Novel 3-(2-Adamantyl)pyrrolidines with potent activity against influenza A virus—identification of aminoadamantane derivatives bearing two pharmacophoric amine groups

The 3-(2-adamantyl)pyrrolidines 8a–g, 14 were synthesized and evaluated for activity against influenza A virus. The parent N–H compound 14 was several times more active than amantadine against H2N2 and H3N2 influenza A virus. The combined use of NMR spectroscopy and computational chemistry showed that the conformation around the pyrrolidine–adamantyl carbon–carbon bond is trans and the pyrrolidine heterocycle has an envelope conformation with C-2 out of the plane of the other ring atoms. N-Dialkylaminoethyl substitution of compound 14 resulted in the potent diamine analogues 8e,f,g. Interestingly, their lactam amine precursors were also active. Compounds 8e,f,g are the first adamantane derivatives, bearing two amine groups, reported to be active against influenza A virus.