This master thesis focuses on the design, synthesis, and biological evaluation of new potential TLR8 receptor antagonists, that could represent a possible solution for the treatment of various immunological disorders, especially autoimmune disorders. TLR8 plays a key role in the immune system and enables the regulation of the immune response, making it an important immunomodulatory target. Based on previous studies using compounds with a 3,5-dimethylisoxazole ring, we designed new compounds by replacing this ring with three different benzene derivatives.
The synthesis of these new compounds contained three steps. In the first step, the synthesis of the main intermediate was initiated to obtain derivatives with different substituents on the benzyl group from methyl 4-hydroxy-3-methoxybenzoate via nucleophilic substitution. In the second step ester hydrolysis in a basic environment was performed, and the third synthetic step was the amide formation, in which final compounds with different amine substituents were synthesized, resulting in nine new compounds. During this process, we introduced a purification technique for the final compounds by adding 10% solution of citric acid, which contributed to greater product purity and higher yield.
The final compounds were characterized by various analytical methods and, furthermore, their TLR8 antagonistic activity was evaluated with a reporter assay using the HEK-Blue™ hTLR8 cell line. We found that most compounds did not exhibit significant antagonistic activity; however, two compounds, especially compound 9, demonstrated promising results.
The research in this master's thesis confirmed that specific structural features, such as the combination of N,N-diethylethylenediamine and dimethylphenyl fragment on the main scaffold, significantly contribute to the antagonistic effect, providing valuable insights for future research and development of more potent TLR8 antagonists.
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