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.
OBJECTIVE
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 K1 (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 microM) and remarkable antiplasmodial (IC50 = 0.28 microM) 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.
Seebacher
Werner
W
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, A-8010 Graz, Austria. we.seebacher@uni-graz.at
Weis
Robert
R
Kaiser
Marcel
M
Brun
Reto
R
Saf
Robert
R
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D051379:Mice; D000442:Octanols / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000502:physiology; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000502:physiology; D014353:Trypanosomiasis, African / Q000188:drug therapy
D019086:Bridged Bicyclo Compounds, Heterocyclic; D000442:Octanols