Zanamivir, analogues structure

Much of the chemistry devoted to side-chain modified zanamivir analogues has been driven by a desire to prepare structurally simpler derivatives, especially from the viewpoint of easier chemical syntheses. Replacement of the glycerol side-chain of zanamivir with an achiral ether substituent has... 

The C-6 carboxamide analogues of zanamivir, represented by the general structure 24, provided an avenue to introduce more hydrophobic side-chains onto the dihydropyran scaffold to interact with the hydrophobic regions of subsites S4 and S5 (reviewed in Islam and von Itzstein 2007). The most active tertiary amides (24 = alkyl) showed comparable inhibitory activity to their glycerol side-... 

A number of C-6 carboxamide analogues were prepared in which the stereo-chemically complex glycerol side-chain of Zanamivir or 4-amino-4-deoxy-Neu5Ac2en was replaced entirely by secondary or tertiary amides with the general structure of 94 or 95.95,96 These series of compounds were prepared from the C-6 carboxylate 92 (prepared by periodate oxidation of the glycerol side-chain of 91) by amide couling via the activated pentafluorophenyl ester 93 (Scheme 3). 

Several NA inhibitor analogues have been synthesised using structure of DANA 6 as a base molecule. An extremely potent influenza NA inhibitor, with Ki value of 10 M, is 2,3-didehydro-2,4-dideoxy-4-guanyl-N-acetylneuraminic acid 7, Zanamivir, GG167, fig. (12) [33,34,35]. 

The discovery, in the early 1990s, that zanamivir was a potent and selective inhibitor of influenza virus sialidase prompted several researchers to investigate the synthesis of Neu5Ac2en based analogues of zanamivir. Much of this effort was a consequence of the fact that zanamivir (12) must be administered as a nasal spray, due to its poor oral bioavailability and rapid excretion [101,102], and the desire to identify new sialidase inhibitors with modified physicochemical properties. Several researchers have described structure-activity relationship studies based on zanamivir (vide infra), with most modifications reported at C-4, C-5, and the glycerol side-chain. 

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