Please use this identifier to cite or link to this item: http://dx.doi.org/10.25673/37420
Title: Structure based design, synthesis and characterization of small molecules as inhibitors of parasitic targets
Author(s): Bayer, Theresa Yasmin CharlotteLook up in the Integrated Authority File of the German National Library
Referee(s): Sippl, WolfgangLook up in the Integrated Authority File of the German National Library
Dobner, Bodo
Holl, RalphLook up in the Integrated Authority File of the German National Library
Granting Institution: Martin-Luther-Universität Halle-Wittenberg
Issue Date: 2021
Extent: 1 Online-Ressource (238 Seiten)
Type: HochschulschriftLook up in the Integrated Authority File of the German National Library
Type: PhDThesis
Exam Date: 2021-01-14
Language: English
URN: urn:nbn:de:gbv:3:4-1981185920-376631
Abstract: Aufgrund eines dringenden Bedarfes an neuen therapeutischen Möglichkeiten gegen parasitäre Erkrankungen werden in dieser Arbeit epigenetische Herangehensweisen für diese Infektionen untersucht. Die Substanz J1075 (3-chlorobenzothiophen-2-hydroxamsäure) wurde in einem virtuellen „Screening” als Inhibitor der smHDAC8 identifiziert. Ziel dieser Arbeit war es strukturähnliche Moleküle von J1075 zu entwerfen, synthetisieren und hinsichtlich ihrer Aktivität an der smHDAC8 und anderen epigenetischen parasitären Zielstrukturen zu untersuchen. Zur Strukturoptimierung wurden sowohl computerbasierte Methoden also auch kristallographische Studien durchgeführt. Die synthetisierten Substanzen wurden in Aktivitätsassays an isolierten Enzymen, in phenotypischen Assays und frühen (ADMET) pharmakokinetischen Assays untersucht. Auch die Selektivität der Substanzen zwischen den parasitären Zielstrukturen und den humanen homologen Enzymen und generelle Toxizität der Substanzen wurden untersucht.
In need for new therapeutic options for the treatment of neglected parasitic diseases this work presents an approach addressing epigenetic structures of the respective parasites. The compound J1075 (3-chlorobenzothiophene-2-hydroxamic acid) had been identified as a hit by virtual screening for the inhibition of smHDAC8. The aim of this work was to synthesize J1075-derived hydroxamic acids which were then to be tested towards their activity on smHDAC8 and other parasitic targets. The fragment-like hit was modified in several positions. The chemical optimization was guided by in silico studies as well as co crystallization studies. The synthesized compounds were tested in enzymatic assays towards their inhibitory activity on the isolated targets as well as phenotypic assays and early pharmacokinetic studies. Moreover the selectivity of the compounds between the target enzymes and the human enzymatic isoforms has been determined and toxicity assays were conducted. This synergistic interplay of the different methodologies allowed an ongoing optimization of the synthesized compounds according to each new finding.
URI: https://opendata.uni-halle.de//handle/1981185920/37663
http://dx.doi.org/10.25673/37420
Open Access: Open access publication
License: In CopyrightIn Copyright
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