EXAM 2 - Functional Groups in Drug Molecules (part 3) Flashcards
Classify these amides.
- primary
- secondary
- tertiary
Draw an amide.
Are amides donors or acceptors?
Amides are both donors and acceptors.
How and why are proteases used in the body?
Direct hydrolysis is very difficult under physiological conditions
* proteases help with cleavage of amides
* (most notably in the stomach with pepsin)
Carbonates, carbamates, and urea: are they stable? common? acceptors or donors?
- common
- very stable
- great H-bond acceptors (on carbonyl O)
- can be acyclic or cyclic
- USE: mimic peptide bonds (more stable than amides)
C. Esters
Carboxylic acids:
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- very popular addition to drug molecules to gain solubility
Key interactions: H-bond acceptor/donor depending on protonation state; ionic interactions
Role for solubility: greatly increase water solubility
Metabolism: Phase II (glucuronidation)
Significant acid-base: weak acid, pKa ~3-6 –> significantly charged at pH 7
Chemical reactivity: nucleophile
Draw a Imine
Draw a oxime.
Draw a hydrazone.
Draw an amidine
Draw a guanadine.
Draw a guanadine.
Basic properties of amidines/guanadines:
- additional nitrogen atom increases basicity of distributing charge
- significantly protonated at pH 7
Draw a nitrile.
What is different about nitriles?
- linear (straight; close proximity)
- very stable
- no significant protonation at pH 7
- useful for making scaffolds
Heteroaromatic amines
Non-nitrogenous:
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
Key interactions: similar to benzenes
Role for solubility: increase water
Metabolism: complex, ring oxidation
Significant acid-base: none
Chemical reactivity: variable
Heteroaromatic amines
nitrogenous:
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- principle scaffolds
- extremely common
Key interactions: similar to amines
Role for solubility: increase water solubility
Metabolism: complex, ring oxidation
Significant acid-base: weakly basic but highly dependent on structure
Chemical reactivity: modest
What are the rules of aromaticity?
- planar
- full conjugation
- 4n+2 pi-electrons
What are the rules of aromaticity?
- planar
- full conjugation
- 4n+2 pi-electrons
D. Non-nitrogenous heteroaromatics interact similar to benzene
Halogens:
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- very common but most often found as aromatic substituents
Key interactions: weak H-band acceptors, hydrophobic interactions
Role for solubility: decrease water solubility, increase lipophilicity
Metabolism: oxidative/reductive dehalogenation
Significant acid-base: none
Chemical reactivity: not very reactive; some photoreactivity
* fluorine is a special case
Describe fluorine and its distinct properties
- highly electronegative
- very weak H-bond acceptor (when bound to C)
- good for substitution
- alkyl fluorides are more stable than other alkyl halides; F is a bad leaving group
- can be used to replace an H that is metabolized (lost in metabolism)
- hydrophobic
Aliphatic halides (I, Br, Cl) are very prone to…
nucleophilic substitution
Aryl Halides: stable? occurance?
- very stable
- very common
Sulfoxides/Sulfones/sulfonamides
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- Often used as a carboxylic acid isostere
- sulfomamides are used as transition state mimics (strong inhibitors)
Key interactions: strong dipole interactions
Role for solubility: increase water solubility
Metabolism: little
Significant acid-base: none
Chemical reactivity: very stable
How can sulfonamide be used in regards to the transitional state?
Amides are prone to hydrolysis through proteases –> one step in the hydrolysis was formation of a tetrahedral intermediate
In the process of amide hydrolysis, the amide is initially binded to the protease and they have some interaction but then there is a shape conformation to have a stronger bind between the two
* we can assume that the tetrahedral intermediate binds more strongly to the protease than the amide in its original state
* we can mimic the transitional state with a sulfonamide –> bind tighter to the protease than amide
* result: no reaction bc we have sulfonamide rather than amide
* binds more strongly to the protease than the inital amide!
B. reduction
Sulphonic acids/sulfates
Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:
- acid with pKa @ 2 (deprotonated in the body)
- used to increase solubility in prodrugs
Key interactions: strong ionic interactions
Role for solubility: increases water solubility
Metabolism: very little, can be cleaved by sulfatases
Significant acid-base: acid
Chemical reactivity: very stable
Phosphonates/phosphates
- used in prodrugs
- highly charged basic functional group
- increases solubility
Why are thiols important for proteins?
Unstable to air oxidation but can form disulfide bonds to form tertiary/quatanary structures.
D. Sulfoxides
