Synthesis and Evaluation of Acylated Derivatives of Hederagenin as Inhibitors of HIV-1 and HCV NS3/4A Proteases

Viral infection imposes a major threat to human health. To develop new potent antiviral agents, Hederagenin (HE), a known inhibitor of HIV-1 and HCV NS3/4A proteases, was used as a starting material to synthesize 4 types of HE derivatives, HE-3,23-diacyl, HES-3,23-diacyl, HES-3-acyl, and HES-3-oxo-23-acyl. We evaluated the in vitro inhibitory activities of the derivatives against HIV-1 and HCV NS3/4A proteases. (3 β,23)-Di- O-diglutaryl-hederagenin (1b) and (3 β,23)-di- O-(3′,3′-dimethylsuccinyl-hederagenin ethyl ester (2b) exhibited potent inhibitory activities against the HIV-1 and/or HCV NS3/4A proteases with IC 50 values < 10 μM, but did not appreciably inhibit general human proteases renin and trypsin. The SARs showed that dicarboxylic acid hemiesters of HE significantly enhance the antiviral activities when C3 or C23 are linked with 6 carbon acyl chains.