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 H 2N 2 and H 3N 2 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. Pyrrolidines 14, 8a, e, g were synthesized and found active against H 2N 2 and H 3N 2 influenza A virus. Through a combination of NMR spectroscopy and molecular mechanics calculations it was shown that the parent 3-(2-adamantyl)pyrrolidine 14 adopts a trans conformation around C3–C2′ bond and an E(2) pyrrolidine conformation. Compounds 8e, g are the first adamantane derivatives, bearing two amine groups, reported to be active against influenza A virus.