6SAM

N-alkylpiperidine carbamates as potential anti-Alzheimer's agents.

(2020) Eur J Med Chem 197: 112282-112282

• PubMed: 32380361 Search on PubMed
• DOI: https://doi.org/10.1016/j.ejmech.2020.112282
• Primary Citation of Related Structures:  
  6SAM


• PubMed Abstract: 
  

  Compounds capable of interacting with single or multiple targets involved in Alzheimer's disease (AD) pathogenesis are potential anti-Alzheimer's agents. In our aim to develop new anti-Alzheimer's agents, a series of 36 new N-alkylpiperidine carbamates was designed, synthesized and evaluated for the inhibition of cholinesterases [acetylcholinesterase (AChE) and butyrylcholinesterase (BChE)] and monoamine oxidases [monoamine oxidase A (MAO-A and monoamine oxidase B (MAO-B)]. Four compounds are very promising: multiple AChE (IC ₅₀ ?=?7.31?μM), BChE (IC ₅₀ ?=?0.56?μM) and MAO-B (IC ₅₀ ?=?26.1?μM) inhibitor 10, dual AChE (IC ₅₀ ?=?2.25?μM) and BChE (IC ₅₀ ?=?0.81?μM) inhibitor 22, selective BChE (IC ₅₀ ?=?0.06?μM) inhibitor 13, and selective MAO-B (IC ₅₀ ?=?0.18?μM) inhibitor 16. Results of enzyme kinetics experiments showed that despite the carbamate group in the structure, compounds 10, 13, and 22 are reversible and non-time-dependent inhibitors of AChE and/or BChE. The resolved crystal structure of the complex of BChE with compound 13 confirmed the non-covalent mechanism of inhibition. Additionally, N-propargylpiperidine 16 is an irreversible and time-dependent inhibitor of MAO-B, while N-benzylpiperidine 10 is reversible. Additionally, compounds 10, 13, 16, and 22 should be able to cross the blood-brain barrier and are not cytotoxic to human neuronal-like SH-SY5Y and liver HepG2 cells. Finally, compounds 10 and 16 also prevent amyloid β _1-42 (Aβ _1-42 )-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ _1-42 anti-aggregation effects.

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Organizational Affiliation: 

University of Ljubljana, Faculty of Pharmacy, A?ker?eva 7, 1000, Ljubljana, Slovenia.