Stylianakis Ioannis, Kolocouris Antonios, Kolocouris Nicolas, Fytas George, Foscolos George B, Padalko Elizaveta, Neyts Johan, De Clercq Erik
Department of Pharmacy, Division of Pharmaceutical Chemistry, University of Athens, Panepistimioupolis-Zografou, Greece.
Bioorg Med Chem Lett. 2003 May 19;13(10):1699-703. doi: 10.1016/s0960-894x(03)00231-2.
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.
对合成的螺[吡咯烷-2,2'-金刚烷]2、3、11、15、12、16、18、20进行了体外评估，发现它们是具有活性的抗甲型流感病毒化合物；研究了C-甲基吡咯烷环取代基位置对抗病毒活性的影响。吡咯烷5-甲基取代似乎对H(2)N(2)毒株活性最为理想。从四种不同的可能质子化构象中，使用核磁共振光谱和分子力学计算的实验观察表明，只有一对构象A(+)H（N-甲基（伪轴向），C-甲基（伪平伏））和B(+)H（（N-甲基伪轴向，C-甲基伪轴向））对C-甲基、N-甲基质子化衍生物15(+)H、16(+)H和20(+)H的生物活性有贡献。相对丰度由核磁共振光谱计算得出。对于化合物15(+)H和20(+)H，构象A(+)H（顺式二甲基取向）是主要的，而对于化合物16(+)H，观察到构象A(+)H和B(+)H（反式二甲基取向）的丰度相似。由于这个新系列的特征是除了金刚烷之外还有一个亲脂性部分，即吡咯烷环，它可以与甲型流感病毒M2蛋白相互作用，最终的未来目标将是对M2亲脂性口袋进行体外测绘。
