Alzheimer's disease (AD) is a form of dementia that affects a person's thinking, memory, and behavior. It is a progressive disease that usually develops slowly and worsens over time. The main feature of AD is the accumulation of abnormal protein clusters in the brain called amyloid plaques and neurofibrillary tangles. In addition to these two features of AD, oxidative stress and a deficiency of acetylcholine have a major impact on the development of the disease. These changes lead to loss of brain tissue and a reduction in the number of neurons, especially in areas of the brain important for memory and cognition. Currently, there is no cure for AD, but medications, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors are available to alleviate the symptoms.
The aim of the master’s thesis was to prepare fluorescently marked BuChE inhibitors, based on the structure of tryptophan based BuChE inhibitors, the analogs of BuChE inhibitors were designed and synthesized, replacing tryptophan with coumarin and its substituted derivatives.
The synthesis went according to plan where we managed to prepare two inhibitors, whose inhibitory activity on BuChE was evaluated using the Ellman’s method.
The most potent inhibitor was compound 6, which simultaneously inhibited AChE, but both prepared compounds inhibited BuChE in the micromolar range, while known inhibitors inhibit in the nanomolar range.
We can conclude that the replacement of tryptophan with coumarin adversely affects the inhibitory activity. To prepare a fluorescently marked BuChE inhibitor, it would be more advantageous to introduce it to some other sites that does not interfere with binding to the active site and represent a starting point for further optimization with the aim of preparing fluorescent probes that will selectively detect BuChE in simple in vitro and in complex in vivo systems.
|
