Spiro[pyrrolidine-2,2′-adamantanes]: synthesis, anti-influenza virus activity and conformational properties

Synthetic spiro[pyrrolidine-2,2′-adamantanes] 2, 3, 11, 15, 12, 16, 18, 20 were evaluated in vitro and found to be active anti-influenza virus A compounds; the effect of the position of C-Me pyrrolidine ring substituent on antiviral activity was examined. Pyrrolidine 5-Me substitution appears to be optimal for H2N2 strain activity. From the four different possible protonated conformers, experimental observation using NMR spectroscopy and molecular mechanics calculations demonstrated only a pair of conformers A+H (N-Me (ps-ax), C-Me (ps-eq)) and B+H ((N-Me ps-ax, C-Me ps-ax)) which can contribute to the biological activity of C-Me, N-Me protonated derivatives 15+H, 16+H and 20+H. The relative populations were calculated from NMR spectra. For compounds 15+H and 20+H conformer A+H (cis dimethyl orientation) is the major one whereas a similar population of conformers A+H and B+H (trans dimethyl orientation) was observed for compound 16+H. Since this new series is characterized by a lipophilic part, that is the pyrrolidine ring, in addition to adamantane, that can interact with influenza A M2 protein, an ultimate future goal would be the in vitro mapping of M2 lipophilic pocket.