Page 245 - Medicinal Chemistry Self Assessment

2.27 Zanamivir and Oseltamivir
Shown below is the structure for the treatment of influenza A and B infections.

Zanamivir

1. Identify all of the of 7.2.
Answer:

Carboxylic acid (Acidic functional group)
Normal pH range = 2.5 to 5
Would be primarily ionized at a pH of 7.2
Guanidine (Basic functional group)
Normal pH range = 12 to 13
Would be primarily ionized at a pH of 7.2
234 Medicinal Chemistry Self Assessment

2. Identify all other water soluble functional groups that are present within the structure of zanamivir.
2. Identify all other water soluble functional groups that are present within the structure of zanamivir.
Answer:
Answer
Primary hydroxyl group Secondary hydroxyl group
(or primary alcohol) (or secondary alcohol)
Secondary hydroxyl group
(or secondary alcohol) Ether oxygen

Amide

The amide and hydroxyl groups can act as hydrogen bond donors and acceptors and thus can form
hydrogen bonds with water. The ether oxygen most likely contributes the least to water solubility;
however, it can function as a hydrogen bond acceptor.
3. Based on your is administered as an oral inhaler instead of an oral tablet or capsule.

3. Based on your answers to questions 1 and 2, explain why zanamivir is administered as an oral inhaler
instead of an oral tablet or capsule.
Answer
The structure of zanamivir contains multiple hydrophilic functional groups that will allow it to easily
dissolve within the aqueous contents of the gastrointestinal (GI) tract. The carboxylic acid and the
guanidine functional groups will be extensively ionized at an intestinal pH=5 which further increases
the overall water solubility of the molecule. Although the structure of zanamivir contains a hydro-
carbon chain and ring, the overall balance between water and lipid solubility hinders its ability
to effectively cross the GI membrane. The oral absorption of zanamivir has been reported to be
between 1% and 5%. Due to this, zanamivir must be administered via oral inhalation.

4. Zanamivir exerts its antiviral action by inhibiting neuraminidase, a viral enzyme that is required for
the spread of the viral infection. A key component of neuraminidase’s action is the hydrolysis of
4. Zanamivir exerts its his, provide an explanation how zanamivir inhibits neuraminidase.
N-acetylsialic acid from surface viral glycoproteins. Shown below is the structure of N-acetylsialic acid
bound to a glycoprotein. Using this structure and the structure of zanamivir, provide an explanation

of how zanamivir inhibits neuraminidase.

Glycosidic bond

N-Acetylsialic acid bound to glycoprotein Zanamivir

Answer
Answer:
Zanamivir is a stable mimic of N-acetylsialic acid. As shown below, the structure of zanamivir retains
Zanamivir is a stable a cleavable glycosidic bond.
many of the structural features of N-acetylsialic acid, but lacks a cleavable glycosidic bond.

Structurally identical
to N-acetylsialic acid
(with exception of
the double bond)

Lacks glycosidic bond

Zanamivir

5. Shown below is a activity is likely to be more active, less active, or similar to that of zanamivir?

6. Shown below is the structure of for oseltamivir