Introduction: Bioisosterism is a fundamental concept in medicinal chemistry and drug design that helps B. Pharm students understand how substituting atoms or functional groups can alter a molecule’s biological action, potency, and ADME properties. By learning classical and non-classical bioisosteres, students can rationalize changes in lipophilicity, electronic distribution, pKa, receptor binding, metabolic stability, and toxicity. Practical examples—like replacing a carboxylate with a tetrazole or hydrogen with fluorine—demonstrate how small structural changes improve drug candidates. Mastery of bioisosterism is essential for structure–activity relationship (SAR) analysis and lead optimization. Now let’s test your knowledge with 50 MCQs on this topic.
Q1. What is the primary goal of applying bioisosterism in drug design?
- To change a drug’s color
- To modify pharmacological properties while retaining biological activity
- To increase manufacturing cost
- To make drugs taste better
Correct Answer: To modify pharmacological properties while retaining biological activity
Q2. Which of the following is a classic example of non-classical bioisosteric replacement?
- Hydrogen replaced by deuterium
- Carboxylic acid replaced by tetrazole
- Chlorine replaced by bromine
- Methyl replaced by ethyl
Correct Answer: Carboxylic acid replaced by tetrazole
Q3. Replacing a hydrogen atom with fluorine in a lead molecule is commonly used to:
- Increase molecular weight drastically
- Block metabolic oxidation and change lipophilicity
- Convert a drug into a prodrug
- Guarantee complete elimination by kidneys
Correct Answer: Block metabolic oxidation and change lipophilicity
Q4. Classical bioisosteres are generally characterized by:
- Completely different valency and size
- Similar valency, size, and electronic configuration
- Only aromatic ring replacements
- Being larger than the original group
Correct Answer: Similar valency, size, and electronic configuration
Q5. Which bioisosteric change is often used to improve oral bioavailability by reducing first-pass metabolism?
- Replacing an ester with an amide
- Replacing benzene with cyclohexane
- Replacing a nitro group with another nitro group
- Adding multiple hydroxyl groups
Correct Answer: Replacing an ester with an amide
Q6. Which property is LEAST likely to be directly affected by a bioisosteric replacement?
- Receptor binding affinity
- Melting point of the raw material
- Metabolic stability
- pKa of an ionizable group
Correct Answer: Melting point of the raw material
Q7. A tetrazole ring is often used to replace which functional group in angiotensin receptor blockers like losartan?
- Primary amine
- Carboxylic acid
- Sulfide
- Ester
Correct Answer: Carboxylic acid
Q8. Which is an example of a non-classical bioisostere pair?
- –CH3 and –CH3
- Carboxylate and tetrazole
- Hydrogen and hydrogen
- Nitrogen and nitrogen
Correct Answer: Carboxylate and tetrazole
Q9. In SAR studies, bioisosteric replacement is primarily used to:
- Optimize biological activity and ADME properties
- Increase the number of stereocenters
- Reduce the number of rotatable bonds only
- Change the compound’s elemental composition randomly
Correct Answer: Optimize biological activity and ADME properties
Q10. Which replacement would most likely reduce basicity of an amine while maintaining steric bulk?
- Replace –NH2 with –OH
- Replace –NH– with –O–
- Replace a tertiary amine with a quaternary ammonium
- Replace a basic amine with an amide
Correct Answer: Replace a basic amine with an amide
Q11. Fluorine is commonly used as a bioisostere because it:
- Is large and bulky
- Has similar size to hydrogen and high electronegativity
- Acts as a strong nucleophile
- Is always metabolically unstable
Correct Answer: Has similar size to hydrogen and high electronegativity
Q12. Which effect is expected when replacing a phenyl ring with a heteroaromatic ring (e.g., pyridine)?
- Unchanged polarity and H-bonding profile
- Altered electronic properties, H-bond accepting ability, and polarity
- Instant loss of all biological activity
- Guaranteed increase in lipophilicity
Correct Answer: Altered electronic properties, H-bond accepting ability, and polarity
Q13. Which bioisosteric change could be used to increase metabolic stability by preventing oxidative cleavage of an ester?
- Replace ester with a more stable amide
- Replace ester with another ester
- Add an extra ester nearby
- Replace ester with a free carboxylic acid
Correct Answer: Replace ester with a more stable amide
Q14. In classical classification, what do monovalent bioisosteres refer to?
