Alzheimer's disease is the most common form of dementia and represents a major public health challenge in modern society. It is characterized by cognitive, functional and behavioral symptoms which are associated with the deposition of amyloid plaques and the formation of the neurofibrillary tangles caused by tau protein hyperphosphorylation. Since the exact mechanism underlying the disease remains unclear, several hypotheses have been proposed, including the amyloid hypothesis, hypothesis protein tau, cholinergic hypothesis, neuroinflammatory and others. Current therapies primarily alleviate symptoms but do not halt the pathological processes. In recent research, the concept of multitarget ligands has gained increasing importance, as it allows simultaneous action on multiple key targets.
The aim of master’s thesis was the synthesis of compounds capable of simultaneously inhibiting butyrylcholine esterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK). BChE plays an important role in the later stages of Alzheimer’s disease, as it becomes the main enzyme responsible for acetylcholine degradation, while p38α MAPK is involved in neuroinflammatory processes associated with the toxic effects of Aβ and tau protein hyperphosphorylation. Their concurrent inhibition represents a potential strategy to improve cognitive functions and influence the pathophysiological progression of the disease.
The experimental work was based on the development of compounds, using compound 41, a known p38α MAPK inhibitor, as the starting molecule. The synthesis included cyclization, aromatic nucleophilic substitution, reduction and diazotization reactions. Several challenges emerged during these procedures, such as instability of products, limited reaction selectivity, the formation of side products and practical difficulties associated with sulfur-containing compounds. Nevertheless, several intermediates were successfully synthesized, representing promising fragments for further development.
Although the final compounds with dual inhibitory activity were not successfully synthesized, the results indicate the relevance of further research. The synthesized fragments can serve as a foundation for optimization and the design of effective multitarget ligands, which may in the future contribute to more comprehensive treatment strategies for Alzheimer’s disease.
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