsCl) with pyridine
• Sodium hydride (NaH)
• Hydrogen peroxide (H2O2)
• Borane (BH3)

Correct Answer: Tosyl chloride (TsCl) with pyridine

Q14. In medicinal chemistry of azole antifungals, coordination of the heterocyclic nitrogen to the heme iron of fungal P450s is crucial. Which heteroatom interaction primarily mediates inhibition of 14α-demethylase by imidazole-containing drugs?

• Hydrogen bonding between imidazole C–H and the heme porphyrin
• Coordination (ligand binding) of an imidazole nitrogen lone pair to the heme iron
• Covalent bond formation between imidazole and the enzyme cysteine residue
• π–π stacking of the imidazole ring with a heme aromatic side chain

Correct Answer: Coordination (ligand binding) of an imidazole nitrogen lone pair to the heme iron

Q15. Which base is commonly employed to deprotonate imidazole to form the N-nucleophile required for many alkylation steps in synthesis of miconazole/ketoconazole analogues?

• Triethylamine (weak base only)
• Sodium hydride (NaH)
• Pyridinium chloride
• Copper(I) iodide

Correct Answer: Sodium hydride (NaH)

Q16. Which analytical technique would most directly confirm the presence of a nitro functional group in a compound like metronidazole?

• Proton NMR showing a singlet at 0 ppm
• IR spectroscopy showing strong bands near 1530 and 1350 cm–1 (NO2 stretches)
• UV-Vis showing absorption at 280 nm characteristic of nitro groups
• Mass spectrometry cannot detect nitro groups

Correct Answer: IR spectroscopy showing strong bands near 1530 and 1350 cm–1 (NO2 stretches)

Q17. In designing analogues of imidazole antifungals, increasing lipophilicity of the aryl substituents most often affects which pharmacokinetic property?

• Decreases membrane permeability and reduces topical potency
• Increases aqueous solubility dramatically
• Increases tissue penetration and membrane permeability, which may enhance potency but can increase systemic exposure
• Has no effect on ADME properties

Correct Answer: Increases tissue penetration and membrane permeability, which may enhance potency but can increase systemic exposure

Q18. Which synthetic challenge is commonly encountered when attempting direct electrophilic nitration of an imidazole ring?

• Imidazole rings are too electron-poor to be nitrated by any reagent.
• Regioselectivity and over-oxidation or decomposition under strong acidic nitration conditions.
• Nitration always yields only N‑nitro imidazole rather than C‑nitro products.
• Nitration of imidazole gives exclusively para-substituted products.

Correct Answer: Regioselectivity and over-oxidation or decomposition under strong acidic nitration conditions.

Q19. Which metabolic interaction is pharmaceutically significant for ketoconazole and is important for safety considerations?

• Ketoconazole induces CYP3A4 leading to increased clearance of other drugs.
• Ketoconazole is an inhibitor of multiple CYP enzymes (notably CYP3A4), causing drug–drug interaction risks.
• Ketoconazole is not metabolized and is excreted unchanged.
• Ketoconazole selectively inhibits phase II glucuronidation only.

Correct Answer: Ketoconazole is an inhibitor of multiple CYP enzymes (notably CYP3A4), causing drug–drug interaction risks.

Q20. For a synthetic route to miconazole analogues, which step sequence best represents a high-level plan: convert benzyl alcohol to benzyl chloride, then couple to imidazole?

• Oxidize benzyl alcohol to benzaldehyde, then perform Wittig with imidazole.
• Convert benzyl alcohol to benzyl chloride (e.g., SOCl2), deprotonate imidazole (e.g., NaH), then perform SN2 alkylation.
• Directly mix benzyl alcohol with imidazole in water without activation and expect coupling.
• First nitrate imidazole, then hydrogenate benzyl alcohol to methane and link the fragments.

Correct Answer: Convert benzyl alcohol to benzyl chloride (e.g., SOCl2), deprotonate imidazole (e.g., NaH), then perform SN2 alkylation.

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