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

Abstract

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 H 2N 2 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.