Medicinal plants as sources of new lead compounds against parasitic diseases: Indoloquinoline derivatives

Malaria is a parasitic disease for which the global impact may not be underestimated. It is rated that there are between 200 and 300 million cases each year, from which more than 2 million with a fatal end. Four different Plasmodium species are responsible for human infection, P. vivax, P. ovale, P. malariae and the most severe one, P. falciparum. Quinoline antimalarials are often used for the treatment of this disease, but against a lot of compounds, such as chloroquine, resistance has appeared or is appearing, especially with regard to P. falciparum . Researchers are working very hard to develop a vaccine against malaria, but until now this has not been successful, and as long as no effective vaccine is available, there is still a high need for finding new antimalarial agents.;Cryptolepine and neocryptolepine, two alkaloids originally isolated from the African plant Cryptolepis sanguinolenta showed antiplasmodial activity in vitro. Neocryptolepine was the subject of investigations, and because of its lower cytotoxicity, compared with cryptolepine, neocryptolepine was a promising compound for further research. The primary aim of this work was to investigate the biological activity of the neocryptolepine derivatives, and in particular the antiplasmodial activity and possible mechanisms of action.;The synthetic 1-, 2-, and 3-monosubstituted and 2,9-disubstituted neocryptolepine derivatives were evaluated for their biological activity in order to obtain compounds showing higher and more selective antiplasmodial activity. Different functional assays and in vitro tests have been used to obtain additional information on the mechanism of action.;During the present work, 2 isomers of cryptolepine were synthesised. The first, isocryptolepine, was also isolated before from C. sanguinolenta whereas the second, for which the name isoneocryptolepine was proposed, was not reported before as a natural product. 1H, 13 C and 15N-NMR spectra were recorded for all four indoloquinoline isomers available, cryptolepine, neocryptolepine, isocryptolepine and isoneocryptolepine, in their unprotonated as well as protonated form, together with two dimensional NMR-spectra: COSY, HSQC and HMBC. Complete 1H, 13C and 15N assignments were made.;The four isomers were also evaluated for their antiplasmodial, antitrypanosomal activity and their cytotoxicity.