Entwicklung von Benzophenon-Derivaten als Inhibitoren der Farnesyltransferase und des hMDR-Transporters

Infectious diseases are a serious threat for the health of mankind. Especially in the developing countries people are affected with the most important parasitic illnesses as Malaria, Trypanosomiasis and Leishmaniasis. All these diseases are caused by infection with different kinds of protozoa. Due to the increasing occurrence multi-resistant parasites and the high toxicity of some of the substances used for treatment an urgent need exists for new active drugs against these threats. In the recent years, farnesyltransferase was established as a new drug target in the development of new antiprotozoals. The group of Prof. Schlitzer works on the development of farnesyltransferase inhibitors based on a benzophenone-scaffold since a long time. The first assignment of this thesis was the completion of some series of farnesyltransferase inhibitors. After the synthesis, all these compounds were tested on their activity against Plasmodium falciparum, Trypanosoma cruzi and T. brucei brucei as well as against Leishmania amazoniensis and braziliensis. As an interesting result it turned out that the most active compounds against Plasmodium falciparum only displayed a weaker activity against Trypanosoma cruzi. During the development of the farnesyltransferase-inhibitors, an analogy of these benzophenone-derivatives with well-known propafenone-based inhibitors of the human multidrug-resistance transporter (hMDR) was conspicuous. Apart from humans, many parasites have such special types of membrane-transport proteins too. With these transporters the parasites are able to get rid of toxic by-products of the cellular metabolism or xenobiotics by effluxing these substances out of the cells. With this method they are able to keep the concentration of drugs in the cell in a subtherapeutic range. In a first test-series two intermediates of the farnesyltransferase-inhibitor synthesis have been tested because of their structural similarity to the propafenone-derivatives upon their activity against the hMDR-transporter. All these substances from this first series showed an activity from the low micromolar range down to 300 nM. By variations of different molecular scaffolds, two substances with an excellent activity (EC50 = 36 i.e. 64 nM) against the hMDR-protein have been developed. To evaluate if the hMDR-inhibitors have an additional anti malaria effect, each substance was tested upon their activity against the multiresistant Dd2-strain of Plasmodium falciparum. Some compounds were able to inhibit the parasites with an IC50 = 110 nM. Due to their structural similarity with literature-known hMDR-Inhibitors and because of the partially excellent activity against hMDR-proteins, it can be speculated that their molecular structural target might be the P-glycoproteine-homolog 1 (Pgh1). Pgh1 is the hMDR-analogon in Plasmodium falciparum species. To proof if the compounds display an activity on Pgh1 too they were tested with a fluorescence-microscopical-assay in cooperation with the University of Heidelberg. One of these most active compounds displayed a partial inhibition of the Pgh1-protein.