Goebel Tim, Ulmer Daniela, Projahn Holger, Kloeckner Jessica, Heller Eberhard, Glaser Melanie, Ponte-Sucre Alicia, Specht Sabine, Sarite Salem Ramadan, Hoerauf Achim, Kaiser Annette, Hauber Ilona, Hauber Joachim, Holzgrabe Ulrike
Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
J Med Chem. 2008 Jan 24;51(2):238-50. doi: 10.1021/jm070763y. Epub 2007 Dec 27.
Malaria, sleeping sickness, Chagas' disease, Aleppo boil, and AIDS are among the tropical diseases causing millions of infections and cases of deaths per year because only inefficient chemotherapy is available. Since the targeting of the enzymes of the polyamine pathway may provide novel therapy options, we aimed to inhibit the deoxyhypusine hydroxylase, which is an important step in the biosynthesis of the eukaryotic initiation factor 5A. In order to identify new lead compounds, piperidines were produced and biologically evaluated. The 3,5-diethyl piperidone-3,5-dicarboxylates 11 and 13 substituted with 4-nitrophenyl rings in the 2 and 6 positions were found to be active against Trypanosoma brucei brucei and Plasmodium falciparum combined with low cytotoxicity against macrophages. The corresponding monocarboxylates are only highly active against the T. brucei brucei. The piperidine oximether 53 demonstrated the highest plasmodicidal activity. Moreover, compounds 11 and 53 were also able to inhibit replication of HIV-1.
