Introduction: QSAR (Quantitative Structure–Activity Relationship) uses physicochemical parameters to predict drug behavior. Key descriptors include the partition coefficient (log P) which measures lipophilicity and membrane permeability, Hammett’s constant (σ) that quantifies electronic (inductive and resonance) effects of aromatic substituents, and Taft’s steric parameter (Es) describing aliphatic steric hindrance. Understanding how log P, σ and Es influence potency, absorption, distribution and metabolic stability is essential for rational drug design in B. Pharm. Practical skills include interpreting Hansch equations, differentiating σp vs σm, accounting for ionization (log D), and applying Taft values to reaction rate changes. Now let’s test your knowledge with 30 MCQs on this topic.
Q1. What does the partition coefficient (P) primarily measure?
- The ratio of compound solubility in octanol to water at equilibrium
- The pKa of a compound
- The binding affinity to plasma proteins
- The rate of enzymatic metabolism
Correct Answer: The ratio of compound solubility in octanol to water at equilibrium
Q2. Which term is commonly used for the logarithm of the partition coefficient?
- pKa
- log P
- pIC50
- log D
Correct Answer: log P
Q3. How does ionization of a drug affect log P versus log D?
- Ionization affects log P but not log D
- log P is pH-dependent while log D is pH-independent
- log P is for neutral species; log D accounts for ionization at a given pH
- Both log P and log D ignore ionization
Correct Answer: log P is for neutral species; log D accounts for ionization at a given pH
Q4. What is the main use of Hammett’s σ constant in QSAR?
- To measure lipophilicity of aliphatic chains
- To quantify electronic effects of substituents on aromatic rings
- To calculate molecular weight
- To assess stereochemistry
Correct Answer: To quantify electronic effects of substituents on aromatic rings
Q5. A positive Hammett σ value indicates what type of substituent effect?
- Electron-donating through resonance
- Electron-withdrawing overall
- No electronic effect
- Steric hindrance only
Correct Answer: Electron-withdrawing overall
Q6. Which Hammett constant applies to para-substituted benzene derivatives?
- σm
- σp
- σI
- σR
Correct Answer: σp
Q7. Taft’s steric parameter (Es) was derived from studies on which type of reaction?
- Aromatic nitration
- Acid-catalyzed ester hydrolysis of aliphatic esters
- Enzymatic oxidation
- Electrophilic aromatic substitution
Correct Answer: Acid-catalyzed ester hydrolysis of aliphatic esters
Q8. A more negative Taft Es value indicates:
- Greater steric hindrance
- Less steric hindrance
- Higher electron-withdrawing ability
- Higher lipophilicity
Correct Answer: Greater steric hindrance
Q9. In Hansch QSAR, which descriptor primarily represents hydrophobic effects?
- σ (Hammett constant)
- Es (Taft steric parameter)
- log P
- pKa
Correct Answer: log P
Q10. Which of the following best describes the relationship between log P and membrane permeability for neutral drugs?
- Higher log P always decreases permeability
- Higher log P generally increases passive permeability up to an optimum then decreases solubility
- log P has no relation to permeability
- Lower log P always increases permeability
Correct Answer: Higher log P generally increases passive permeability up to an optimum then decreases solubility
Q11. Hammett σ values separate resonance and inductive contributions as which constants?
- σI (inductive) and σR (resonance)
- σp and σm only
- Es and Ea
- log P and log D
Correct Answer: σI (inductive) and σR (resonance)
Q12. Which substituent would likely have a negative Hammett σ value (electron-donating)?
- Nitro (-NO2)
- Trifluoromethyl (-CF3)
- Methoxy (-OCH3)
- Cyano (-CN)
Correct Answer: Methoxy (-OCH3)
Q13. In constructing a QSAR model, why include Taft Es values?
- To model electronic effects on aromatic systems
- To quantify steric hindrance of aliphatic substituents affecting reactivity and binding
- To replace log P entirely
- Because Es correlates directly with pKa
Correct Answer: To quantify steric hindrance of aliphatic substituents affecting reactivity and binding
Q14. Which method is commonly used to measure experimental log P?
- PAMPA assay
- Shake-flask method
- HPLC retention time only
- NMR titration
Correct Answer: Shake-flask method
Q15. For para-substituted benzoic acids, a Hammett plot (log k vs σ) with slope ρ > 0 indicates what about the reaction?
