Log P Value and Substituent Effects Quiz

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Questions and Answers

What is the impact of replacing a methoxy group with a SOMe group on the log P value?

Decreases log P to 1.2

How are log P values typically determined?

Experimental determination

What does a positive hydrophobicity constant (π) indicate about a substituent compared to hydrogen?

More hydrophobic than H

How are log P values calculated for lead compounds when modified with different substituents?

Based on π values Signup and view all the answers

What is the role of Hammett substituent constant (σ) for aromatic substituents?

Expresses electronic effects Signup and view all the answers

How are steric effects quantified in drug design?

Difficult to quantify Signup and view all the answers

What is the interpretation for the lower activity of 4‐Br in comparison to Cl?

The lower activity of 4‐Br could be due to the larger hydrophobicity. Signup and view all the answers

Why is the 4-Nitro derivative considered to have the highest activity?

The NO2 group has a smaller hydrophobicity and a large electron-withdrawing effect. Signup and view all the answers

What is the general trend observed for high activities in relation to hydrophobicity and electronic effects?

High activities are obtained with a large value of σ and a smaller value of π. Signup and view all the answers

Why are tables of substituent constants useful in drug design?

Tables of substituent constants help decide which bioisosteres to use in drug design. Signup and view all the answers

What is the rule-of-thumb suggested for the number of molecules to be synthesized per parameter studied in QSAR studies?

At least 5 molecules should be synthesized per parameter studied. Signup and view all the answers

Why is it recommended not to use substituents that could ionize or be metabolized in initial QSAR studies?

To avoid interference with the initial QSAR equation generation. Signup and view all the answers

What is the purpose of QSAR studies?

To identify/quantify physicochemical properties of a drug and establish their effect on biological activity. Signup and view all the answers

Why is it best to focus on two or three physicochemical properties in QSAR?

To establish relationships with molecules that vary in one property at a time while keeping the other properties roughly constant. Signup and view all the answers

What is the significance of the partition coefficient, P, in QSAR studies?

The hydrophobic character of a molecule is crucial for interactions with targets and crossing membranes. Signup and view all the answers

What does a small range of log P values imply in a linear relationship?

A small range of log P values results in a linear relationship between hydrophobicity and biological activity. Signup and view all the answers

What happens when the hydrophobicity of a molecule increases beyond log P = 4?

The molecule may become insoluble or remain in the lipid bilayer, potentially decreasing its biological activity. Signup and view all the answers

What log P value is associated with the highest biological activity for general anaesthetics?

A log P of 2.3 is associated with the highest biological activity for general anaesthetics. Signup and view all the answers

What type of relationship is often obtained when analyzing the anaesthetic properties of ethers?

A parabolic relationship is often obtained, with the maximum indicating the highest biological activity. Signup and view all the answers

What does a linear relationship between log P values and biological activity suggest?

A linear relationship suggests a direct correlation between hydrophobicity and biological activity. Signup and view all the answers

How can changing log P values affect the presence of side effects like CNS effects?

Changing log P values can help remove CNS side effects by altering the drug's ability to enter the CNS. Signup and view all the answers

Why is it important to fit QSAR data using various equations and consider errors?

Fitting data using different equations and considering errors helps make accurate predictions for new molecules. Signup and view all the answers

Study Notes

Impact of Replacing Methoxy Group

Replacing a methoxy group (OMe) with a SOMe group generally leads to a decrease in log P value.
SOMe groups are more polar and hydrophilic than OMe groups.

Determining log P Values

Log P values are typically determined using experimental methods like shaker-flask method or HPLC method.

Hydrophobicity Constant (π)

A positive hydrophobicity constant (π) indicates that the substituent is more hydrophobic than hydrogen.

Calculating log P for Modified Compounds

Log P values for lead compounds modified with different substituents can be calculated using additivity rules and substituent constants.

Hammett Substituent Constant (σ)

Hammett substituent constant (σ) quantifies the electronic effects of substituents on aromatic rings.
Positive σ value represents an electron-withdrawing substituent, while a negative σ value represents an electron-donating substituent.

Quantifying Steric Effects

Steric effects can be quantified using steric constants such as Taft's Es values.

Interpretation of Activity Differences

4-Br having lower activity than Cl is likely due to its larger size and steric hindrance, impacting binding.
4-Nitro having highest activity is due to its strong electron-withdrawing effect, potentially enhancing binding interactions.

Trend for High Activities

High activities are often observed with molecules exhibiting a balance between hydrophobicity (log P) and electronic effects (σ).

Utility of Substituent Constant Tables

Tables of substituent constants are useful for predicting the effects of different substituents on log P, electronic properties, and biological activity.

Rule-of-Thumb in QSAR Studies

Rule-of-thumb for QSAR studies suggests synthesizing about 10 molecules per parameter studied.

Avoiding Ionizable or Metabolizable Substituents

It is recommended to avoid using substituents that could ionize or be metabolized in initial QSAR studies.

Purpose of QSAR Studies

QSAR studies aim to establish relationships between chemical structure and biological activity using mathematical models.

Focus on Physicochemical Properties

It's best to focus on two or three key physicochemical properties in QSAR studies for simplicity and effectiveness in the initial stages.

Significance of Partition Coefficient (P)

The partition coefficient (P) is the ratio of a compound's concentration in octanol to its concentration in water.
It reflects the hydrophobicity of the molecule.

Implication of Small log P Range

A small range of log P values in a linear relationship suggests a strong dependence of activity on hydrophobicity.

Impact of High Hydrophobicity

When hydrophobicity increases beyond log P = 4, the activity may decrease due to poor solubility and permeability.

Log P for Highest Anaesthetic Activity

Log P value of around 2 is associated with the highest biological activity for general anaesthetics.

Relationship for Anaesthetics

Analyzing the anaesthetic properties of ethers often results in a linear relationship between log P values and activity.

Linear Relationship Implication

A linear relationship between log P values and biological activity indicates a strong correlation between hydrophobicity and activity.

Impact of Log P on Side Effects

Changing log P values can influence the presence of side effects like CNS effects, as they often correlate with hydrophobicity.

Importance of Equation Fit and Error Analysis

It is crucial to fit QSAR data using various equations and consider errors for reliable and robust predictions.

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Description

Test your knowledge on how substituent groups impact the log P value of compounds and their physiological effects. Learn about experimental determination of log P values and estimating them using substituent hydrophobicity constants.