Malathion Synthesis: Alkene as Electrophile

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Questions and Answers

What enables the alkene to act as an electrophile in the chemical synthesis of malathion?

Presence of π electrons in the double bond

Resonance effect with the ketone functional group (correct)

High electronegativity of oxygen atoms

Formation of a carboxylic acid functional group

What functional group is formed upon acid hydrolysis of the –CN functional group in the chemical synthesis of atropine?

Carboxylic acid group (correct)

Amine group

Ester group

Aldehyde group

What is the primary reason behind the brief duration of action of Succinylcholine Chloride?

Its resonance effect with the ketone functional group

Its ability to form a carboxylic acid functional group

Its presence of π electrons in the double bond

Its rapid hydrolysis and inactivation by esterase enzymes (correct)

Why is compound A preferred over compound B in the chemical synthesis?

Due to the high electronegativity of chloride and oxygen atoms Signup and view all the answers

What is the primary reason why compound B is preferred over compound C in the chemical synthesis?

Due to the moderate electrophilicity of the carbonyl carbon Signup and view all the answers

What is the result of the rapid hydrolysis of Succinylcholine Chloride by esterase enzymes?

Inactivation of the molecule Signup and view all the answers

What is the primary reason why compound A is a better choice than compound B in the chemical synthesis?

Due to the high electronegativity of chloride and oxygen atoms Signup and view all the answers

Why is compound C not preferred in the chemical synthesis?

Due to the weak electrophilicity of the carbonyl carbon Signup and view all the answers

What is the primary purpose of drug metabolism in the body?

To convert lipid-soluble compounds into water-soluble forms Signup and view all the answers

Which of the following reactions is involved in Phase I metabolism?

Oxidation Signup and view all the answers

What is the primary characteristic of the Lipinski Rule of 5?

Molecular mass less than 500 Dalton Signup and view all the answers

What is the primary objective of bioisosterism in drug design?

To replace a functional group with a similar functional group Signup and view all the answers

What is the active form of enalapril?

A carboxylic acid Signup and view all the answers

What is the primary characteristic of NAPQI, the most toxic metabolite of paracetamol?

Strong binding affinity with proteins and nucleic acids Signup and view all the answers

What is the role of esterase enzymes in the metabolism of enalapril?

To convert the prodrug form of enalapril into its active form Signup and view all the answers

What is the primary characteristic of Phase II metabolism?

Conjugation reactions Signup and view all the answers

What is the primary purpose of bioisosterism in drug design?

To create new compounds for various purposes Signup and view all the answers

Which of the following is an optimal isostere for a carboxylic acid functional group?

Tetrazole ring Signup and view all the answers

Why do ester-containing drug molecules exhibit high in vivo lability and low metabolic stability?

Due to the presence of esterases in blood, liver, kidneys, and various organs Signup and view all the answers

How can the metabolic stability of ester-containing drugs be enhanced through chemical modification?

By replacing the ester group with an amide bond Signup and view all the answers

Why is it crucial to have multiple drugs covering a broad spectrum of lipophilicity and hydrophilicity profiles in clinical and pharmaceutical research?

To accommodate patients with different excretion site limitations Signup and view all the answers

What is the typical excretion site for hydrophilic drugs?

Kidneys Signup and view all the answers

What is the primary reason why patients with liver failure should avoid lipophilic medications?

Because lipophilic drugs are metabolized by the liver Signup and view all the answers

What is the role of bioisosterism in replacing metabolically unstable moieties in drug design?

To replace metabolically unstable moieties with more stable ones Signup and view all the answers

Study Notes

Chemical Synthesis of Malathion

The alkene acts as an electrophile in the chemical synthesis of malathion due to its resonance effect with the ketone functional group.
The movement of the double bond to the upper or lower side induces a positive charge at the double bond position, making it available for attack by the nucleophile (-SH).

Chemical Synthesis of Atropine

The acid hydrolysis of the –CN functional group results in the formation of a carboxylic acid (-COOH) functional group.

Succinylcholine Chloride

The brief duration of action of Succinylcholine Chloride is due to its rapid hydrolysis and subsequent inactivation by esterase enzymes, which act on both ester bonds in the molecule.

Chemical Synthesis

Compound A is preferred over compound B, and compound B is preferred over compound C due to the strength of the electrophilic carbonyl carbon.
The carbonyl carbon in compound A (acyl chloride derivative) exhibits strong electrophilicity due to the high electronegativity of both the chloride and oxygen atoms.
The carbonyl carbon in compound B (acetic anhydride) exhibits moderate electrophilicity due to the presence of two carbonyl functional groups.
The carbonyl carbon in compound C (acetic acid) exhibits weak electrophilicity due to the presence of resonance effects between the two oxygen atoms.

Bioisosterism

Bioisosterism refers to the substitution of one atom or group of atoms in a parent compound with another having similar electronic and steric configurations.
The strategy is employed in drug design to facilitate the creation of new compounds for various purposes, such as enhancing patent positions, replacing metabolically unstable moieties, seeking more favorable receptor interactions, and crafting improved pharmacodynamic profiles.

Isosteres for Functional Groups

The optimal isosteres for the following functional groups are:
- Pyridine ring for phenyl rings
- Tetrazole ring for carboxylic acids
- Amide for ester bonds
- Fluorine for the methyl group

Ester-Containing Drug Molecules

Ester-containing drug molecules exhibit high in vivo lability and low metabolic stability due to the ubiquitous presence of esterases found in blood, liver, kidneys, and various organs.
Bioisosteric substitution of the ester group with an amide bond can enhance the metabolic stability of ester-containing drugs.

Lipophilicity and Hydrophilicity

The preference for having multiple drugs covering a broad spectrum of lipophilicity and hydrophilicity profiles is crucial in both clinical and pharmaceutical research.
Hydrophilic drugs are typically excreted via the kidneys, whereas lipophilic drugs are eliminated through the liver.
Patients with renal failure should avoid hydrophilic drugs, whereas those with liver failure should steer clear of lipophilic medications.

Prodrugs

Prodrugs are modified derivatives of drug molecules designed to undergo enzymatic or chemical changes within the body, leading to the release of the active parent drug responsible for the desired pharmacological effect.
Enalapril is an example of a prodrug, which undergoes enzymatic hydrolysis of its ester bond by esterase enzymes found in the liver, bloodstream, and cells, converting it into the active form, a carboxylic acid.

Drug Metabolism

The purpose of drug metabolism is to convert lipid-soluble compounds into water-soluble forms, aiding their easier excretion from the body through various processes.
Phase I metabolism involves mild reactions like oxidation, reduction, dealkylation, and hydroxylation.
Phase II metabolism includes conjugation reactions.

Metabolism of Paracetamol

The most toxic metabolite in the metabolism of paracetamol is NAPQI, which contains a quinone-imine aromatic ring, forming a potent nucleophile with negative charges.
NAPQI's strong binding affinity with proteins and nucleic acids contributes to its heightened toxicity.

Lipinski Rule of 5

The Lipinski Rule of 5 serves as a guideline to differentiate between drug-like and non-drug-like molecules, providing insights into their potential success or failure as drugs.
The rule consists of parameters such as:
- A molecular mass less than 500 Dalton
- High lipophilicity (LogP less than 5)
- Fewer than 5 hydrogen bond donors
- Fewer than 10 hydrogen bond acceptors
- A molar refractivity ranging between 40-130

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Description

Understand why alkene acts as an electrophile in the chemical synthesis of malathion, despite having π electrons. Learn about the resonance effect with the ketone functional group.