Synthese neuer Inhibitoren der Peptiddeformylase als potentielle Antimalariawirkstoffe

Malaria ist weltweit eine der bedeutendsten parasitären Erkrankungen, die unbehandelt zum Tod führen kann. Hervorgerufen wird sie durch Parasiten der Gattung Plasmodium. Der Erkrankung steht lediglich eine begrenzte Anzahl an wirksamen Medikamenten entgegen, deren Anwendungsbereiche durch Nebenwirku...

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Bibliographic Details
Main Author: Degenhardt, Inga
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
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Malaria is one of the most important parasitic diseases worldwide and can lead to death if left untreated. It is caused by parasites of the genus plasmodium. Only a limited number of effective drugs are available for treatment. Moreover, their application areas are severely limited by side effects and drug resistances. As a new potential target a specific organelle has been described: the apikoplast. The endosymbiotic origin of this organelle explains its susceptibility to antibiotics. They are targeted on the housekeeping functions of the apikoplast which are essential for the survival of the parasite. Many antibiotics show a delayed type of action, the delayed death effect. One possible target within the apikoplast is the peptide deformylase, a metalloprotease that catalyzes the hydrolytic cleavage of the formyl group of formylmethionine. In a virtual screening of the ZINC database three compounds have been identified as possible leads. These inhibitors displayed IC50 values against the multidrug-resistant Dd2 strain of P. falciparum in a nanomolar range. Based on these three molecules this thesis presents newly synthesized derivatives which have been used to establish structure-activity relationships (SAR). The influence of different functional groups as well as the length of the alkyl chains has been the focus of this investigation. In addition, the synthetic routes for the three agents are presented.