EXAM 2 - Functional Groups in Drug Molecules (part 3)

Question 1

Classify these amides.

Answer 1

1. primary
2. secondary
3. tertiary

Question 2

Draw an amide.

Answer 2

Question 3

Are amides donors or acceptors?

Answer 3

Amides are both donors and acceptors.

Question 4

How and why are proteases used in the body?

Answer 4

Direct hydrolysis is very difficult under physiological conditions
* proteases help with cleavage of amides
* (most notably in the stomach with pepsin)

Question 5

Carbonates, carbamates, and urea: are they stable? common? acceptors or donors?

Answer 5

• common
• very stable
• great H-bond acceptors (on carbonyl O)
• can be acyclic or cyclic
• USE: mimic peptide bonds (more stable than amides)

Question 6

Answer 6

C. Esters

Question 7

Carboxylic acids:

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 7

• 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

Question 8

Draw a Imine

Answer 8

Question 9

Draw a oxime.

Answer 9

Question 10

Draw a hydrazone.

Answer 10

Question 11

Draw an amidine

Answer 11

Question 12

Draw a guanadine.

Answer 12

Question 13

Draw a guanadine.

Answer 13

Question 14

Basic properties of amidines/guanadines:

Answer 14

• additional nitrogen atom increases basicity of distributing charge
• significantly protonated at pH 7

Question 15

Draw a nitrile.

Answer 15

Question 16

What is different about nitriles?

Answer 16

• linear (straight; close proximity)
• very stable
• no significant protonation at pH 7
• useful for making scaffolds

Question 17

Heteroaromatic amines
Non-nitrogenous:

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 17

Key interactions: similar to benzenes
Role for solubility: increase water
Metabolism: complex, ring oxidation
Significant acid-base: none
Chemical reactivity: variable

Question 18

Heteroaromatic amines
nitrogenous:

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 18

• 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

Question 19

What are the rules of aromaticity?

Answer 19

• planar
• full conjugation
• 4n+2 pi-electrons

Question 20

What are the rules of aromaticity?

Answer 20

• planar
• full conjugation
• 4n+2 pi-electrons

Question 21

Answer 21

D. Non-nitrogenous heteroaromatics interact similar to benzene

Question 22

Halogens:

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 22

• 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

Question 23

Describe fluorine and its distinct properties

Answer 23

• 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

Question 24

Aliphatic halides (I, Br, Cl) are very prone to…

Answer 24

nucleophilic substitution

Question 25

Aryl Halides: stable? occurance?

Answer 25

• very stable
• very common

Question 26

Sulfoxides/Sulfones/sulfonamides

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 26

• 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

Question 27

How can sulfonamide be used in regards to the transitional state?

Answer 27

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!

Question 28

Answer 28

B. reduction

Question 29

Sulphonic acids/sulfates

Key interactions:
Role for solubility:
Metabolism:
Significant acid-base:
Chemical reactivity:

Answer 29

• 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

Question 30

Phosphonates/phosphates

Answer 30

• used in prodrugs
• highly charged basic functional group
• increases solubility

Question 31

Why are thiols important for proteins?

Answer 31

Unstable to air oxidation but can form disulfide bonds to form tertiary/quatanary structures.

Question 32

Answer 32

D. Sulfoxides