Concept and classification of bioisosterism MCQs With Answer

Introduction: Bioisosterism is a key concept in medicinal chemistry that involves replacing one atom or functional group with another to retain or improve biological activity. This concept and classification of bioisosterism help B. Pharm students understand how classical bioisosteres and non-classical bioisosteres are used in drug design, lead optimization, and scaffold hopping. Knowledge of common replacements—such as carboxylic acid to tetrazole, benzene to heterocycles, or hydrogen to fluorine—helps predict changes in potency, selectivity, ADME, pKa, lipophilicity, and toxicity. Grasping these principles aids rational modification of drug candidates and patent strategies. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. What is the best definition of bioisosterism?

• The replacement of an atom or group by another with similar physical or chemical properties that produces similar biological effects
• The replacement of any functional group solely to change color
• The process of breaking down drugs in the liver
• The addition of bulky groups to increase molecular weight

Correct Answer: The replacement of an atom or group by another with similar physical or chemical properties that produces similar biological effects

Q2. What is the primary goal of applying bioisosteric replacements in drug design?

• To maintain or improve biological activity while modifying pharmacokinetic or toxicological properties
• To increase the molecular weight as much as possible
• To randomly change functional groups without testing
• To eliminate all hydrogen bond donors

Correct Answer: To maintain or improve biological activity while modifying pharmacokinetic or toxicological properties

Q3. Which statement correctly contrasts classical and non-classical bioisosteres?

• Classical bioisosteres obey strict valence and electron count similarities; non-classical do not but mimic biological properties
• Classical bioisosteres are always larger molecules; non-classical are always smaller
• Classical bioisosteres are synthetic only; non-classical occur in nature only
• There is no difference—both terms are interchangeable in all contexts

Correct Answer: Classical bioisosteres obey strict valence and electron count similarities; non-classical do not but mimic biological properties

Q4. Which pair is a classic medicinal chemistry example of a bioisosteric replacement used in angiotensin receptor blockers?

• Carboxylic acid replaced by tetrazole
• Hydroxyl replaced by methyl
• Benzene replaced by cyclohexane
• Sulfide replaced by phosphate

Correct Answer: Carboxylic acid replaced by tetrazole

Q5. Why is fluorine often used as a hydrogen bioisostere in drug design?

• Fluorine can mimic hydrogen sterically while altering electronic properties and increasing metabolic stability
• Fluorine always increases solubility drastically
• Fluorine makes molecules heavier but inert biologically
• Fluorine converts acids into bases

Correct Answer: Fluorine can mimic hydrogen sterically while altering electronic properties and increasing metabolic stability

Q6. Replacing a phenyl ring with pyridine is a common non-classical bioisosteric strategy primarily to:

• Introduce a basic heteroatom to improve solubility or enable hydrogen bonding interactions
• Eliminate all aromaticity to increase flexibility
• Convert a neutral drug into a protein
• Increase molecular rigidity exclusively

Correct Answer: Introduce a basic heteroatom to improve solubility or enable hydrogen bonding interactions

Q7. Which of the following is an example of a classical monovalent isostere group?

• H, F, Cl (monovalent atoms)
• COOH and NH2 (divalent groups)
• Benzene and cyclohexane (ring systems)
• Phosphate and sulfate (polyvalent groups)

Correct Answer: H, F, Cl (monovalent atoms)

Q8. Which property is most directly influenced by replacing a carboxylic acid with a tetrazole?

• Acidity (pKa) and lipophilicity while retaining anionic character
• Total elimination of polarity
• Conversion to a strong base
• Complete loss of receptor binding capacity

Correct Answer: Acidity (pKa) and lipophilicity while retaining anionic character

Q9. Which of the following is a correct example of a non-classical bioisostere?

• Replacing a phenyl ring with thiophene to preserve aromaticity but change electronics
• Replacing sodium with potassium in an inorganic salt
• Changing carbon to nitrogen while keeping exact valence electron count
• Substituting oxygen with sulfur only when both have identical size and electronegativity

Correct Answer: Replacing a phenyl ring with thiophene to preserve aromaticity but change electronics

Q10. What is “scaffold hopping” in the context of bioisosterism?

