Lecture 5 - Structure Activity Relationships (SAR1) Flashcards
(15 cards)
What are 3 ways the shapes and sizes of molecules are modified?
- Changing number of methylene groups in chains and rings (increasing number of groups increases size and lipophilicity of lead compound under investigation)
- Increasing/decreasing degree of unsaturation
- Introduce/remove ring system
What are the properties of an antimalarial chalcone molecule, when is it active and what happens when a double bond on one is reduced?
- Prevent parasite from feeding on host haemoglobin
- Active at 200 nM vs drug resistant parasites
- Reduced analogue inactive, loss of antimalarial activity
What kind of molecule is cortisol? What happens when a double bond is introduced into its A ring? What molecule is produced? What is the effect of the change in geometry?
- Steroid molecule (anti-inflammatory) aka hydrocortisone
- Molecule prednisone (also anti-inflammatory) produced with 30x greater activity (much more potent)
- Change in geometry increases affinity for receptor
What is Rolipram and how is it made (what is added)? What are its properties compared to its starting molecule?
- Antidepressant
- Made from introducing cyclopentyl ring onto a molecule with a dimethoxy ring
- 10x more effective than dimethoxy counterpart
- Cyclopentyl ring can occupy hydrophobic pocket
What is tranylcypromine and how is it made (what’s added/removed)? What properties does it have compared to its starting molecule?
- Antidepressant
- Made from introducing cyclopropyl ring in place of double bond
- More potent and more stable
What happens if a ring system is incorporated into the side chain of penicillin G (what does it do)? How is it then administered and why?
- Provides steric protection against beta lactamases (resists lactamase cleavage)
- Still acid sensitive so has to be given via IV
What happens if methyl groups are introduced into a structure?
- Usually increase lipophilicity/reduce water solubility
- If adjacent to aromatic substituent, can produce steric hindrance
- Me group on aromatic ring very susceptible to metabolism to carboxylic acid
- Compounds containing heteroatoms attached to Me groups i.e. X-CH3 (X = S, O, N) undergo demethylation
How is the hydrophobic character of a drug measured?
- Can be measured experimentally in octanol/water mixture
- Hydrophobic molecules dissolve in octanol layer, hydrophilic compounds dissolve in water layer
- Partition coefficient gives equation: P = Concentration of drug in octanol/Concentration of drug in aqueous solution
What is the effect of chlorine substitution?
- Increases lipophilicity more than methyl group substitution
- Can also have a steric effect
What is the effect of hydroxy group substitution?
- Increases water solubility
- Provides new site for H bonding with receptor (can act as donor or acceptor)
- Provides site for Phase II metabolism (can shorter lipophilic drugs’ half-life so reducing toxicity through accumulation
What are the effects of basic groups, what are they formulated as, what are the issues with them, how do they interact with receptors?
- Most important groups in drugs are amines, pyridine and quinoline heterocycles
- Many basic drugs formulated as salts so presence of amine substituent enhances water solubility
- Number of basic groups in drug should be limited since if drug molecule is too highly charged, will not pass across biological membranes
- Aromatic amines avoided as can be metabolised to toxic metabolites
-Permits drug to interact with receptor/enzyme via H bonding, salt-bridge formation and ionic bonding
What are the effects of carboxylic acid and sulphonic acid groups? Give a specific example.
- Increase water solubility (carb. acid-containing drug can be formulated as water soluble sodium salt)
- Aromatic carb. acid function can have big effect on pharmacology and toxicology of small organic drug molecules:
- e.g. intro of carb. acid into toxic antiseptic phenol –> analgesic and anti-inflammatory salicylic acid
What are isosteres and why are they sometimes used?
- Groups that exhibit some similarities in chemical and physical properties
- Replacing substituent group with closely related functional group can lead to analogues with improved properties
What are classical isosteres? Give examples.
- Atoms and molecules with identical outer shells of electrons
- E.g. Uracil & 5-fluorouracil, phenothiazine drugs & dibenzazepine drugs
What are bioisosteres?
- Groups that when introduced provide analogues with similar biological activity
- Do not have same number of atoms
- Do not fit steric and electronic rules of classical isosteres
