Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols.
Only three drugs are available for the treatment of East African trypanosomiasis. Patients suffer from painful application, severe side effects and increasing resistance against these drugs. Malaria tropica kills more than 2 million people every year mainly due to growing drug resistance. 4-Dialkylaminobicyclo[2.2.2]octan-2-ols and some of their esters have shown activity against both the causative organisms, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Ethers and new esters with markedly higher lipophilicity were prepared in three-step procedures from acyclic synthons. The new compounds were screened for their antiprotozoal activities against T. b. rhodesiense (STIB 900) and P. falciparum K1 (resistant to chloroquine and pyrimethamine), and for their cytotoxicity with L-6 cells by means of in vitro microplate assays. The results were compared to those of the parent compounds indicating that higher lipophilicity increases the antiprotozoal activities. The pivalate 10a showed the highest antitrypanosomal activity. The 4-chlorobenzoate 9b exhibited good antiplasmodial activity and low cytotoxicity. The most active antiplasmodial agent was the benzhydryl ether 13c which was nearly as active as chloroquine against sensitive strains.
Weis
Robert
R
Institute of Pharmaceutical Sciences, Pharmaceutical Chemistry, Karl-Franzens-University, Universitätsplatz 1, A-8010 Graz, Austria. robert.weis@uni-graz.at
Schlapper
Christian
C
Brun
Reto
R
Kaiser
Marcel
M
Seebacher
Werner
W
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D004952:Esters / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D010963:Plasmodium falciparum / Q000187:drug effects*; D013056:Spectrophotometry, Ultraviolet; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D000962:Antimalarials; D001643:Bridged Bicyclo Compounds; D004952:Esters; D014344:Trypanocidal Agents