• Replacing the central molecular framework with a different core while retaining biological activity
• Moving a molecule physically from one lab bench to another
• Adding more side chains to increase size without changing activity
• Converting small molecules into proteins

Correct Answer: Replacing the central molecular framework with a different core while retaining biological activity

Q11. Which factor is most important to preserve when applying a bioisosteric replacement to maintain binding to a target receptor?

• The pharmacophore geometry and essential interactions with the receptor
• The color of the compound
• The exact molecular weight to the decimal
• Only the number of aromatic rings regardless of orientation

Correct Answer: The pharmacophore geometry and essential interactions with the receptor

Q12. Replacing an -OH group with -F typically leads to which immediate change in molecular properties?

• Loss of hydrogen-bond donor capacity and altered polarity
• Gain of an extra hydrogen-bond donor
• Complete conversion to an acid
• Instant dimerization in solution

Correct Answer: Loss of hydrogen-bond donor capacity and altered polarity

Q13. Which of these is a strategic reason to replace an ester linkage with an amide in a drug candidate?

• To increase metabolic stability by reducing susceptibility to esterases
• To make the molecule smell better
• To make the compound more volatile for inhalation
• To always decrease potency regardless of target

Correct Answer: To increase metabolic stability by reducing susceptibility to esterases

Q14. Which bioisosteric replacement was key in the development of several angiotensin II receptor antagonists (sartans)?

• Carboxylate replaced by tetrazole to mimic acidity and improve oral bioavailability
• Methyl replaced by ethyl to increase polarity
• Amide replaced by ester to increase hydrolysis
• Phenyl replaced by cyclohexane to increase planarity

Correct Answer: Carboxylate replaced by tetrazole to mimic acidity and improve oral bioavailability

Q15. Non-classical bioisosteric replacements often rely on which of the following considerations?

• Similar steric shape or electronic distribution rather than strict valence equality
• Identical atomic number for all atoms
• Only matching molecular weights
• Replacing atoms exclusively with noble gases

Correct Answer: Similar steric shape or electronic distribution rather than strict valence equality

Q16. Which outcome is NOT a typical objective when applying bioisosteric changes?

• Guaranteed increase in toxicity
• Improved metabolic stability
• Enhanced target selectivity
• Optimized solubility and permeability

Correct Answer: Guaranteed increase in toxicity

Q17. What is a common effect of introducing a heteroatom into an aromatic ring as a bioisosteric change?

• Altered electronic distribution, possible H-bonding, and changed pKa or solubility
• Complete loss of all biological activity always
• Turning the compound into an inorganic salt instantly
• Making the molecule fluorescent in all solvents

Correct Answer: Altered electronic distribution, possible H-bonding, and changed pKa or solubility

Q18. Which computational approaches are commonly used to evaluate potential bioisosteric replacements?

• Molecular modeling, docking, and QSAR to predict binding and ADME changes
• Only manual drawing on paper with no computation
• Using unrelated weather models
• Checking only the periodic table without molecular context

Correct Answer: Molecular modeling, docking, and QSAR to predict binding and ADME changes

Q19. Which of these is a risk or limitation when applying bioisosteric replacements?

• Unpredictable effects on activity, selectivity, or toxicity despite similar physicochemical properties
• Guaranteed improvement in every parameter simultaneously
• Immediate conversion into an enzyme inhibitor in all cases
• Removal of all chiral centers automatically

Correct Answer: Unpredictable effects on activity, selectivity, or toxicity despite similar physicochemical properties

Q20. How can bioisosterism help to reduce metabolic clearance of a drug candidate?

