In search for novel agents in therapy of tropical diseases and human immunodeficiency virus

Abstract

Malaria, sleeping sickness, Chagas´ disease, and Aleppo boil are among the tropical diseases causing millions of infections and cases of the deaths per year. In addition, AIDS is an emerging health problem, mainly in Africa and India. No efficient chemotherapy is available for all diseases. Since targeting the enzymes of the polyamine pathway may a therapy option it was aimed to inhibit the deoxyhypusine hydroxylase (DOHH) which is an important step in the biosynthesis of the eurokaryotic initiation factor 5A (eIF-5A). Previously, piperidone compounds have been shown to efficiently inhibit the DOHH by complexing the metal ion in the catalytic unit of the enzyme. In order to find new lead compounds for the development of drugs against the aforementioned diseases a library of piperidones was produced and tested against the corresponding microorganisms. The 3,5-diethyl piperidone 3,5-dicarboxylates 11 and 13 being substituted with 4-nitrophenyl rings in 2- and 6-position were found to be active against Trypanosoma brucei brucei and Plasmodium falciparum combined with a low cytotoxicity against macrophages. Additionally these compounds are able to inhibit the HIV-1 replication. The corresponding monocarboxylates are only highly active against the T.b.b. The dichlorobenzyl ether of the piperidine oxime 53 showed the highest plasmodicidal activity and is, thus, a promising lead compound for future drug development.