Medicinal Chemistry: Structure, Ionisation and Prodrugs
Functional groups drive everything
Identify acidic and basic groups, hydrogen-bond donors and acceptors, and lipophilic rings. Roughly: pKa and logP determine where a molecule is ionised and how well it crosses membranes; the unionised fraction is the membrane-permeant one. Use Henderson–Hasselbalch qualitatively: weak acids are more unionised in acid, weak bases more unionised in base. In practice, the large surface area of the small intestine often outweighs gastric pH effects for absorption.
Metabolism as a design tool
Phase I reactions (CYP-mediated oxidation, reduction, hydrolysis) usually create or expose a polar handle; phase II conjugation (glucuronidation, sulfation, acetylation, glutathione) increases water solubility for excretion. Ester groups are frequently built in to make short-lived prodrugs that are hydrolysed by plasma esterases.
Prodrugs and stereochemistry
Know the principle, not just the list: a prodrug is inactive until chemically or enzymatically converted. Classic examples include enalapril to enalaprilat, codeine to morphine (CYP2D6), clopidogrel to its active thiol metabolite (CYP2C19), and several proton-pump inhibitors that require acid activation. Stereochemistry questions test whether you know enantiomers can differ in potency, metabolism and safety - thalidomide, S-warfarin versus R-warfarin, S-omeprazole, levocetirizine.
Traps
Assuming "more potent" means "better" - potency is affinity/efficacy per milligram, not clinical superiority. Forgetting that bioisosteric replacement (e.g., replacing a carboxylic acid) can preserve activity while changing metabolism. Ignoring that a chiral centre may invert or racemise in vivo.
Worked example
A weak base with pKa 9 is largely ionised at plasma pH 7.4, which limits passive diffusion but improves aqueous solubility - ideal for an intravenous or oral-solution product, poor for a transdermal one.