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

1
Q

Classify these amides.

A
  1. primary
  2. secondary
  3. tertiary
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2
Q

Draw an amide.

A
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3
Q

Are amides donors or acceptors?

A

Amides are both donors and acceptors.

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4
Q

How and why are proteases used in the body?

A

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

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5
Q

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

A
  • common
  • very stable
  • great H-bond acceptors (on carbonyl O)
  • can be acyclic or cyclic
  • USE: mimic peptide bonds (more stable than amides)
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6
Q
A

C. Esters

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7
Q

Carboxylic acids:

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

A
  • 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
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8
Q

Draw a Imine

A
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9
Q

Draw a oxime.

A
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10
Q

Draw a hydrazone.

A
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11
Q

Draw an amidine

A
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12
Q

Draw a guanadine.

A
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13
Q

Draw a guanadine.

A
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14
Q

Basic properties of amidines/guanadines:

A
  • additional nitrogen atom increases basicity of distributing charge
  • significantly protonated at pH 7
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15
Q

Draw a nitrile.

A
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16
Q

What is different about nitriles?

A
  • linear (straight; close proximity)
  • very stable
  • no significant protonation at pH 7
  • useful for making scaffolds
17
Q

Heteroaromatic amines
Non-nitrogenous:

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

A

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

18
Q

Heteroaromatic amines
nitrogenous:

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

A
  • 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

19
Q

What are the rules of aromaticity?

A
  • planar
  • full conjugation
  • 4n+2 pi-electrons
20
Q

What are the rules of aromaticity?

A
  • planar
  • full conjugation
  • 4n+2 pi-electrons
21
Q
A

D. Non-nitrogenous heteroaromatics interact similar to benzene

22
Q

Halogens:

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

A
  • 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

23
Q

Describe fluorine and its distinct properties

A
  • 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
24
Q

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

A

nucleophilic substitution

25
Aryl Halides: stable? occurance?
* very stable * very common
26
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
27
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!**
28
B. reduction
29
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
30
Phosphonates/phosphates
* used in prodrugs * highly charged basic functional group * increases solubility
31
Why are thiols important for proteins?
Unstable to air oxidation but can form disulfide bonds to form tertiary/quatanary structures.
32
D. Sulfoxides