Synthesis of Tamiflu and its Phosphonate Congeners Possessing Potent Anti-Influenza Activity

摘要

Influenza remains a major health problem for humans and animals. At present, four drugs are approved for influenza prophylaxis and treatment: amantadine and rimantadine act as the M2 ion channel blockers, whereas Tamiflu (the phosphate salt of oseltamivir ethyl ester) and Relenza (zanamivir) inhibit the activity of neuraminidase (NA). The NA inhibitors (NAIs) are designed to have (oxa)cyclohexene scaffolds to mimic the oxonium transition-state in the enzymatic cleavage of sialic acid. Tamiflu (1, shown in Scheme 1) is an orally administrated anti-influenza drug. On hydrolysis by hepatic esterases, the active carboxylate, oseltamivir (2, also known as GS4071), is exposed to interact with three arginine residues (Arg118, Arg292, and Arg371) in the active site of NA.