Entwicklung von Dithiocarbazat- und Dithiocarbamat-Derivaten als potenzielle Anthelminthika gegen Schistosoma mansoni

Schistosomiasis oder Bilharziose ist eine Infektionskrankheit, die durch Saugwürmer der Gattung Schistosoma verursacht wird und zu akuten und chronischen Erkrankungen des Wirts führt, die insbesondere in armen Gemeinden in tropischen und subtropischen Gebieten erhebliche gesundheitliche und wirtscha...

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Bibliographic Details
Main Author: Gallinger, Tom Lukas
Contributors: Schlitzer, Martin (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2022
Online Access:PDF Full Text
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Schistosomiasis or bilharzia is an infectious disease caused by blood flukes of the genus Schistosoma and leads to acute and chronic conditions of the host, resulting in considerable health and economic effects especially in poor communities in tropical and subtropical areas. Recent estimates of the World Health Organization (WHO) showed that at least 236.6 million people required preventive treatment in 2019 with 105.4 million being treated. Since this large-scale treatment relies on only one single drug – praziquantel (PZQ) – new antischistosomal compounds need to be developed. In close collaboration with the lab of Prof. Grevelding, dithiocarbamates with antischistosomal activity were found by the group of Prof. Schlitzer, starting from the former drug and aldehyde dehydrogenase inhibitor disulfiram. In this preliminary work by Patrick Mäder and Georg A. Rennar substances with in vitro antischistosomal activities in the low micromolar range were identified. The present work represents the continuation of the development of dithiocarbamates and the author's own preliminary work in the field of structurally related dithiocarbazates as potential anthelmintics. The centrepiece of the first part of the work was the investigation on the biological effects of a further branching of the dithiocarbazate structure. To this end, the best possible unbranched dithiocarbazate analogs were first identified and then further derivatized. After extensive optimization of the synthesis conditions branched dithiocarbazates could be obtained. While N-unbranched dithiocarbazates were found to be less antischistosomally active than dithiocarbamates, the activity was increased by further N-substitution. Thus, compounds with an in vitro antischistosomal activity of 5 µM were obtained, placing them in the same activity range as the best dithiocarbamates. Due to the elaborate synthesis, the branched dithiocarbazates – containing a N-aminopiperazine – were simplified, but the resulting branched dithiocarbamates – containing a 4-aminopiperidine – were considerably less effective. The second part of the work concerned on the further development of the dithiocarbamates. In this substance class, the initial focus was on replacing the nitro benzyl group and on evaluating new functional groups on the side of the nitrogen substituent. By the introduction of heteroaromatic substituents only one derivative with an activity comparable to the nitro benzyl derivative was identified. The exchange of the sulfone amide or S,S-dioxide moieties on the nitrogen side for sulfonimidamide or sulfoximine structures led to a tremendous loss of antischistosomal activity. This decline in activity could not be compensated by further substitution of these new, medicinal-chemically interesting functional groups. Since no additional development candidates were identified through these modifications, a total of seven dithiocarbamates already obtained in earlier work were further characterized. In cooperation with Merck KGaA, in vitro ADMET-data were obtained and most of the compounds were found to be poorly soluble but otherwise showed no major limiting properties. Subsequently, the two most promising candidates were tested in an in vivo model for their antischistosomal activity. Unfortunately, one compound was found to be inactive and the other was only moderately active, paired with a high toxicity potential. Since the two compounds evaluated in vivo failed to provide a basis for further development, initial approaches for a structure-based inhibitor design of a schistosomal aldehyde dehydrogenase (ALDH) were developed in this work. In addition, by synthesis of fluorescence labelled dithiocarbamates and through docking studies a possible mode of action of the dithiocarbamates was investigated. Furthermore, potential metabolites of a dithiocarbamate derivative were synthesized and subsequently characterized by means of NMR and X-ray crystallography.