Introduction to Pharmaceutical Chemistry

Introduction to Pharmaceutical Chemistry

• Pharmaceutical (Medicinal) Chemistry studies drugs from a chemical viewpoint, including design, synthesis, and structural analysis.
• Medicinal Chemistry is an interdisciplinary science, encompassing various branches of chemistry and biology.
• It involves isolating, characterizing, and synthesizing compounds for treating diseases, linking chemical structure to biological activity.
• It contributes to organic chemistry (synthesis routes) and pharmacology (spectrum of action).
• Medicinal chemistry leads to products like hormones, vitamins and biochemical drugs derived from biological sources.
• It's viewed as an interdisciplinary research area combining chemistry and biology (e.g., synthetic chemistry, organic chemistry, biochemistry, pharmacology, molecular biology) to enhance drug discovery.
• Medicinal chemistry entails discovering and designing new, enhanced therapeutic chemicals and developing them into medicines and drugs.

Drug Classification

• Pure organic compounds are primary agents for diseases, categorized by origin.
  • Natural compounds: Plant and animal sources (vitamins, hormones, amino acids, antibiotics, alkaloids).
  • Synthesis compounds: Created through pure synthesis or from naturally occurring compounds(morphine, atropine, steroids, cocaine) to decrease costs.
  • Semi-synthesis compounds: Combining natural intermediates to produce a desired product (e.g., semi-synthetic penicillins) due to high cost or isolation challenges.
• Two main categories based on medicinal use:
  • Pharmacodynamic agents: Act on body's physiological functions (e.g., general anesthetics, hypnotics, sedatives, analgesics).
  • Chemotherapeutic agents: Target pathogenic agents (e.g., sulfonamides, antibiotics, antimalarials, antivirals, anticancer agents).

Drugs and Diseases

• Drugs treat various diseases:
  • Infectious diseases: Transmitted via agents including bacteria, viruses, fungi, and parasites.
  • Non-Infectious diseases: Stem from genetic factors, environment, aging, stress and more (e.g., diabetes, heart disease, cancer, etc.).
  • Non-diseases: Address pain relief (analgesics), pregnancy prevention (contraception), or anesthesia.

Physicochemical Properties in Relation to Biological Action

• Drugs typically interact with targets like proteins, enzymes, cell lipids, or DNA/RNA fragments.
• The pharmacological effect of a compound is influenced by its physicochemical properties.
• Key influential physicochemical properties of organic medicinal agents (OMAs) include:
  • Solubility
  • Acidity and basicity
  • Reactivity

Importance of Solubility

• Solubility is crucial for drug formulation (appropriate dosage form) and bio-disposition (absorption, distribution, metabolism, excretion).
• Solubility is measured by affinity (or repulsion)/philicity(or phobicity) between the drug molecule and either an aqueous (hydrophilic) or lipid (lipophilic) solvent.

Solubility Prediction (cont.)

• Solubility of OMAs is a spectrum between high lipophilicity and high hydrophilicity.
• A compound's solubility in a particular solvent is determined by attractive forces between the compound and solvent molecules.
• It's possible to estimate OMAs' solubility (hydrophilic vs. lipophilic) by evaluating the structure (analyzing the presence of structural features promoting affinity for aqueous or lipid media).

Intermolecular Attractive Forces

• Essential intermolecular forces in the solubilization process are:
  • Van der Waals attraction: Weakest electrostatic force between nonpolar molecules (e.g., hydrocarbons).
  • Dipole-dipole bonding: Electrostatic linkage between electron deficient and rich atoms (e.g., hydrogen bonding).
  • Ionic bonding: Electrostatic attraction between cations and anions (found in inorganic salts and salts of organic molecules).
  • Ion-dipole interaction: Electrostatic interaction between an ion and a dipole (especially important for interactions between OMAs and water).

Mathematical Estimation of Relative Solubility

• Mathematical methods estimate solubility based on the differential contribution from various structural attributes.
• Solubility prediction involves summing the contribution of each group and substituent.
• Water-insoluble compounds (lipophilic) typically have log Pcalc values > +0.5.
• Water-soluble compounds (hydrophilic) usually have log Pcalc values < +0.5.

Laboratory Estimation of Relative Solubility

• Relative solubility of an organic compound is determined by experimental measurement (partition coefficient).
• This involves determining the extent of distribution between aqueous (usually pH 7.4 buffer) and lipid (typically n-octanol) solvents.
• The calculated partition coefficient (P) signifies the relative distribution of the compound between the two solvents.

QSAR

• QSAR is a computational method for predicting the biological activity, toxicity, or physicochemical properties of a molecule based on its chemical structure.
• It can aid in designing new molecules, reduce experimentation and estimate relative solubility of drugs.

Acidity and Basicity

• Acid/Base properties of OMAs is significant in both the pharmaceutical phase (dosage formulation) and the pharmacological phase (disposition and impact on target sites).
• Acid/base recognition involves identifying acidic and basic organic functional groups and evaluating their relative acid/base strengths.
• Identifying these groups is essential to determine the relative acid/base strength using ionization constants (Ka) and pKa.

Salt Formation

• Salt formation (combining an acid and base) elevates drug solubility compared to parent molecules.
  • Inorganic salts: Created by combining drug molecules with inorganic acids/bases(e.g., HCl, H2SO4, KOH, NaOH). Common usage is to increase the aqueous solubility.
  • Organic salts: Formed through combining an acidic and a basic drug molecule or combining a drug with organic acids/bases. Usage is to increase lipid solubility enabling depot injections.

Drug Activity Classifications

• Structurally Non-specific: Activity depends on physical properties like solubility, partition coefficients and vapor pressure and does not require explicit interaction with cellular targets.
• Structurally Specific: Activity depends on functional group presence, 3D structure and the interaction between the drug and a cellular receptor.

Drug-Receptor Interaction

• Receptors are sites in a biological system where drugs exert their effects.
• Most drugs function by interacting (combining) with receptors.
• The strength of binding between a drug and a receptor is measured by the drug's affinity for the receptor.
• Receptor concentration affects drug response.
• Agonists initiate response after binding to a receptor.
• Antagonists bind to a receptor but do not trigger response leading to blockage.

Stereochemistry

• Stereochemistry is critical in pharmacological properties.
  • Differences in stereospecificity(the specific 3D arrangement of atoms) affect activity.
  • Enantiomers (mirror image isomers) exhibit significant differences in potency, receptor fit, biological action, transport, and metabolism.
    • Example: Levophanol has various pharmacological properties while dextrophanol has a limited set of effects.
  • Geometric isomers (cis-trans) have different activity due to varied physical properties and differences in receptor fit.
  • Conformational isomers result from rotating around single bonds, and different conformations may exhibit different receptor binding capabilities.
    • Example: Acetylcholine exists in different conformations with distinct receptor binding.
• Isosterism and Bioisosterism: The process of creating structural analogues where substituted atoms or groups have similar properties to the parent molecule. This helps in maintaining biological activity while adjusting other properties like potency or side effects.

This quiz explores the fundamentals of Pharmaceutical Chemistry, focusing on the design, synthesis, and analysis of drugs from a chemical perspective. It highlights the interdisciplinary nature of this field, linking chemistry and biology in the context of drug discovery and development. Ideal for students interested in understanding how medicinal chemistry impacts healthcare.