Alzheimer's disease (AD) is a chronic, progressive and irreversible neurodegenerative disease that imposes a heavy social and economic burden and is especially challenging for the patient and his family. It is the most common cause of dementia and is characterised by cognitive decline (especially in memory), which may be accompanied by neuropsychiatric symptoms. The pathophysiology of the disease is not yet fully understood, but there are various hypotheses that attribute the onset and progression of the disease to different changes in the brain, such as the atrophy of cholinergic neurons in parts of the brain important for memory formation and a change in the metabolism of amyloid precursor protein leading to the deposition of amyloid β, which contributes to the neuroinflammation and oxidative stress already present in the disease, and to the increased production of the hyperphosphorylated protein tau. We still do not have a cure, but we are using existing choline esterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist to alleviate the symptoms of the disease and monoclonal antibodies to slow cognitive decline.
In the context of this thesis, we set out to design and synthesise 1H-pyrazol-5-yl carbamate dual inhibitors of butyrylcholine esterase (BChE) and p38α mitogen-actived protein kinase (p38α MAPK). The design of the compounds was based on DP-802, a known non-competitive inhibitor of p38α MAPK, but to allow simultaneous action on the BChE enzyme, the urea fragment of this compound was replaced by carbamate. We then designed our compounds as disubstituted carbamates, namely as alkyl aryl carbamates, where the alkyl moiety in all our final compounds (11A-C) is the methyl group and the aryl moiety is the phenyl ring, which is substituted with a chlorine at the ortho site in compound 11A, with a chlorine at the meta site in compound 11B and with a methyl group at the ortho and meta sites in compound 11C.
The inhibitory activity on BChE was determined by the Ellman method and the inhibitory activity on p38α MAPK by the ADP-Glo test. None of the compounds showed activity on acetylcholinesterase, which is desirable as all were selective on BChE, but only compound 11B is a nanomolar pseudo-irreversible inhibitor of BChE. Compounds 11A and 11C are micromolar competitive inhibitors of BChE. However, none of the compounds showed inhibitory activity on the p38α MAPK enzyme, which is probably due to the loss of the hydrogen bonds lost by the replacement of urea by carbamate and by methylation of carbamate nitrogen.
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