Pharmaceutical Chemistry: Structure, Reactivity and Drug Design
Core concepts
This domain rewards systematic thinking about functional groups and their reactions, stereochemistry, drug metabolism pathways (phase I oxidation, reduction, hydrolysis; phase II conjugation), and structure–activity relationships (SAR). You should be able to predict acidity/basicity from pKa and ionisation at physiological pH, recognise prodrugs and their activation, and explain how physicochemical properties (logP, hydrogen bonding, molecular weight) drive absorption and receptor binding. Know the classic medicinal chemistry strategies: bioisosteric replacement, homologation, ring contraction/expansion, and rigidification. Analytical content - UV–visible, IR, NMR, mass spectrometry, and chromatographic assay - appears as identification and quantification questions.
Traps examiners use
- Assuming every ester is a prodrug; many are simply hydrolytically labile.
- Confusing enantiomers (same physical properties except optical rotation; different biological activity) with diastereomers (different physical properties).
- Predicting that a basic drug is mostly ionised in the stomach - it is mostly ionised in acid, but absorption occurs in the intestine where the unionised fraction rises.
- Overlooking that N-dealkylation and O-dealkylation both count as phase I oxidation.
Rule of thumb
For SAR items, change one structural feature at a time and ask: does this alter lipophilicity, ionisation, steric bulk, or hydrogen bonding? Name the property changed before naming the biological effect. For pKa questions, use the Henderson–Hasselbalch relationship: a weak acid at pH = pKa is 50% ionised; each pH unit above pKa raises the ionised fraction roughly tenfold.