Synthesis, reactions and antileishmanial activity

Bachelor thesis - University of Veterinary Medicine Vienna - 2022

Leishmaniasis is a vector-borne disease caused by an intracellular parasite Leishmania spp., transmitted through a vector (sandfly). Therefore, the occurrence of the disease is connected to the natural habitat of a sandfly. Considering it being endemic in 98 countries, it is a widespread disease and a global health problem. Endoperoxides (EP) possess the ability to avoid the cellular detoxification pathways in host cells, allowing them to also exhibit their cytotoxic properties on intracellular Leishmania. Their antileishmanial potency is supported by the fact that they tend to be activated via the reaction with Fe2+ turning them into radicals. This is favoured since Leishmania spp. possess a high labile iron pool and get a sufficient iron supply from their surrounding. In this bachelor thesis, the synthesis and the antileishmanial effects of sterol endoperoxides ergosterol EP, and 7-dehydrocholesterol EP, were examined. The goal was to establish a method that could lead to high yields and purity of the product. Afterwards, the products were studied in viability assays, where the IC50 values for Leishmania tarentolae promastigotes were determined. Our synthethic approach based on different irradiation times, solvent combinations and photosensitizers yielded an EP purity up to 96.2 %. This allowed us to carry out the viability assays with high-quality products and provided reliable results. IC50 values for EP lower than 10 μM were measured during our experiments, which showed that the antileishmanial properties of sterol EP are higher compared to respective sterols. The viability assays in the presence of the radical scavenger N-acetyl cysteine showed that it is highly likely that the antileishmanial effects of sterol EP rely on their transformation into radicals by single electron reduction. A reaction of our products with xylenol orange and Fe2+, which was spectrophotometrically evaluated, was conducted to determine if this transition into radicals is influenced by the reaction with Fe2+. The reaction rates of the EP obtained during the experiment indicate that there is a high possibility of Fe2+ activation not only for sterol EP, but for sterols as well. During this work we have managed to obtain important data regarding the production process of sterol EP, as well as the background of their antileishmanial activity.

Bachelorarbeit - Veterinärmedizinische Universität Wien - 2022

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