ABSTRACT
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.
Subject(s)
Anti-HIV Agents/chemical synthesis , Antimalarials/chemical synthesis , Piperidines/chemical synthesis , Trypanocidal Agents/chemical synthesis , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Cell Line , Ethers/chemical synthesis , Ethers/chemistry , Ethers/pharmacology , HIV-1/drug effects , Humans , Leishmania major/drug effects , Macrophages/drug effects , Mice , Mice, Inbred C57BL , Oximes/chemical synthesis , Oximes/chemistry , Oximes/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Plasmodium falciparum/drug effects , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Virus Replication/drug effectsABSTRACT
The increasing resistance of the malaria parasites has enforced new strategies of finding new drug targets. We have isolated two genes involved in spermidine metabolism, encoding deoxyhypusine synthase (DHS) and eukaryotic initiation factor 5A (eIF-5A) in the malaria parasites. eIF-5A is activated by the formation of the unusual amino acid hypusine. This process occurs in two steps. DHS transfers an aminobutyl moiety from the triamine spermidine to a specific lysine residue in the eIF-5A precursor protein to form deoxyhypusine. In a second step, deoxyhypusine hydroxylase (DHH), completes hypusine biosynthesis. We used DHH inhibitors, being effective in mammalian cells, to study an antiplasmodicidal effect in Plasmodium falciparum. Experiments with the antifungal drug ciclopiroxolamine, an alpha-hydroxypyridone, and the plant amino acid L: -mimosine, a 4-pyridone, resulted in an antiplasmodial effect in vitro. Using mimosine as a lead structure, alkyl 4-oxo-piperidine 3-carboxylates were found to have the most efficient antiplasmodial effects in vitro and in vivo.