Medicinal Chemistry · Short notes

Structure Activity Relationship: Short Notes & Cheat Sheet

How structural changes alter activity: the classic SAR of penicillins, sulfonamides, barbiturates, benzodiazepines, catecholamines, opioids and quinolones.

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Short notes

Read these before you attempt the topic's MCQs.

Classic SAR rules to remember

Most SAR questions test one essential group per class. Learn the essential group first, then the modifications.

Core ideas

A pharmacophore is the minimum arrangement of groups a molecule needs to bind its target and act.
SAR studies change one part of a molecule at a time and watch what happens to potency, selectivity and duration.
QSAR puts numbers on SAR. Hansch analysis relates activity to lipophilicity (π), electronic effects (σ) and steric effects (Es).
Lipinski's rule of five predicts oral absorption: molecular weight ≤ 500, log P ≤ 5, no more than 5 H-bond donors and no more than 10 H-bond acceptors.

Antibacterials

Penicillins: the β-lactam ring fused to a thiazolidine ring is essential. The acyl side chain on 6-APA decides acid stability, spectrum and β-lactamase resistance.
Bulky groups next to the side-chain amide (methicillin, cloxacillin) block penicillinase. An α-amino group (ampicillin, amoxicillin) extends activity to Gram-negatives.
Sulfonamides: a free para-amino group (N4) is essential, because it mimics PABA. Heterocyclic groups on the sulfonamide nitrogen (N1) raise potency.
Quinolones: the 3-carboxylic acid and 4-keto group are essential for binding DNA gyrase. A fluorine at C6 greatly raises potency (the fluoroquinolones). A piperazine at C7 adds anti-Pseudomonas activity.

CNS and autonomic drugs

Barbiturates need two substituents at C5 for hypnotic activity (total 6–10 carbons is best). Swapping C2 oxygen for sulphur (thiopental) makes them faster and shorter acting.
Benzodiazepines need an electron-withdrawing group at C7 (Cl, NO₂). A halogen at the 2′ position raises potency. A 3-hydroxyl group (oxazepam, lorazepam) allows direct glucuronidation.
Catecholamines: the 3,4-dihydroxy (catechol) ring gives maximum activity but makes them substrates for COMT. Larger groups on the nitrogen shift selectivity towards β receptors (isoprenaline; tert-butyl in salbutamol gives β2).
An α-methyl group blocks MAO (ephedrine, amphetamine), which allows oral use and longer action.
Morphine: the phenolic 3-OH is essential. Methylating it gives codeine (weaker). Replacing the N-methyl with an N-allyl or N-cyclopropylmethyl group gives antagonists (naloxone, naltrexone).

Cheat sheet

High-yield facts in one place. Cover the right-hand column and test yourself.

Change → effect

Structural change	Effect
Bulky group near penicillin side-chain amide	Penicillinase resistance
α-Amino group on penicillin	Gram-negative activity
6-Fluoro on quinolone	Much higher potency
Free para-NH₂ on sulfonamide	Essential for activity
C2 O → S in barbiturate	Faster onset, shorter action
7-Cl on benzodiazepine	Essential for activity
Larger N-substituent on catecholamine	β selectivity
α-Methyl on phenylethylamine	MAO resistance, oral activity
3-OMe on morphine	Codeine, weaker analgesic
N-allyl on morphinan	Opioid antagonist

Lipinski's rule of five

Property	Limit
Molecular weight	≤ 500 Da
log P	≤ 5
H-bond donors	≤ 5
H-bond acceptors	≤ 10
Breaking more than one rule	Poor oral absorption likely

Memory aids

Rule of FIVE: all multiples of five: 500 Da, log P 5, 5 donors, 10 acceptors.

Exam traps

Sulfonamide activity needs the para-amino group free; the substituent goes on the sulfonamide nitrogen (N1).
Adding groups to the nitrogen of adrenaline increases β activity and reduces α activity.
Thiopental is short-acting because it redistributes out of the brain, helped by its high lipid solubility from the C2 sulphur.
Naloxone differs from oxymorphone mainly in its N-allyl group, which turns an agonist into an antagonist.

Revised? Now test yourself.

Attempt the Structure Activity Relationship MCQs while the notes are fresh. Anything you get wrong is saved to your incorrect list for the next revision round.