- Groups with the same valency of one and similar size/electrons (e.g., H and F)
- Groups with four valency only
- Bioisosteres used only in peptides
- Large polyatomic groups
Correct Answer: Groups with the same valency of one and similar size/electrons (e.g., H and F)
Q15. Which bioisosteric replacement is often used to mimic a carbonyl oxygen’s hydrogen bond acceptor property while reducing polarity?
- Replace C=O with CH2
- Replace carbonyl with sulfone
- Replace carbonyl with isoxazole or oxadiazole
- Remove the functional group entirely
Correct Answer: Replace carbonyl with isoxazole or oxadiazole
Q16. Which computational approach helps identify bioisosteric replacements by analyzing matched molecular pairs?
- Thermodynamic integration
- Matched molecular pair analysis (MMPA)
- Mass spectrometry
- Elemental analysis
Correct Answer: Matched molecular pair analysis (MMPA)
Q17. Replacing a metabolically labile alkyl chain with a bioisostere can primarily reduce:
- Binding affinity to the target always
- Metabolic clearance and formation of toxic metabolites
- Molecular weight below 50 Da
- Solubility to zero
Correct Answer: Metabolic clearance and formation of toxic metabolites
Q18. Which is a typical goal when using bioisosterism to modify pKa of an ionizable center?
- Change pKa to improve membrane permeability and receptor ionization state
- Ensure the drug is never ionized at any pH
- Convert all ionizable centers into quaternary salts
- Make the drug unstable in plasma
Correct Answer: Change pKa to improve membrane permeability and receptor ionization state
Q19. Which replacement would increase a molecule’s lipophilicity most reliably?
- Replace a methyl group with a polar hydroxyl
- Replace a hydrogen with fluorine
- Replace a polar amide with a lipophilic alkyl
- Replace an aromatic ring with a charged group
Correct Answer: Replace a polar amide with a lipophilic alkyl
Q20. Which of the following is an example of a bioisosteric replacement that maintains anionic character at physiological pH?
- Replace carboxylate with a tetrazole
- Replace carboxylate with methyl
- Replace carboxylate with an alcohol
- Replace carboxylate with a neutral ether
Correct Answer: Replace carboxylate with a tetrazole
Q21. Which bioisosteric strategy is useful to reduce off-target activity mediated by H-bond donors?
- Replace H-bond donors with H-bond acceptors or neutral groups
- Add more H-bond donors
- Replace hydrophobic groups with charged groups
- Introduce multiple rotatable bonds
Correct Answer: Replace H-bond donors with H-bond acceptors or neutral groups
Q22. The concept of isosteres originated from studies of:
- Enzymatic catalysis only
- Atomic and molecular similarity in physical chemistry
- Astrophysics
- Microbiology
Correct Answer: Atomic and molecular similarity in physical chemistry
Q23. Which change is a bioisosteric approach to decrease basicity and reduce P-gp efflux susceptibility?
- Convert tertiary amine to a tertiary ammonium salt
- Convert tertiary amine to an amide
- Introduce multiple primary amines
- Add polar zwitterionic groups
Correct Answer: Convert tertiary amine to an amide
Q24. Which of the following is NOT typically considered when selecting a bioisosteric replacement?
- Electronic effects
- Size and steric hindrance
- Color of the compound in solution
- Hydrogen bonding capacity
Correct Answer: Color of the compound in solution
Q25. Which heteroatom substitution is commonly used to alter electronic distribution without large steric changes?
- Replace carbon in aromatic ring with nitrogen (e.g., phenyl to pyridyl)
- Replace carbon with uranium
- Replace hydrogen with neon
- Replace carbon with a large metal ion
Correct Answer: Replace carbon in aromatic ring with nitrogen (e.g., phenyl to pyridyl)
Q26. Which bioisosteric change would likely increase water solubility while maintaining similar size?
- Replace methyl with hydroxymethyl
- Replace hydroxyl with methyl
- Replace carboxylate with methyl
- Replace polar group with halogen
Correct Answer: Replace methyl with hydroxymethyl
Q27. Which of the following is a risk when applying bioisosteric replacement without thorough evaluation?
