Beiträge zur Entwicklung von potentiellen Inhibitoren gegen das apikoplastäre Ferredoxin-Ferredoxin-NADP(H)-Reduktase-System, sowie Hemmstoffen des eukaryotischen Initiationsfaktors 4A und der bakteriellen RNaseP Teil 1 und Teil 2 und 3

Parasiten der Gattung Apicomplexa verursachen einige schwerwiegende Erkrankungen des Menschen. Darunter findet sich das Malariafieber sowie die Toxoplasmose. Die Behandlung einer Malariaerkrankung wird auf Grund aufkommender Resistenzen immer schwieriger. Eine Toxoplasmose kann derzeit nur in ihrer...

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Bibliographic Details
Main Author: Schäfer, Eva-Maria
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2022
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Apicomplexan parasites are the reason for some severe diseases in mankind such as malaria or toxoplasmosis. For malaria infections the medical options are running shorter due to resistances. A cure for latent toxoplasmosis is not available yet. Thus, the need for new drugs against new targets is urgent. The first part of the thesis is about the development of compounds with inhibitory activity towards the apicomplexan ferredoxin-ferredoxin-NADP(H)-reductase system. This redox-system is essential in apicomplexan parasites like Plasmodium and Toxoplasma and seems to be a promising drug target. 83 compounds out of six structural classes were synthesized and their and the activity of 42 other compounds against Toxoplasma gondii Ferredoxin-NADP(H)-reductase was measured in a photometric enzyme-assay. Chosen compounds were also measured in a lactate-dehydrogenase assay against P. falc. in a cell-based assay. Promising structural classes are benzothiazole-derivatetives and thiazolidinone-derivatives, which were derived from a herbizide structure. The measurement of these compounds were able to give us a hint about structure-activity-relationships. As a complete new active class of inhibitory molecules propagylic alkohols were found. The second part of the thesis is about addressing a host target to fight viral diseases. Viruses like the Ebola Virus use the eukaryotic translational system to replicate itself. Silvestrol is a natural compound that inhibits the eukaryotic initiation factor 4A (eIF4A). Computer-supported we designed and subsequently synthesised 43 compounds out of four structural classes which were measured in a cell-based assay for their activity against eIF4A. Triazine derivatives were able to inhibit eIF4A in micromolar range, hydantoine derivates were found as activators of eIF4A – just like isosorbide-derivatives. The third part is about targeting RNase P a bacterial enzyme involved in tRNA maturation. Addressing this enzyme with an inhibitor successfully would give us a new class of antibiotics, that is so urgently needed. We were able to synthesise diacylthiosemicarbazides and diacylsemicarbazides to check their inhibitory activity.