Synthesis of 4-Guanidino-7-Modified-Neu5Ac2en Derivatives and Their Biological Activities as Influenza Sialidase Inhibitors

摘要

Substitution of 7-OH with small hydrophobic groups on zanamivir resulted in the retention of low nanomolar inhibitory activities against not only influenza A virus sialidase but also influenza A virus in cell culture. These compounds were prepared by treatment of the corresponding 7-substituted sialic acids derived from 4-modified N-acetyl-D-mannosamine (ManNAc) using enzyme-catalyzed aldol condensation. A series of 7-alkyl ether derivatives related to Zanamivir were synthesized using direct alkylation of the C-7 alcohol of sialic acid. An alkyl ether moiety of less than 12 carbons in length showed low nanomolar inhibitory activity against influenza A virus sialidase. A series of ester prodrugs of compound (10b) was synthesized and their efficacy was evaluated in an influenza infected mouse model by intranasal administration. The compound (25c: CS-8958), octanoyl ester prodrug of the C-9 alcohol of compound (10b), was found to be much longer acting than Zanamivir. Polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en analogues on the polyglutamic acid backbone, via a spacer of alkyl ether at the C-7 position, were synthesized. The multivalent conjugates (32) and (33) showed enhancement of antiviral activity against influenza A virus and more potent efficacy in vivo relative to monomeric sialidase inhibitors.