- Unexpected loss of target binding or emergence of toxicity
- Guaranteed clinical success
- Instant regulatory approval
- Elimination of the need for ADME testing
Correct Answer: Unexpected loss of target binding or emergence of toxicity
Q28. Sulfonamide can sometimes act as a bioisostere for which functional group to provide similar H-bonding interactions?
- Ether
- Amide or urea
- Alkane
- Metal ion
Correct Answer: Amide or urea
Q29. Which replacement is commonly used to reduce basicity while preserving lipophilicity in heterocycles?
- Exchange a pyridine nitrogen for carbon
- Replace a basic nitrogen with oxygen or sulfur in the ring
- Introduce an extra protonatable amine
- Convert heterocycle to inorganic salt
Correct Answer: Replace a basic nitrogen with oxygen or sulfur in the ring
Q30. Which analytical assay is most relevant to evaluate the effect of bioisosteric changes on metabolic stability?
- In vitro microsomal stability assay
- Colorimetric pH test only
- X-ray crystallography of solids only
- Paper chromatography for pigments
Correct Answer: In vitro microsomal stability assay
Q31. Methyl-to-fluorine substitution often affects which of the following most directly?
- Hydrophilicity and hydrogen donor ability
- Electronic properties and metabolic vulnerability
- Number of stereocenters
- Protein tertiary structure
Correct Answer: Electronic properties and metabolic vulnerability
Q32. Which of the following is a strategy to reduce potential formation of toxic metabolites via bioisosteric change?
- Replace metabolically liable groups (e.g., exposed methylenes) with more stable bioisosteres
- Increase the number of metabolically labile sites
- Remove all polar groups
- Add heavy metals
Correct Answer: Replace metabolically liable groups (e.g., exposed methylenes) with more stable bioisosteres
Q33. Which bioisosteric change is useful to mimic peptide bond geometry but resist proteolysis?
- Replace peptide amide with a reduced amide
- Replace peptide amide with isosteric non-peptidic linkers like 1,2,3-triazoles or olefins
- Replace peptide bond with simple alkane chain
- Replace peptide bond with inorganic phosphate
Correct Answer: Replace peptide amide with isosteric non-peptidic linkers like 1,2,3-triazoles or olefins
Q34. Which bioisosteric replacement might decrease plasma protein binding and increase free drug concentration?
- Replace a lipophilic aromatic ring with a polar heterocycle
- Replace polar group with a large lipophilic chain
- Add multiple halogens to increase lipophilicity
- Convert neutral groups to quaternary ammonium
Correct Answer: Replace a lipophilic aromatic ring with a polar heterocycle
Q35. Which is a correct statement about isoelectronic bioisosteres?
- They have different numbers of electrons but identical size
- They have the same number of electrons and similar electronic structure
- They always increase potency
- They are only used in inorganic chemistry
Correct Answer: They have the same number of electrons and similar electronic structure
Q36. Which is an example where bioisosterism improved selectivity for a receptor subtype?
- Replacing bulky lipophilic groups with polar isosters to reduce off-target binding
- Adding random halogens to increase promiscuity
- Removing the pharmacophore entirely
- Adding detergents to the molecule
Correct Answer: Replacing bulky lipophilic groups with polar isosters to reduce off-target binding
Q37. Which is true when replacing an aromatic ring with a saturated bioisostere (e.g., bicycloalkyl)?
- It can reduce planar pi-stacking interactions and change binding mode
- It always preserves pi-pi interactions
- It is chemically impossible
- It increases aromaticity
Correct Answer: It can reduce planar pi-stacking interactions and change binding mode
Q38. Which bioisosteric approach can be used to reduce blood–brain barrier (BBB) penetration of a drug?
- Increase lipophilicity drastically
- Introduce polar groups or reduce basicity to lower passive diffusion
- Convert the drug to a neutral, highly lipophilic compound
- Add structural motifs that increase P-gp efflux avoidance
Correct Answer: Introduce polar groups or reduce basicity to lower passive diffusion
Q39. Which pair represents a bioisosteric concept where two groups are functionally similar but structurally distinct?
- Carboxylate and tetrazole
- Hydrogen and hydrogen
- Methane and methane
- Oxygen and helium
Correct Answer: Carboxylate and tetrazole
Q40. When replacing a labile aromatic methyl group to prevent CYP-mediated oxidation, which bioisostere is often considered?
