Bioisosteric replacement strategies MCQs With Answer

Bioisosteric replacement strategies MCQs With Answer present focused practice for B. Pharm students to master medicinal chemistry concepts. This introduction covers key ideas such as bioisosteres, classical and non-classical replacements, scaffold hopping, and practical goals like improving potency, selectivity, metabolic stability, and ADME/Tox profiles. Keywords: bioisosteric replacement, bioisosteres, scaffold hopping, pharmacophore, pKa modulation, lipophilicity, metabolic stability, toxicity reduction, and lead optimization. Questions examine examples (e.g., carboxylate → tetrazole, H → F), electronic and steric effects, and strategy selection during drug design. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the primary definition of a bioisostere in medicinal chemistry?

• A structural fragment with identical molecular weight to the original
• A substituent or group that mimics biological properties of another while altering physicochemical properties
• A group that always increases lipophilicity when substituted
• A fragment used only to block metabolic enzymes

Correct Answer: A substituent or group that mimics biological properties of another while altering physicochemical properties

Q2. Which statement best distinguishes classical from non-classical bioisosteres?

• Classical bioisosteres are always atoms; non-classical are always rings
• Classical bioisosteres share the same valence electron count; non-classical do not require strict electronic or steric similarity
• Non-classical bioisosteres are less useful in drug design than classical
• Classical bioisosteres change stereochemistry permanently

Correct Answer: Classical bioisosteres share the same valence electron count; non-classical do not require strict electronic or steric similarity

Q3. Which replacement is a classic example of a non-classical bioisosteric change used to mimic carboxylic acids?

• Carboxylic acid → methyl group
• Carboxylic acid → tetrazole
• Carboxylic acid → nitro group
• Carboxylic acid → benzyl ether

Correct Answer: Carboxylic acid → tetrazole

Q4. Replacing a hydrogen atom with fluorine (H → F) is commonly used because fluorine often:

• Greatly increases molecular size and flexibility
• Acts as a strong hydrogen bond donor
• stabilizes C–H bonds by electronic effects and blocks metabolism at that site
• Always converts acids to bases

Correct Answer: stabilizes C–H bonds by electronic effects and blocks metabolism at that site

Q5. Which heterocycle is often used as a bioisostere for benzene to modify electronic properties and H-bonding?

• Pyridine
• Cyclohexane
• Toluene
• Ethane

Correct Answer: Pyridine

Q6. How can bioisosteric replacement influence a drug candidate’s pKa and thus ionization at physiological pH?

• Only by changing molecular weight
• By altering electron-withdrawing/donating groups close to the ionizable center
• By changing stereochemistry far from the ionizable center only
• By adding nonpolar alkyl chains exclusively

Correct Answer: By altering electron-withdrawing/donating groups close to the ionizable center

Q7. Which bioisosteric strategy is most appropriate to reduce a compound’s metabolic oxidation at a benzylic position?

• Replace benzylic hydrogen with fluorine
• Convert aromatic ring to aliphatic chain
• Introduce a nitro group on the benzylic carbon
• Replace benzylic carbon with oxygen

Correct Answer: Replace benzylic hydrogen with fluorine

Q8. Which replacement can reduce a drug’s basicity and potentially lower P-gp efflux if the basic center is problematic?

• Replace tertiary amine with oxygen or amide
• Replace hydroxyl with tertiary amine
• Add an additional tertiary amine
• Convert a carbonyl to a ketal

Correct Answer: Replace tertiary amine with oxygen or amide

Q9. Which functional group is commonly replaced because of toxicity concerns and poor metabolic profile?

• Phenyl → pyridyl
• Nitro group → bioisostere such as cyano or sulfonamide
• Methyl → ethyl
• Hydroxyl → methoxy in all cases

Correct Answer: Nitro group → bioisostere such as cyano or sulfonamide

Q10. Scaffold hopping refers to:

• Replacing an entire core scaffold with a different core while preserving key pharmacophore elements
• Only changing side chains without altering the core
• Making the molecule larger to increase molecular weight
• Converting small molecules to peptides exclusively

Correct Answer: Replacing an entire core scaffold with a different core while preserving key pharmacophore elements

Q11. Which replacement is commonly used to mimic a carbonyl oxygen’s lone pair distribution without retaining reactivity?

• Carbonyl → sulfone
• Carbonyl → oxadiazole or isoxazole heterocycle
• Carbonyl → methylene
• Carbonyl → nitrobenzene

Correct Answer: Carbonyl → oxadiazole or isoxazole heterocycle

Q12. In matched molecular pair analysis for bioisosteric evaluation, what is the primary comparison?

• Two molecules with unrelated scaffolds
• Pairs differing by a single, well-defined substitution to assess property changes
• Comparing two enantiomers only
• Only comparing molecules with identical pKa values

Correct Answer: Pairs differing by a single, well-defined substitution to assess property changes

Q13. Which bioisosteric change can increase membrane permeability by reducing polarity?

• Replace methyl group with hydroxyl
• Replace carboxylic acid with a neutral isostere like tetrazole (depending on pKa) or ester prodrug
• Replace an aliphatic chain with a charged group
• Introduce additional hydroxyl groups

Correct Answer: Replace carboxylic acid with a neutral isostere like tetrazole (depending on pKa) or ester prodrug

Q14. Which substitution is a classic classical bioisosteric exchange based on valence electron similarity?

