Alzheimer's disease is a progressive neurodegenerative disorder characterized by changes in the central nervous system. Around 40-50 million people have Alzheimer’s disease worldwide, and this number is expected to double within the period of the next twenty years. The disease manifests in memory loss, speech difficulties and brain fog (difficulty thinking). According to the latest research, neuroinflammation plays a key role in the onset and progression of Alzheimer’s disease, which can be prevented by targeting mitogen-activated protein kinase 38α (p38α MAPK). Another target is butyrylcholinesterase (BChE), which breaks down the neurotransmitter acetylcholine, crucial for signal transmission between neurons. By inhibiting BChE, the symptoms of Alzheimer’s disease can be relieved.
In the master's thesis, we designed, synthesized, and evaluated three potential dual inhibitors of BChE and p38α MAPK, all containing the same fragment phenyl-1H-pyrazole. For the desiqn of these compounds, we used the carbamate derivative of the previously discovered p38α MAPK inhibitor, DP-802, as a base. We attempted to replace the urea group with carbamate analogs, aiming to synthesize various aryl-alkyl carbamates. The tert-butyl group was replaced with a trifluoromethyl group. The acetamide group at position 1 of the benzene ring was replaced with a nitrile group to improve solubility and ease of synthesis.
We synthesized three final drug molecules– 7a-c. Based on the residual enzyme activity in in vitro tests, we can state that all of them exhibited inhibitory effects on BChE, with 7a and 7b being nanomolar covalent inhibitors, while 7c acts in the micromolar range as a non-covalent inhibitor. For greater selectivity in inhibiting BChE, the tert-butyl group should be replaced with a larger aromatic fragment, thereby filling the acyl-binding pocket. Our compounds 7a-7c also inhibited acetylcholinesterase in the nanomolar range. At tested micro-/nanomolar concentrations, compounds 7a-7c did not inhibit p38α MAPK. The most likely reason for this is the loss of three hydrogen bonds with the amino acid residues of the DFG pocket of p38α MAPK when the urea group of compound DP-802 was replaced by a carbamate.
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