- Replace methyl with CF3 or fluorine at strategic positions
- Replace methyl with a larger alkyl that is more prone to oxidation
- Replace methyl with a hydroxyl to increase metabolism
- Leave the methyl unchanged always
Correct Answer: Replace methyl with CF3 or fluorine at strategic positions
Q41. Which bioisosteric replacement can preserve H-bond donor/acceptor geometry while improving metabolic stability?
- Replace hydroxyl with fluorine
- Replace hydroxyl with an isosteric heterocycle that mimics H-bonding
- Replace hydroxyl with a methyl group
- Replace hydroxyl with elemental sulfur
Correct Answer: Replace hydroxyl with an isosteric heterocycle that mimics H-bonding
Q42. Which of the following best describes a “privileged scaffold” in relation to bioisosterism?
- A structural framework that tolerates diverse bioisosteric substitutions while maintaining activity
- An unstable scaffold avoided in drug design
- A scaffold only used in agricultural chemistry
- An obsolete concept no longer relevant
Correct Answer: A structural framework that tolerates diverse bioisosteric substitutions while maintaining activity
Q43. Which is a rationale for replacing an aromatic nitro group with a less toxic bioisostere?
- Nitro groups can be reduced to reactive metabolites causing toxicity; replacement reduces risk
- Nitro groups are always required for potency
- Nitro groups increase water solubility only
- Nitro replacement always increases molecular weight by 200 Da
Correct Answer: Nitro groups can be reduced to reactive metabolites causing toxicity; replacement reduces risk
Q44. Which bioisosteric change is typically explored to improve selectivity for a hydrophobic pocket?
- Introduce polar charged groups into the pocket-binding region
- Replace polar substituents with lipophilic isosteres to better complement the pocket
- Remove all substituents to reduce interactions
- Convert the molecule to a peptide
Correct Answer: Replace polar substituents with lipophilic isosteres to better complement the pocket
Q45. Which experimental technique can reveal how a bioisosteric replacement alters binding interactions at atomic detail?
- X-ray crystallography of ligand–receptor complex
- Thin-layer chromatography
- Infrared spectroscopy of the solid only
- Kjeldahl nitrogen analysis
Correct Answer: X-ray crystallography of ligand–receptor complex
Q46. Which bioisosteric change might be chosen to reduce a molecule’s tendency to form glucuronide conjugates?
- Replace phenolic OH with a bioisostere that reduces H-bond donor ability (e.g., fluorinated analog or heterocycle)
- Add more phenolic groups
- Convert all groups into primary alcohols
- Introduce more glucuronidation sites
Correct Answer: Replace phenolic OH with a bioisostere that reduces H-bond donor ability (e.g., fluorinated analog or heterocycle)
Q47. Which statement about bioisosteric replacement and intellectual property (IP) is true?
- Bioisosteric modifications can create new patentable chemical entities while retaining activity
- Bioisosteric changes never affect patentability
- Bioisosteric replacements are not allowed in patents
- IP is irrelevant in medicinal chemistry
Correct Answer: Bioisosteric modifications can create new patentable chemical entities while retaining activity
Q48. Which bioisosteric approach helps in designing reversible enzyme inhibitors that avoid covalent modification?
- Replace reactive electrophilic warheads with non-covalent bioisosteric groups
- Introduce more reactive electrophiles
- Convert reversible inhibitors into irreversible ones
- Remove all functional groups responsible for binding
Correct Answer: Replace reactive electrophilic warheads with non-covalent bioisosteric groups
Q49. Which of the following is an example where bioisosterism can tune selectivity between closely related enzymes?
- Subtle changes in substituent H-bonding or steric bulk that favor one active site geometry over another
- Randomly adding heavy atoms without rationale
- Replacing the core pharmacophore with an unrelated scaffold immediately
- Only changing the salt form of the drug
Correct Answer: Subtle changes in substituent H-bonding or steric bulk that favor one active site geometry over another
Q50. Which best practice should B. Pharm students follow when proposing bioisosteric changes during lead optimization?
- Use multidisciplinary evaluation — consider SAR, ADME, toxicity, and structure-based insights
- Rely only on intuition without experiments or modeling
- Change multiple unrelated features at once to speed up results
- Avoid consulting literature precedents
Correct Answer: Use multidisciplinary evaluation — consider SAR, ADME, toxicity, and structure-based insights
I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.
Mail- Sachin@pharmacyfreak.com