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  • 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.

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.

Journal of medicinal chemistry (2013-11-19)
Matias Rey-Carrizo, Eva Torres, Chunlong Ma, Marta Barniol-Xicota, Jun Wang, Yibing Wu, Lieve Naesens, William F DeGrado, Robert A Lamb, Lawrence H Pinto, Santiago Vázquez
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pyrrolidine, ≥99.5%, purified by redistillation
Sigma-Aldrich
Pyrrolidine, 99%
Sigma-Aldrich
Pyrrolidine, FG
Sigma-Aldrich
Pyrrolidine, ≥99.0%
Sigma-Aldrich
Amantadine hydrochloride