Pharmaceutical Chemistry: Structure, Reactivity, and Drug Design
Core concepts
Expect questions linking chemical structure to physicochemical behavior, metabolism, and receptor binding. Master functional-group pKa behavior: carboxylic acids (pKa ~4–5) are ionized at physiologic pH; amines (pKa ~8–10) are protonated; phenols and sulfonamides have intermediate pKa. Ionization governs water solubility, lipid permeability, and renal reabsorption. The Henderson–Hasselbalch relationship explains trapping: weak acids accumulate in basic compartments, weak bases in acidic ones.
Stereochemistry and conformation
Know that enantiomers differ in pharmacodynamics and pharmacokinetics (e.g., S-warfarin more potent than R; S-omeprazole). Diastereomers differ in physical properties. cis/trans and E/Z assignments, plus conformational restriction (bioisosterism, ring contraction) are common. Bioisosteric replacements (e.g., –COOH ↔ tetrazole; –O– ↔ –NH–; –Cl ↔ –CF3) preserve activity while altering metabolism or pKa.
Metabolism and prodrugs
Phase I reactions (oxidation, reduction, hydrolysis) usually unmask or add a polar group via CYP450; Phase II conjugations (glucuronidation, sulfation, acetylation, methylation, glutathione) increase water solubility. Prodrugs improve absorption or target delivery (e.g., ester prodrugs hydrolyzed by esterases; enalapril → enalaprilat). Know that ester and amide hydrolysis rates differ and that amides are more stable.
Traps and rule of thumb
Questions often ask which drug is a prodrug, or which functional group causes a specific interaction (e.g., catechol oxidation, Michael acceptor toxicity). Rule of thumb: if a structure has an ester, suspect hydrolysis and short shelf life; if it has an amine, suspect protonation and possible salt formation for solubility.