Sialidase Inhibitors Based on a Cyclohexene Scaffold

Comparative early work on the influenza virus sialidase inhibition of the cyclohexene isomers 132 and 133 revealed that 133 was a much more potent compound (IC50 = 6.3 pM) than its isomer 132, which failed to demonstrate inhibition of the enzyme at concentrations up to 200 pM, supporting the significance of the position of the unsaturation.121 Interestingly in seeming contrast 

Systematic functionalization of the hydroxyl group of lead inhibitor 133 with various alkyl chains allowed for the introduction of hydrophobic groups designed to interact with nonpolar regions of subsites S4 and S5. In every reported case, alkyl ether derivatives were superior inhibitors to the alcohol.121 Analysis of a range of inhibitors led to the conclusion that the length, branching, and 

The combined effects of a carbocyclic scaffold and replacement of the glycerol side-chain with an amide group were also investigated.125 Neither GS4071-like 

158 nor Zanamivir-like 159 were as effective against NA(A) as Zanamivir 1, though these positional isomers lacked a substituent at C-4 for interaction with the S2-binding pocket (Fig. 19). Notably, the position of the double bond had a large impact on the effect of the inhibitor on NA activity, and both inhibitors exhibited selectivity for influenza A virus NA, as previously observed in the C-6 amide series. 

NA in the latter two cases. However, the guanidine analogue of GS4071 had only modestly improved inhibition (compare 166 with 147). The origins of this differential improvement are unclear, but suggest that the nature of the alkyl ether component affects the hydrogen-bonding network in S2. 

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A Sialidase Inhibitor Based on a Cyclohexene Scaffold The Development of Oseltamivir... 

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