• By replacing metabolically labile groups (e.g., benzylic hydrogen, ester) with more stable bioisosteres like fluorine substitution or amide linkage
• By adding more ester bonds to increase enzyme action
• By replacing carbon with helium
• By eliminating all polar groups to make the drug completely insoluble

Correct Answer: By replacing metabolically labile groups (e.g., benzylic hydrogen, ester) with more stable bioisosteres like fluorine substitution or amide linkage

Q21. Which of the following is an example of a ring bioisostere used to maintain aromatic character while changing electronics?

• Benzene replaced by thiophene
• Cyclohexane replaced by propane
• Alkane chain replaced by sugar
• Phosphate replaced by chloride

Correct Answer: Benzene replaced by thiophene

Q22. In lead optimization, why might a chemist replace a phenolic -OH with a methoxy (-OCH3) as a bioisosteric change?

• To reduce metabolic conjugation and modulate hydrogen-bonding while retaining polarity
• To make the molecule a gas at room temperature
• To always increase acidic strength
• To convert the molecule into a peptide

Correct Answer: To reduce metabolic conjugation and modulate hydrogen-bonding while retaining polarity

Q23. Which statement about tetrazoles as carboxylate bioisosteres is TRUE?

• Tetrazoles often improve metabolic stability and lipophilicity while mimicking carboxylate anionic behavior
• Tetrazoles always convert drugs into prodrugs
• Tetrazoles are never used in orally active drugs
• Tetrazoles completely eliminate binding to all receptors

Correct Answer: Tetrazoles often improve metabolic stability and lipophilicity while mimicking carboxylate anionic behavior

Q24. Which replacement is likely to increase lipophilicity of a molecule?

• Replacing a polar hydroxyl group with a nonpolar methyl group
• Replacing a methyl with a hydroxyl
• Replacing an aromatic ring with multiple charged groups
• Converting an alkyl chain into a polyether

Correct Answer: Replacing a polar hydroxyl group with a nonpolar methyl group

Q25. Which is the best example of a non-classical bioisosteric replacement that preserves size but alters electronic properties?

• Replacing CH with N in an aromatic ring (e.g., phenyl to pyridine)
• Replacing sodium ion with calcium ion in solution
• Replacing benzene with a long alkyl chain
• Replacing an amide with elemental carbon

Correct Answer: Replacing CH with N in an aromatic ring (e.g., phenyl to pyridine)

Q26. How does bioisosterism contribute to intellectual property strategy in drug development?

• By enabling structural modifications that may create novel chemical entities for new patent claims
• By eliminating the need to file any patents
• By ensuring products are always off-patent immediately
• By making compounds identical to competitors’ molecules

Correct Answer: By enabling structural modifications that may create novel chemical entities for new patent claims

Q27. Which replacement would most likely decrease basicity (increase acid character) of a molecule?

• Replacing an amine with an amide
• Replacing an amide with a tertiary amine
• Replacing a fluorine with hydrogen
• Replacing carbonyl oxygen with sulfur with no other changes

Correct Answer: Replacing an amine with an amide

Q28. Which of the following is NOT a typical outcome when a successful bioisosteric replacement is made?

• Complete and guaranteed lack of side effects in all patients
• Altered ADME profile
• Improved selectivity for the target
• Modified physicochemical properties like pKa or lipophilicity

Correct Answer: Complete and guaranteed lack of side effects in all patients

Q29. Which approach best helps predict whether a proposed bioisosteric change will retain biological activity?

• Combining SAR data with molecular modeling and docking studies
• Choosing replacements at random without data
• Only changing the molecule’s color and observing effects
• Consulting unrelated clinical trial reports

Correct Answer: Combining SAR data with molecular modeling and docking studies

Q30. Which of the following pairs is a commonly exploited bioisosteric strategy to block metabolic oxidation at a benzylic site?

• Replacing a benzylic hydrogen with fluorine to reduce CYP-mediated oxidation
• Replacing a benzylic hydrogen with another hydrogen to increase oxidation
• Replacing the entire aromatic ring with a sugar moiety always
• Replacing benzylic carbon with helium

Correct Answer: Replacing a benzylic hydrogen with fluorine to reduce CYP-mediated oxidation

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