Synthesis of 2-azabicyclo[3.2.2] nonanes from bicyclo[2.2.2] octan-2-ones and their activities against Trypanosoma brucei rhodesiense and Plasmodium falciparum K1

Purpose: 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. Methods: 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 K-1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. Results: 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 mu M) and remarkable antiplasmodial (IC50 = 0.28 mu M) activity. However, the in vivo activity of this compound against Plasmodium berghei in mice is moderate. Conclusions: 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.