The structures of zanamivir (Relenza), oseltamivir (Tamiflu) and a hypothetical

Question

The structures of zanamivir (Relenza), oseltamivir (Tamiflu) and a hypothetical transition state for sialoside hydrolysis are shown below. i) Highlight one feature of the zanamivir structure that specifically mimics the transition state of sialoside hydrolysis. ii) Highlight three structural features of zanamivir that can be used to rationalize its poor oral availability. iii) Highlight one functional group within zanamivir that is unstable to the strongly acidic conditions of the stomach. iv) Highlight three structural features of oseltamivir that represent significant structural changes relative to zanamivir and that help explain why it is an orally available drug.

Explanation / Answer

Solution: 1.) In zanamivir moleculer structure there are Ester group (R-O-R), Corboxylic group (COOH), Hydroxy group (OH) and acetyl amine group (AcNH). Due to the presence of these group it mimics the transition state of sialoside hydrolysis.

2.) Structural features of Zanamivir that can be used to rationalize its poor oral availability are follows:

a. Zanamivir contains both carboxylic and amine group in its moleculer structure. therefore it act as a zwitterion. Due to its zwitterionic character human body is unable to absorb the dose completely.

b.) Zanamivir is an ester prodrug, if taken orally, the medicine will not successfully distribute thoughout the body and therefore, will not fight against the infectious disease.

c.) One of the zanamivir excipient which contain milk protien also rationalize its poor oral availability.

3.) Functional group within zanamivir that is unstable to acidic condition is Lactose monohydrate (which contains milk protein).

4.) a. In oseltamivir carboxylate is an ethyl ester prodrug, which enhancing the molecule to be cationic, and therefore, an increase in oral absorption.

b. In oseltamivir Hydroxy groups of zanamivir are replaced with alkyl group to make it more stable.

c. In oseltamivir Carboxylic acid of zanamivir is replaced with a carbocyclic scaffold to prevent it acting as a zwitterion hence increasing absorption.

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