Summary of Organic Pharmaceutical Chemistry: Drug Metabolism & Isosterism

1. Drug Metabolism

Drug metabolism refers to the chemical alteration of drugs and xenobiotics in the
body, primarily to:

• Enhance excretion (by increasing water solubility),

• Inactivate the drug, or sometimes

• Activate a prodrug.

Phases of Metabolism

• Phase I (Functionalization Reactions):

• Modify the drug by oxidation, reduction, or hydrolysis.

• Introduce or expose polar groups (OH, NH₂, COOH).

• Often prepares the molecule for Phase II.

• Phase II (Conjugation Reactions):

• Attach polar endogenous groups (e.g., glucuronic acid, sulfate).

• Greatly increases water solubility for excretion.

• Usually inactivates the drug.

Sites of Metabolism

• Liver (main site, first-pass metabolism).

• Intestinal mucosa (enzymes like CYP3A4, esterases, P-glycoprotein).

• Other tissues: Kidneys, lungs, brain, skin, etc.

Cytochrome P450 System (CYP450)

• Key enzyme system in oxidative metabolism (Phase I).

• Involves heme-containing enzymes (like CYP3A4).

• Requires cofactors (NADPH, cytochrome P450 reductase).

• Responsible for detoxifying or activating many drugs.

Purpose of Metabolism

1. Inactivation: e.g., Isoniazid by acetylation.

2. Activation (Prodrugs): e.g., Enalapril converted in liver.

3. Enhancement: e.g., Diazepam metabolized to more active forms.

Clinical Implications

• Metabolism affects drug duration, toxicity, and efficacy.

• Some active metabolites are more potent or toxic than the parent drug.

• Disease states or genetic differences can influence metabolic rate.

• Lipophilic drugs must be metabolized or they accumulate in tissues.

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2. Isosterism in Drug Design

Isosterism is the concept of replacing atoms or groups in a molecule with others

that have similar size, shape, or electronic properties—without drastically
altering biological activity.

Types of Isosteres

• Classical isosteres: Same number of atoms and electrons.

• e.g., N₂ and CO (14 electrons each).

• Bioisosteres: Groups that mimic steric/electronic behavior in biological

systems.

Examples of Isosteric Pairs

• Carboxylate (COO ) Sulfonamide (SO₂NR)

• Ketone (C O) Sulfone (O=S=O)

• Cl CF₃

• OH NH₂ or SH

•H F

Applications in Drug Design

• Modify solubility, stability, and receptor binding.

• Improve selectivity or reduce toxicity.

• Create antagonists or enhance potency.

• May alter hydrogen bonding (e.g., 6-NH₂ vs. 6-OH in nucleic acids).
Examples in Practice

• 6-Mercaptopurine: Sulfhydryl replacement reduces DNA synthesis.

• Methotrexate: Modified folic acid structure inhibits folate metabolism.

• 5-Fluorouracil: Fluorine substitution blocks thymine synthesis in DNA.

Significance

• Allows rational drug design with predictable modifications.

• Aids in understanding enzyme-receptor interactions

Overview of Drug Metabolism

Drug metabolism refers to the biochemical modification of pharmaceutical
substances in the body. It serves two main purposes:

1. Detoxification and elimination of drugs and foreign compounds (xenobiotics).

2. Conversion into active or inactive forms, influencing their therapeutic effect.

Phases of Drug Metabolism

Phase I – Functionalization Reactions

• Reactions: Oxidation, reduction, hydrolysis.

• Goal: Introduce or expose functional groups (e.g., OH, NH₂, COOH).

• Outcomes: Increases water solubility and often prepares the molecule for Phase II.

• Examples:

• Oxidation: Adds hydroxyl groups.

• Reduction: Converts ketones/aldehydes to alcohols.

• Hydrolysis: Breaks esters/amides to produce acids and amines.

Phase II – Conjugation Reactions

• Reactions: Attach polar groups (e.g., glucuronic acid, sulfate, amino acids) to the
drug or Phase I metabolite.

• Purpose: Greatly increase solubility for urinary or biliary excretion.

• Characteristics:

• Usually inactivates the drug.

• Methylation and acetylation reduce activity.

• Glutathione conjugation detoxifies reactive intermediates.

Sites of Drug Metabolism

1. Liver (Main Site)

• Rich in drug-metabolizing enzymes.

