3-azatetracyclo[5.2.1.1^5,8.0^1,5]undecane Derivatives: From wild-type inhibitors of the M2 ion channel of influenza A virus to derivatives with potent activity against the V27A mutant

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1^5,8.0^1,5]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC₅₀. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.