Entwicklung strukturell neuartiger Typ II FAS-Inhibitoren als Wirkstoffe gegen multiple Entwicklungsstadien von Apicomplexa und Entwicklung potenzieller Bid-Inhibitoren als Wirkstoffe gegen neuronalen Zelltod

Infektionen durch Apicomplexa zählen sowohl zu den häufigsten parasitären Erkrankungen als auch zu den häufigsten globalen Todesursachen des Menschen. Zu diesem Stamm gehören neben mehreren tausend weiteren Protozoen die Erreger der Malaria (Plasmodium spp.) und der Toxoplasmose (Toxoplasma gondii)....

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Bibliographic Details
Main Author: Schrader, Florian Christoph
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2012
Online Access:PDF Full Text
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Apicomplexan-borne diseases account for the most lethal and most widespread parasitic infections of man. This phylum consists of several thousands of protozoa including the malaria- and toxoplasmosis parasite. These parasites show a complex life cycle involving a host and a vector species. Inhibitors of fatty acid synthesis perfectly qualify as drug against apicomplexan-borne infectious diseases. These parasites synthesize fatty acids by means of discrete enzymes. In contrast, fatty acid synthesis in mammals is performed by a single enzyme. Structurally novel FAS II Inhibitors were identified by virtual screening. Out of these results, eight structurally diverse compounds were synthesized. Out of these, an amide derivative of salicylic acid was found to be active in a low micromolar concentration against blood-stage P. falciparum and T. gondii tachyzoites. By means of structure-based drug design and subsequent synthesis a derivative was developed, which showed improved activity against both blood- and liver stage malarial parasites. The most active compound is considerably more active than Primaquin, which is used in today’s therapy. Moreover, one of these compounds displays an IC50 of less than 1µM against T. gondii. Normally, there is a balance of cell death and proliferation in mammalian tissue. Cellular death of neurons physiologically only occurs in prenatal development. Apart from that, it occurs only in neurodegenerative diseases. Programmed neuronal cell death is linked to a number of neurodegenerative diseases like Alzheimer’s, Parkinson’s, stroke and traumatic brain injuries. The bid-inhibitor BI-6C9 was originally developed by the group of Maurizio Pellecchia. This compound acts as an anti-apoptotic agent and displays remarkable neuroprotective activity in vitro. However, we failed to reproduce these effects in the animal model for acute brain trauma and ischemia. In order to overcome possible pharmacokinetic deficiencies which may account for the poor performance of BI 6C9 in vivo, we developed a series of structurally diverse small-molecule derivatives. We started off identifying key structural elements of BI-6C9 taking different approaches such as ligand-based virtual screening. We showed that the metabolically instable thioether moiety can be replaced with bioisosteres while preserving the neuroprotective potency. In an even further effort to reduce the molecular structure of BI-6C9 to its essential elements we confirmed, that the diaryl-ether moiety itself is a key element in the neuroprotective activity. In the following, we developed three structurally diverse classes of compound, one of which was synthetically optimized to potently rescue HT-22 cells in a low micromolar concentration from Glu-induced toxicity.