GPAT practice: Medicinal chemistry
20 original GPAT-style questions on medicinal chemistry: SAR, pharmacophores, prodrugs, drug metabolism and stereochemistry, with answers and explanations. Tap an option to check your answer, or open "Show answer".
1. In drug design, a pharmacophore is best defined as
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Answer: B — A pharmacophore is the set of features needed to interact with the target and elicit a response. It is not tied to one particular chemical skeleton.
2. Replacing a hydrogen with fluorine at a metabolically labile aromatic position is commonly done to
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Answer: B — The C-F bond is strong and fluorine is similar in size to hydrogen, so it can block hydroxylation by CYP enzymes while changing sterics little.
3. Which pair are classical bioisosteres?
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Answer: C — Methyl and chloro are classical monovalent bioisosteres with similar size. The other pairs differ greatly in electronics and hydrogen-bonding behaviour.
4. The penicillin nucleus (6-aminopenicillanic acid) consists of a thiazolidine ring fused to
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Answer: C — Penicillins have a four-membered beta-lactam ring fused to a five-membered thiazolidine ring. The strained beta-lactam is essential for activity and is attacked by beta-lactamases.
5. Which feature of the sulphonamide structure is essential for antibacterial activity?
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Answer: D — The free p-NH2 allows the molecule to mimic para-aminobenzoic acid and inhibit dihydropteroate synthase. Acylating or substituting this amine gives inactive compounds unless they act as prodrugs.
6. Which of the following is a prodrug that is converted by esterase hydrolysis to its active form?
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Answer: B — Enalapril is an ethyl ester hydrolysed (mainly in the liver) to the active diacid enalaprilat. Captopril is active as such and the other drugs are given in active form.
7. Chloramphenicol palmitate is used in paediatric suspensions mainly because the ester
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Answer: B — The palmitate ester is practically tasteless and is hydrolysed by intestinal lipases to release chloramphenicol. It is a taste-masking prodrug approach.
8. Which of the following is a phase I metabolic reaction?
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Answer: C — Phase I reactions (oxidation, reduction, hydrolysis) introduce or unmask a functional group, with aromatic hydroxylation by CYP enzymes as a common example. Glucuronide, glycine and sulphate conjugation are phase II.
9. Which enzyme family is chiefly responsible for oxidative drug metabolism in the liver?
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Answer: C — The cytochrome P450 system catalyses most phase I oxidations. The other enzymes listed catalyse phase II conjugations.
10. Paracetamol overdose causes liver damage because of accumulation of
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Answer: B — When glucuronidation and sulphation are saturated, more drug is oxidised by CYP to NAPQI, which depletes glutathione and binds to hepatic proteins. N-acetylcysteine replenishes glutathione.
11. Isoniazid is inactivated mainly by which phase II reaction?
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Answer: C — Isoniazid is acetylated by N-acetyltransferase 2, and genetic slow and fast acetylator phenotypes cause variable plasma levels.
12. Which statement about stereochemistry in drugs is correct?
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Answer: B — Receptors and enzymes are chiral, so enantiomers can differ in potency, metabolism or toxicity. Diastereomers are not mirror images, and a racemate shows no net optical rotation.
13. Levodopa rather than dopamine is given in Parkinson's disease because levodopa
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Answer: D — Dopamine cannot cross the blood-brain barrier, whereas levodopa enters via the large neutral amino acid transporter and is decarboxylated to dopamine in the brain.
14. The 4-hydroxycoumarin structure is the pharmacophore of which anticoagulant group?
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Answer: B — Warfarin is a 4-hydroxycoumarin derivative that inhibits vitamin K epoxide reductase, reducing synthesis of functional clotting factors II, VII, IX and X.
15. Which structural change in the catecholamine nucleus gives resistance to COMT and improves oral activity?
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Answer: B — COMT methylates the catechol hydroxyl, so replacing it (as with the hydroxymethyl group of salbutamol) prevents inactivation. An alpha-methyl group likewise shields against MAO.
16. In the synthesis of aspirin, salicylic acid is converted to acetylsalicylic acid by
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Answer: B — The phenolic OH of salicylic acid is acetylated by acetic anhydride, typically with an acid catalyst. The carboxyl group is retained.
17. Which feature is typical of the quinolone antibacterial pharmacophore?
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Answer: D — The 3-carboxylic acid and 4-oxo groups bind to DNA gyrase and topoisomerase IV, and a fluorine at C-6 improves potency in fluoroquinolones.
18. Which structural change in 1,4-benzodiazepines generally increases anxiolytic activity?
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Answer: C — An electronegative substituent at C-7 (as in diazepam) enhances activity. The 5-phenyl ring is also required, and bulky groups at ring positions reduce potency.
19. Which structural feature of phenothiazines like chlorpromazine is needed for neuroleptic activity?
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Answer: D — A three-carbon propyl linker gives antipsychotic activity, while a two-carbon linker favours antihistaminic activity (as in promethazine). An electron-withdrawing group at position 2 also increases potency.
20. Which type of reaction converts a primary alcohol in a drug to a carboxylic acid during phase I metabolism?
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Answer: B — Alcohol dehydrogenase (or CYP enzymes) oxidises the alcohol to an aldehyde, which aldehyde dehydrogenase converts to the carboxylic acid. Glucuronidation is a phase II conjugation.