New antimalarial + antitrypanosolmal Anminobicyclooctanone

4-Aminobicyclo[2.2.2]octanones are part of a scarcely investigated substance class. No pharmacological and biological activities of these compounds have yet been reported. We prepared derivatives with an oxo group and two aromatic substituents using a one pot procedure and tested them as well as their corresponding reduction products for their activities against causative organisms of tropical deseases. They showed activity against Trypanosoma rhodesiense, a causative organism of sleeping illness, and Plasmodium falciparum, the causative organism of Malaria tropica. Malaria tropica is the most widespread form of malaria with the highest mortality. The global letality of malaria is approximately at 2.000.000 per year. A main problem in the control of malaria is the fast development of resistance of causative organisms against the so far applied therapeutics. Therefore the investigation of this substance class which show activity against the multiresistant K1 strain of Plasmodium falciparum is of vital interest. Aim of this project is the synthesis of new 4-aminobicyclo[2.2.2]octanones with higher antitrypanosomal and antiplasmodial activities. For that purpose, their substitution pattern will be varied: Other amino groups will be introduced as well as other aromatic residues. We will investigate if both aromatic moieties are essential for the activities of those compounds. Furthermore the contribution of the oxo function to the activities will be checked by reduction as well as by insertion of a second oxo group. Thiosemicarbazones have already been reported as antimalarial compounds, therefore the thiosemicarbazone of the most active ketone should be prepared. The corresponding bicyclo-octanols will be glycosylated with a sugar moiety to enhance the solubility in physiological media. The above-mentioned derivatization steps will be done only for those compounds showing the highest activities. Structures of those compounds will be developed further by recognition of essential substituents. The most active compounds should be subjected to a racemic resolution, because for the present all substances will be yielded as their racemates. All substances will be tested first by an in vitro assay to investigate their activities against Trypanosoma rhodesiense and Plasmodium falciparum. The most active compounds will be tested by in vivo assays. This project should contribute to the combat against sleeping illness and malaria.