Symmetry-Based Design for the Chemoenzymatic Synthesis of Oseltamivir (Tamiflu) from Ethyl Benzoate

摘要

The possibility of a major influenza pandemic (especially the avian H5N1 influenza) continues to be a serious health concern. The development of effective antiviral medicines is hampered by the exceptionally high mutation rates of the influenza virus and, for the research effort to be successful, any new drugs must target the molecular mechanisms specific to the proliferation of the virus. The mechanism of infection involves the protein neuraminidase (NA), which is essential to viral replication. It is responsible for the glycosidic cleavage of sialic acid from a glycoprotein of a host cell in a process that liberates the virion from the infected cell. Of the compounds that have been found to be effective as inhibitors of NA, by mimicking the oxonium intermediate of sialic acid glycolysis, oseltamivir (1), as its phosphate, or Tamiflu appears to be superior. It is orally active and serves as a prodrug, the active form of which is the corresponding carboxylic acid. It also has a superior bioavailability and is active at nanomolar levels.