- Negative charge is developed in the transition state
- Electron-withdrawing groups accelerate the reaction
- Electron-donating groups accelerate the reaction
- No sensitivity to substituent electronics
Correct Answer: Electron-withdrawing groups accelerate the reaction
Q16. Which statement about log D is true?
- log D equals log P at all pH values
- log D accounts for all species (ionized + unionized) distribution at a given pH
- log D is measured only in non-aqueous solvents
- log D increases linearly with molecular weight
Correct Answer: log D accounts for all species (ionized + unionized) distribution at a given pH
Q17. Which descriptor would best explain reduced enzymatic access due to bulky substituents?
- Hammett σ
- log P
- Taft Es
- pKa
Correct Answer: Taft Es
Q18. A positive Hammett ρ (rho) value indicates the reaction rate increases with:
- Electron-donating substituents
- Electron-withdrawing substituents
- Increasing steric bulk
- Higher lipophilicity only
Correct Answer: Electron-withdrawing substituents
Q19. Which factor can cause discrepancy between calculated log P and experimental log P?
- Tautomerism, hydrogen bonding, and ionization
- Exact match of Hammett σ values
- Taft Es being zero
- Presence of only aromatic rings
Correct Answer: Tautomerism, hydrogen bonding, and ionization
Q20. Which substituent would likely increase log P significantly?
- Hydroxyl (-OH)
- Carboxyl (-COOH)
- Long alkyl chain (–C8H17)
- Amino (-NH2)
Correct Answer: Long alkyl chain (–C8H17)
Q21. In QSAR equations, multicollinearity between descriptors (e.g., log P and molecular surface area) is problematic because:
- It improves predictive accuracy always
- It inflates variance and destabilizes coefficient estimates
- It eliminates the need for validation
- It prevents use of Hammett constants
Correct Answer: It inflates variance and destabilizes coefficient estimates
Q22. Taft Es values are most applicable to which class of substituents?
- Aromatic substituents with resonance effects
- Aliphatic substituents lacking conjugation
- Ionic functional groups
- Transition metal ligands
Correct Answer: Aliphatic substituents lacking conjugation
Q23. Which best describes an electron-donating group by resonance for a para position?
- –NO2
- –NH2
- –CF3
- –CN
Correct Answer: –NH2
Q24. When building Hansch QSAR, a negative coefficient for log P suggests what about potency?
- Increasing lipophilicity increases potency
- Increasing lipophilicity decreases potency
- No relationship to potency
- Only steric effects matter
Correct Answer: Increasing lipophilicity decreases potency
Q25. Which experiment or calculation helps separate inductive and resonance effects of a substituent?
- Measurement of log P in octanol
- Use of σI and σR component constants or dual-parameter Hammett analysis
- Calculation of Taft Es only
- Measuring boiling point
Correct Answer: Use of σI and σR component constants or dual-parameter Hammett analysis
Q26. Which property often correlates with oral absorption and can be estimated using log P/log D?
- pKa only
- Plasma protein binding exclusively
- Passive membrane permeability and bioavailability tendencies
- Covalent binding to enzymes
Correct Answer: Passive membrane permeability and bioavailability tendencies
Q27. A substituent with σp = +0.45 is most likely to be:
- A strong electron-donating group
- A moderately electron-withdrawing group
- Sterically bulky but electron-neutral
- Highly lipophilic and electron-donating
Correct Answer: A moderately electron-withdrawing group
Q28. Which descriptor would you prioritize to explain variation in reaction kinetics for aliphatic esters?
- Hammett σp
- Taft Es and polar substituent constants (σ*)
- log P only
- Topological polar surface area exclusively
Correct Answer: Taft Es and polar substituent constants (σ*)
Q29. What is a limitation of using log P alone in QSAR?
- It fully accounts for electronic effects
- It ignores ionization, specific hydrogen bonding, and steric effects
- It is identical to Hammett σ
- It cannot be measured experimentally
Correct Answer: It ignores ionization, specific hydrogen bonding, and steric effects
Q30. In a multi-parameter QSAR including log P, σ and Es, a model shows positive coefficients for σ and negative for Es. This implies:
- Electron-withdrawing substituents increase activity; increased steric hindrance reduces activity
- Electron-donating substituents increase activity; steric hindrance increases activity
- Both electronic and steric effects are irrelevant
- Lipophilicity is the only determinant
Correct Answer: Electron-withdrawing substituents increase activity; increased steric hindrance reduces activity
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