Synthesis of bicyclic amines and their activities against Trypanosoma brucei rhodesiense and Plasmodium falciparum K1.
New alkenes, aziridines, and diamines were prepared from antiprotozoal 4-dialkylaminobicyclo[2.2.2]octan-2-imines to investigate the influence of several functional groups in position 2 of the ring skeleton on the antitrypanosomal and antiplasmodial activities. They were synthesized from 4-dialkylaminobicyclo[2.2.2]octan-2-imines and tested for their activities against Trypanosoma b. rhodesiense and Plasmodium falciparum K1 (resistant to chloroquine and pyrimethamine) using in vitro microplate assays. 4-Aminobicyclo[2.2.2]oct-2-enes and 3-azatricyclo[3.2.2.0(2,4)]nonylamines exhibit similar antiprotozoal activities as 4-aminobicyclo[2.2.2] octanes. 4-Aminobicyclo[2.2.2]oct-2-ylamines and their N-benzyl derivatives showed decreased antiplasmodial but enhanced antitrypanosomal (IC50 = 0.22-0.41 microM) activities compared to their parent oximes and to formerly synthesized 4-amino-2-azabicyclo[3.2.2]nonanes. Some of the 4-aminobicyclo[2.2.2]oct-2-ylamines exhibit moderate in vivo activity in mice against Trypanosoma brucei brucei.
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Universitätsplatz 1, A-8010, Graz, Austria.
Robert
R
Weis
Heinrich
H
Berger
Marcel
M
Kaiser
Reto
R
Brun
Robert
R
Saf
Werner
W
Seebacher
D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology
D000588:Amines; D000962:Antimalarials; D001643:Bridged Bicyclo Compounds; D014344:Trypanocidal Agents