Alzheimer's disease (AD) is a chronic, progressive, and irreversible neurodegenerative disease characterized by cognitive, behavioural, and functional changes in the patient. The primary mechanisms of its development include the death of neurons essential for memory formation, the accumulation of amyloid β, hyperphosphorylation of the tau protein, neuroinflammation and oxidative stress. Current therapeutic approaches for AD, apart from monoclonal antibodies, whose long-term effects remain unexplored, target only symptomatic treatment using cholinesterase inhibitors and NMDA receptor antagonists.
Mitogen-activated protein kinase p38α (p38α MAPK), which is directly linked to an excessive neuroinflammatory response, and butyrylcholinesterase (BChE), which degrades acetylcholine, play crucial roles in the onset and progression of AD. Within the scope of this master's thesis, we designed, synthesized, and biochemically evaluated eight new potential dual inhibitors of BChE and p38α MAPK (9a–9h). Our starting point was the existing compound ARRY-371797, known as a selective p38α/β MAPK inhibitor, which also possesses certain structural similarities to BChE inhibitors. To optimize the dual inhibitory action, we attached methylcyclohexyl or benzyl groups to different positions (N1 and N2) of the starting compound's indazole ring. We hypothesized that the isobutyl fragment of ARRY-371797 binds into the acyl-binding pocket of hBChE; consequently, larger substituents at this position could potentially form more interactions with the hydrophobic amino acid residues Ile286 and Val288 of the hBChE acyl-binding pocket. Simultaneously, by replacing the N,N-dimethylethylenediamine group derivatives at position 6 of the indazole scaffold, we aimed to use a polar group to interact with the amino acids of the hBChE catalytic triad, potentially forming additional hydrogen bonds. The in vitro activity of the compounds was measured using biochemical assays on recombinant enzymes. Among all synthesized compounds, only 9a, 9g, and 9h exhibited dual inhibitory activity against hBChE and p38α MAPK; however, none showed improved inhibitory potency against p38α MAPK compared to the reference compound ARRY-371797.
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