Alzheimer's disease (AD) is a progressive irreversible neurodegenerative disorder of the central nervous system characterized by memory loss and other symptoms of cognitive decline. Development of AD is often associated with acetylcholine deficiency in the brain, formation of amyloid beta aggregates, neurofibrillary tangles, neuroinflammation and oxidative stress, nonetheless, a unified hypothesis of AD pathogenesis is still lacking. Currently approved drugs for symptomatic treatment of AD are cholinesterase inhibitors and memantine as an NMDA receptor antagonist. There are two enzymes in the central nervous system responsible for the decomposition of acetylcholine, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). With the progression of AD the activity of AChE decreases. On the other hand, the activity and significance of BChE compensatively increases and this observation proposes BChE as a promising therapeutic target.
The aim of the work was to synthesize analogues of 1-(2-piperidin-1-yl)pyrrolidin-2-one, which was identified with ligand-based virtual screening software LiSiCA, and thus improve BChE inhibitory potencies. By varying the substituents on the position 3 of piperidine we aimed to optimize the binding of compounds to the acyl binding pocket of BChE.
The synthesis started from nipecotic acid, which was protected as tert-butylcarbamate and transformed into an aldehyde via corresponding Weinreb amide. The aldehyde obtained was combined with a Wittig salt in the Wittig reaction furnishing 3-vinylpiperidines. Following the reduction of double bond in the spacer and Boc deprotection, the secondary amine was alkylated using N-(2-bromoethyl)pyrrolidin-2-one. Final compounds synthesized were biochemically evaluated for their inhibition of isolated recombinant human BChE (hBChE) and AChE (hAChE) using the Ellman's method. To conclude, the most potent and selective BChE inhibitor was compound 46 with 3-trifluoromethylphenyl moiety (IC50 = 48 nM). Potent hBChE inhibitors with IC50 values in nanomolar range were also compounds 41–44 and 47. Most of the synthesized compounds were not as selective for BChE in comparison to AChE as expected. Nonetheless, compounds still represent a good starting point for the development and optimization of selective BChE inhibitors and multifunctional ligands for AD therapy.
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