Alzheimer's disease (AD) is a complex neurodegenerative disease that affects mainly the elderly population and represents a significant health challenge. It is the most common form of dementia, leading to a progressive decline in memory and other cognitive functions, which limits the ability to perform daily activities. Currently, there is no cure for AD. Available treatments only relieve symptoms and slow disease progression. This master's thesis focused on two key targets: butyrylcholine esterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK), for which we developed multi-target-directed ligands (MTDLs). This approach offers promising therapeutic potential for AD, as inhibition of BChE increases the concentration of acetylcholine in the brain, potentially improving cognitive functions, while inhibition of p38α MAPK reduces neuroinflammation and tau hyperphosphorylation, which may slow disease progression.
In this thesis, we designed, synthesized, and biochemically evaluated four dual inhibitors. The design was based on compound DP-802, a potent and selective p38α MAPK inhibitor that forms multiple hydrogen bonds at the enzyme's active site. DP-802 binds to an allosteric site, stabilizing the enzyme’s inactive conformation. To ensure that our new compounds also acted as covalent inhibitors of BChE, we substituted carbamate with a phenylurea group. We also made several other structural modifications, such as replacing the 2,3-dichlorophenyl fragment with a benzyl group, methylating the nitrogen in the carbamate group, and modifying the carbamoyl group. Removing the phenylurea significantly reduced the binding affinity for p38α MAPK. Using the Ellman method, we found that all four compounds inhibited BChE, but they also inhibited AChE. Testing at Reaction Biology Corporation confirmed that our compounds did not inhibit human p38α MAPK. Unlike the carbamate group, the phenylacetic group enables the formation of two additional hydrogen bonds, resulting in weaker inhibitors of p38α MAPK.
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