Zanamivir, analogues

A series of fourteen 4-triazole-modified Zanamivir analogues were synthesized from the 4-azido-4-deoxy-Neu5Ac2en derivative using click chemistry, and their inhibitory potencies against influenza virus sialidase were determined. These modifications were not that successful as 33-35 demonstrated only 6-40% protective rate at a concentration of 50 pM against the virus infection compared to Zanamivir which shows 86% at the same concentration. The best result was obtained for compound 36, which showed a protective rate of >61%.76... 

The 5-acetamido group in zanamivir is also important in terms of influenza sialidase inhibition. Removal of this group, to give the 5-desacetamido derivative (19) resulted in a compound with a 25,000-fold reduced affinity for influenza virus sialidase [103]. However both the 5-trifluoroacetamido zanamivir analogue (20) and the 5-sulphonamide derivative (21) retain potent inhibitory activity against both influenza A and B strains, although the reported [104] IC50 values [2 x 10"8 M and 9 x 10 8 M, respectively, for (20)... 

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... 

An iron-promoted cascade cyclization to dihydropyran motifs was discovered while preparing zanamivir analogues and other probes useful in... 

Scheme 13 Application to the synthesis of of zanamivir analogues 46 and 49 and 2,3-unsaturated sialic acid 45 and 46.

The result of this FeCls 6H20-cascade of transformations is a very concise and highly flexible preparation of antiviral zanamivir analogues. This synthetic route has also potential for the fast generation of dihy-dropyrans of this type for other applications. 

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-... 

Further SAR studies on the cyclopentane scaffold have included variation of the hydrophobic side-chain to incorporate a carboxamide substituent (Chand et al. 2004), equivalent to the C6-carboxamide derivatives of zanamivir, and extension of the length of the hydrophobic side-chains (Chand et al. 2005a). Analogues that incorporate a longer 4-heptyl side-chain showed comparable efficacy to 34 upon oral and intranasal administration in mice, and comparable or better efficacy than oseltamivir and zanamivir (Chand et al. 2005a). 

Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PE, Shaw CD, Swanson S (1999) Synthesis and influenza virus siahdase inhibitory activity of analogues of 4-guanidino-Neu5Ac2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem 34 563-574... 

Complex imide 169 was prepared during an investigation into the preparation of analogues of the antiviral compound zanamivir Cyclization of imide 169 in acidic media, followed by treatment with trifluoroacetic acid, gave the corresponding 1,2,4-triazole 170 in a yield that was reported to be high (Equation 54) <1997BML2239>. 

Several carbocylic analogues of zanamivir that have been developed subsequently that display the same antiviral activity as zanamivir. The importance of the first of these, oseltamivir, more familiarly known as Tamiflu , has attracted the attention of academic chemists. Departing briefly from the organizing principle of this book. 

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). 

To overcome the limits of oral bioavailability of zanamivir, the development of second-generation zanamivir was pointed toward improving its pharmacokinetic properties. In this context, the most encouraging results were obtained with the phos-phonate analogue of zanamivir, with modification of the C7-hydroxy group or with a replacement of the glycerol side chain that also improved oral bioavailability compared to the original inhibitor 13 (Fig. 17.10). 

FIGURE 17.10 Analogues of zanamivir with improved bioavailability (a) phosphonate... 

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]. 

Zanamivir (GG167) is an analogue of transition state which exhibits the potent NA inhibitory activity. 

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. 

Other carbohydrate based analogues of zanamivir which have been synthesized as potential influenza virus sialidase inhibitors include the sulfur isostere (37), which was prepared from the known [113] 6-thio-Neu5Ac derivative (38) via a sequence analogous to that shown in Scheme 1.2 for the preparation of zanamivir [114]. The sulphur isostere (37) was found to have comparable activity (IC50 = 5 x 10 9 M) to zanamivir [114]. 

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