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

Abstract 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 2 N 2 and H 3 N 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.