Divalent copper complexes as influenza A M2 inhibitors

New M2 blockers effective against the ubiquitous amantadine-resistant S31N M2 mutation in influenza A are needed. Six copper complexes, 2, 4, 6, 8, 9, and 10, were synthesized and found to block both wild type and S31N M2. Free Cu²⁺ also blocks M2 S31N but not S31N/H37A. The copper complexes do not block M2 H37A (either S31 or S31N). The complexes were effective against three influenza A strains in cell-culture assays, but less toxic to cells than CuCl₂. For example 4, Cu(cyclooctylamineiminodiacetate), which was stable at pH > 4 in the buffers used, had an EC₅₀ against A/Calif/07/2009 H1N1 of 0.7 ± 0.1 μM with a CC₅₀ of 147 μM (therapeutic index, averaged over three strains, 67.8). In contrast, CuCl₂ had an EC₅₀ of 3.8 ± 0.9 μM and CC₅₀ of 19 μM. Because M2 H37 is highly conserved, these complexes show promise for further testing as drugs against all strains of influenza A.