Medicinal Chemistry Lecture Notes

Course Title: PHRM 513 – Medicinal Chemistry
Recommended Books:
- Review of Organic Functional Groups: Introduction to Medicinal Chemistry, 5th Edition by Thomas L. Lemeke; Lippincott Williams & Wilkins
- Sigler’s Prescription Top 300 Drug Cards, 32nd Edition
- Foye's Principles of Medicinal Chemistry, 7th Edition (2008) by Thomas L. Lemke (Editor), David A. Williams (Editor); Lippincott Williams & Wilkins

Visual Aid: Diagram showing drug delivery processes (disintegration, dispersion, dissolution, permeation) and interactions within the stomach, small intestine, and colon.

Key Learning Goals:
- Review important functional groups in drug-like small molecules.
- Nomenclature: Recognize common names.
- Chemical properties: Focus on acid-base properties, chelation, and oxidation-reduction in metabolism.
- Understand how bonding impacts physicochemical properties of drugs.
- Physical properties: Related to water and lipid solubility.
- Competence in:
- Identifying functional groups in simple and complex drug molecules.
- Predicting ionization, solubility, and stability.

Definition: A functional group is a group of atoms within a molecule that has characteristic behavior, enabling classification by reactivity.
Example: Acetylsalicylic Acid (Aspirin).

Overview: Chemical bonding significantly affects the solubility of drugs in water and lipids.

Definitions:
- Intermolecular Forces: Forces occurring between molecules (e.g., Dipole-Dipole Interaction).
- Intramolecular Forces: Forces occurring within a molecule (e.g., Covalent Bonding).
- Importance of these forces in determining physical properties: boiling point, melting point, vapor pressures, and viscosities.

Covalent Bonds: ~ 4000 kJ/mol (Strongest)
Ionic Bonds: ~ 1000 kJ/mol
Ion-Dipole Bonds
Hydrogen Bonds
Dipole-Dipole
London Forces (Van der Waals Forces): Weakest; present in all organic compounds.

Van der Waals Force: Weak bonds influenced by distance and temperature; critical for lipid solubility in organic compounds.

Electronegativity values for primary elements:
- H: 2.2, C: 2.5, N: 3.0, O: 3.4, F: 4.0, etc.
Definition: A bond's dipole moment (m) is calculated as:
m = ext{charge separation} imes ext{bond length}
Example:
- Ethane (C-C bond): non-polar
- Chloromethane (C-Cl bond): polar

Definition: Occurs due to unequal sharing of electron pairs in covalent bonds, primarily between atoms of differing electronegativity.
Characteristics:
- Stronger than Van der Waals forces
- Less affected by temperature/distance
- Contributes to hydrophilic character in molecules

Definition: Electrostatic attraction between a charged ion and a dipole (polar molecule).
Importance in solubility, especially in aqueous solutions.

Key Understanding:
- Drugs experience both aqueous and non-aqueous interactions.
- Classification of molecules based on solubility:
- Hydrophilic: Soluble in water.
- Lipophilic or Hydrophobic: Soluble in lipids.
Resulting classifications lead to the development of water-soluble and lipid-soluble compounds.

Basic categories include: Alkanes, Alkenes, Alkynes, Aromatic Hydrocarbons, Alcohols, Aldehydes, and Ketones.
Functional groups impact biochemical pathways and therapeutic qualities.

Structurally: ext{R-C-OH}
Types:
- Primary Alcohol: Hydroxyl group bonded to a carbon atom that is attached to one other carbon.
- Secondary Alcohol: Hydroxyl group attached to a carbon atom connected to two other carbons.
- Tertiary Alcohol: Hydroxyl group on a carbon atom attached to three other carbons.
Properties: Increased boiling points due to hydrogen bonding; solubility enhanced by permanent dipole interactions.

Physical-Chemical Properties: Similar to alcohols with emphasis on acidity and reactivity.
Brønsted-Lowry Acidity: Phenols act as weak acids capable of donating protons.

Ethers Structure: ext{R-O-R'}
- Physical properties include lower boiling points and some water solubility.
Thioethers Structure: ext{R-S-R'}
- Characterized as strong nucleophiles; notable for their solubility parameters.

General Structure:
- Aldehyde: ext{RCHO}
- Ketone: ext{RC(O)R'}
Importance in chemical reactions, particularly in forming hemiacetals and acetals under specific conditions.
Stability: Ketones are generally stable, while aldehydes can be reactive.

Review the types of chemical bonding and its impacts on solubility.
Analyze functional groups and how they modify physicochemical properties of compounds.
Types of functional groups (alkanes, alkenes, alkynes, aromatics, halo-hydrocarbons, alcohols, aldehyde and ketones) and how they affect solubility of compounds