Heterodimers of histidine and amantadine as inhibitors for wild type and mutant M2 channels of influenza A

Inhibitors bearing the imidazole, adamantane and related structures were synthesized and tested against WT, S31N and S31N-L261 mutant M2 channels. Although amantadine (1) only inhibited WT M2 channel, compound 6 containing the imidazole and adamantane groups showed good inhibitory activity to WT and mutant M2 channels. The stereochemistry and basic pK(a) of alpha-amine are important for the activity of inhibitors and our data showed that derivatives of natural histidine are more active for M2 channels than those of unnatural histidine. The significance of our present results is that we have established a prospective strategy of drug discovery of WT and mutant M2 channels against influenza A.