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 H(2)N(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.
Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou, Greece.
Ioannis
I
Stylianakis
Antonios
A
Kolocouris
Nicolas
N
Kolocouris
George
G
Fytas
George B
GB
Foscolos
Elizaveta
E
Padalko
Johan
J
Neyts
Erik
E
De Clercq
D000218:Adamantane / Q000031:analogs & derivatives*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011759:Pyrrolidines / Q000737:chemistry; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011759:Pyrrolidines; C032519:pyrrolidine; D000218:Adamantane