Malathion Synthesis: Alkene as Electrophile

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