• Orally administered drugs undergo the first-pass effect, reducing their

bioavailability.

• Examples of drugs with strong first-pass metabolism: Morphine, Lidocaine,

Propranolol, Nitroglycerin.

2. Intestinal Mucosa

• Contains enzymes like CYP3A4 and P-glycoprotein.

• Functions:

• Sulfation (e.g., of isoproterenol).

• Hydrolysis of ester prodrugs.

• Drug re-secretion and metabolism by intestinal flora.

• Supports enterohepatic recycling.

3. Other Tissues

• Kidneys, lungs, brain, placenta, adrenal glands, and skin.

• Perform selective metabolic reactions, especially oxidation and glucuronidation.

Cytochrome P450 (CYP450) System

A superfamily of enzymes vital for Phase I oxidative metabolism:

• Nomenclature: CYP3A4 = Family 3, Subfamily A, Enzyme 4.

• Function: Inserts one oxygen atom into the drug (oxidation).

• Reaction requires:

• Drug (RH), Oxygen (O₂), and NADPH.

• Produces an oxidized metabolite (ROH) and water.

• Structure:

• Heme-containing enzymes (iron at the active site).

• Requires NADPH-cytochrome P450 reductase and cytochrome b₅ for electron

transfer.

• Location: Mainly in liver, but also in other tissues.

Key Concepts

• Detoxification: Primary goal of metabolism.

• Prodrugs: Designed to be activated by metabolic enzymes.

• Variability: Enzyme levels differ among individuals, affecting drug response.

 Oxidative Reactions.

Cytochrome P450 System (CYP)

 A major enzyme system in the liver responsible for metabolizing a wide range of drugs.
 Forms a spectroscopic complex with CO (absorbs at 450 nm).
 Not substrate-specific, explaining its versatility.
 Can be induced by certain chemicals.

� Phase I Oxidation Reactions

1. Aromatic Hydroxylation

 Converts aromatic compounds (arenes) into phenolic metabolites (arenols).

 Involves arene oxide intermediates, which are often toxic unless detoxified.
 Hydroxylation typically occurs at the para position.
 Activating groups (e.g., –OH, –NH₂) enhance hydroxylation.
 Deactivating groups (e.g., –NO₂, –Cl) reduce it.

Detoxification of Arene Oxides:

 Rearranged to arenols (via NIH shift).

 Hydration to trans-dihydrodiols (via epoxide hydrolase).
 Conjugation with GSH → mercapturic acid.

2. Oxidation of Olefins

 Converts C=C double bonds into epoxides.

 Epoxides may undergo hydration or GSH conjugation.
 Some olefins (e.g., in fluroxene) destroy CYP by covalently binding to its heme group.
3. Benzylic Oxidation

 Occurs at carbons attached to aromatic rings → alcohols → aldehydes/carboxylic acids.

 E.g. Tolbutamide.

4. Allylic Oxidation

 Hydroxylation adjacent to C=C bonds.

 E.g. Hexobarbital → 3′-OH metabolite.

5. Oxidation α to Carbonyl/Imines

 Happens adjacent to carbonyls or imines.

 E.g. Diazepam.

6. Aliphatic & Alicyclic Oxidation

 ω-oxidation: at terminal carbon.

 ω-1 oxidation: at penultimate carbon.
 E.g. Valproic acid, Acetohexamide.

7. Oxidation of Carbon–Heteroatom Systems

a. Nitrogen-containing systems

 N-dealkylation: Removes alkyl groups (via carbinolamine).

o E.g. Imipramine, Lidocaine.
 N-oxidation: Forms N-oxides (can be active).
o E.g. Imipramine.
 Deamination: Removes amino group → aldehyde + NH₃.
o E.g. Propranolol.
 Lactam formation: From cyclic amines (e.g. Nicotine).
b. Primary Aromatic Amines

 N-hydroxylation → nitroso or nitro derivatives.

 E.g. Aniline.

c. Amides

 Oxidative N-dealkylation and hydroxylation.

 E.g. Diazepam, Cotinine.

b. Oxygen-containing systems (Ethers)

 α-carbon hydroxylation → cleavage → alcohol + carbonyl.

c. Sulfur-containing systems

 S-dealkylation: Like N/O-dealkylation.

 Desulfuration: C=S → C=O.
 S-oxidation: Forms sulfoxides and sulfones.