• Oxygen (O) for sulfur (S)
• Methyl for ethyl
• Phenyl for cyclohexyl
• Carboxylate for tetrazole

Correct Answer: Oxygen (O) for sulfur (S)

Q15. Replacing an aromatic hydrogen with deuterium (H → D) is used primarily to:

• Increase basicity dramatically
• Alter metabolic rates due to kinetic isotope effect and improve metabolic stability
• Make the molecule fluorescent
• Prevent hydrogen bonding entirely

Correct Answer: Alter metabolic rates due to kinetic isotope effect and improve metabolic stability

Q16. Which is a beneficial outcome of replacing a metabolically soft site with a sterically hindered bioisostere?

• Increased clearance
• Improved metabolic stability and longer half-life
• Always increased toxicity
• Complete loss of target affinity

Correct Answer: Improved metabolic stability and longer half-life

Q17. Which bioisosteric swap can retain H-bond donor capability while reducing polarity slightly?

• Hydroxyl → thiol
• Hydroxyl → fluorine
• Hydroxyl → methoxy
• Hydroxyl → amino (NH2)

Correct Answer: Hydroxyl → thiol

Q18. Why is tetrazole often chosen as a carboxylate bioisostere in angiotensin receptor blockers?

• Tetrazole is neutral and eliminates H-bonding
• Tetrazole mimics acidity, provides similar pKa, and improves membrane permeability and metabolic profile
• Tetrazole is always less lipophilic than carboxylate
• Tetrazole formation is cheaper in synthesis

Correct Answer: Tetrazole mimics acidity, provides similar pKa, and improves membrane permeability and metabolic profile

Q19. Which replacement is commonly used to mimic an aromatic ring’s π-system while introducing polarity and potential H-bond acceptor?

• Replace benzene with pyridine
• Replace benzene with cyclohexane
• Replace benzene with tert-butyl
• Replace benzene with ethane

Correct Answer: Replace benzene with pyridine

Q20. What is a key consideration when applying bioisosteric replacement to improve oral bioavailability?

• Only increase molecular weight regardless of solubility
• Balance lipophilicity, polarity, pKa, and permeability while retaining target interaction
• Always remove polar groups to increase lipophilicity
• Only alter stereocenters

Correct Answer: Balance lipophilicity, polarity, pKa, and permeability while retaining target interaction

Q21. Which change could reduce off-target binding caused by planar aromatic surfaces?

• Increase planarity by adding conjugated double bonds
• Introduce sp3 centers or replace aromatic ring with saturated bioisostere to reduce flatness
• Add more halogens to increase planarity
• Convert ring to polyaromatic system

Correct Answer: Introduce sp3 centers or replace aromatic ring with saturated bioisostere to reduce flatness

Q22. Which bioisosteric replacement can preserve a hydrogen bond acceptor but decrease basicity compared with an amine?

• Primary amine → amide
• Amine → tertiary ammonium salt
• Amine → nitro group
• Amine → alkyl chain

Correct Answer: Primary amine → amide

Q23. In lead optimization, bioisosteric replacement is often used to:

• Randomly change structures without data
• Systematically tune potency, ADME properties, and safety based on SAR
• Guarantee immediate clinical success
• Eliminate the need for biological assays

Correct Answer: Systematically tune potency, ADME properties, and safety based on SAR

Q24. Which of the following is an example of a classical bioisosteric pair based on similar outer electron configuration?

• Chlorine and methyl
• Oxygen and sulfur
• Benzene and cyclohexane
• Nitro and amino

Correct Answer: Oxygen and sulfur

Q25. Replacing a labile ester with which group can increase metabolic stability while maintaining similar geometry?

• Replace ester with amide
• Replace ester with free carboxylate always
• Replace ester with nitrate
• Replace ester with peroxide

Correct Answer: Replace ester with amide

Q26. Which replacement would likely reduce basicity and PKa of an aromatic amine?

• Introduce an electron-withdrawing group (e.g., nitro) on the aromatic ring
• Introduce an electron-donating group (e.g., methoxy)
• Reduce ring substitution
• Convert aromatic amine to aliphatic amine

Correct Answer: Introduce an electron-withdrawing group (e.g., nitro) on the aromatic ring

Q27. Which bioisosteric swap is commonly used to decrease a molecule’s tendency to form glucuronide conjugates at phenolic sites?

• Phenol → methoxy or fluorine substitution
• Phenol → additional hydroxyl groups
• Phenol → sulfate group
• Phenol → free carboxylate

Correct Answer: Phenol → methoxy or fluorine substitution

Q28. Which of the following best explains why replacing an aromatic ring with a heterocycle can change selectivity?

• Heterocycles lack pi-electrons entirely
• Heterocycles introduce heteroatoms that alter H-bonding, dipole and electronics, affecting receptor interactions
• Heterocycles always increase molecular weight by 100 Da
• Heterocycles only change color of the compound

Correct Answer: Heterocycles introduce heteroatoms that alter H-bonding, dipole and electronics, affecting receptor interactions

Q29. What is a practical experimental method to validate a proposed bioisosteric replacement?

• Rely solely on computational predictions without synthesis
• Synthesize the analog and test in relevant biological and ADME assays (SAR, metabolic stability, permeability)
• Only measure melting point
• Skip assays and proceed to clinical trials

Correct Answer: Synthesize the analog and test in relevant biological and ADME assays (SAR, metabolic stability, permeability)

Q30. Which concept links bioisosteric replacement to preservation of key molecular interactions with the biological target?

• Random modification
• Pharmacophore mapping and maintenance of key interaction points (H-bond donors/acceptors, hydrophobic anchors, ionic interactions)
• Only increasing molecular weight
• Removing all polar interactions

Correct Answer: Pharmacophore mapping and maintenance of key interaction points (H-bond donors/acceptors, hydrophobic anchors, ionic interactions)

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