Seebacher Werner, Weis Robert, Kaiser Marcel, Brun Reto, Saf Robert
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, A-8010 Graz, Austria.
J Pharm Pharm Sci. 2005 Oct 28;8(3):578-85.
New 2-azabicyclo[3.2.2]nonanes were prepared from antiprotozoal bicyclo[2.2.2]octan-2-ones to investigate the influence of the replacement of the rigid bicyclo-octane structure by the more flexible bicyclo-nonane system on the antiplasmodial and antitrypanosomal activity.
The 2-azabicyclo[3.2.2]nonanes were synthesized via a one-step procedure from bicyclo[2.2.2]octan-2-ones and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays.
2-azabicyclo[3.2.2]non-5-ylamines exhibit higher antiprotozoal activities than 4-aminobicyclo[2.2.2]octanes, 4-aminobicycl [2.2.2]octan-2-ones and 4-amino-2-azabicyclo[3.2.2]nonan-3-ones. (7, 8-Diphenyl-2-azabicyclo[3.2.2]non-5-yl)-dimethylamine shows enhanced anti-trypanosomal (IC50 = 0.60 microM) and remarkable antiplasmodial (IC50 = 0.28 microM) activity. However, the in vivo activity of this compound against Plasmodium berghei in mice is moderate.
Due to their promising in vitro antiprotozoal activity and their low cytotoxicity, 2-azabicyclo[3.2.2]nonanes should serve as lead compounds for further modifications.
从抗疟原虫的双环[2.2.2]辛烷 - 2 - 酮制备新型2 - 氮杂双环[3.2.2]壬烷，以研究用更灵活的双环壬烷体系取代刚性双环辛烷结构对抗疟和抗锥虫活性的影响。
通过一步法从双环[2.2.2]辛烷 - 2 - 酮合成2 - 氮杂双环[3.2.2]壬烷，并使用体外微孔板试验测试其对布氏罗得西亚锥虫和恶性疟原虫K1（对氯喹和乙胺嘧啶耐药）的活性。
2 - 氮杂双环[3.2.2]壬 - 5 - 基胺表现出比4 - 氨基双环[2.2.2]辛烷、4 - 氨基双环[2.2.2]辛烷 - 2 - 酮和4 - 氨基 - 2 - 氮杂双环[3.2.2]壬 - 3 - 酮更高的抗疟原虫活性。(7, 8 - 二苯基 - 2 - 氮杂双环[3.2.2]壬 - 5 - 基) - 二甲胺显示出增强的抗锥虫活性（IC50 = 0.60 microM）和显著的抗疟活性（IC50 = 0.28 microM）。然而，该化合物对小鼠伯氏疟原虫的体内活性中等。
由于其有前景的体外抗疟原虫活性和低细胞毒性，2 - 氮杂双环[3.2.2]壬烷应作为进一步修饰的先导化合物。
