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

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 (IC₅₀ = 7.31 μM), BChE (IC₅₀ = 0.56 μM) and MAO-B (IC₅₀ = 26.1 μM) inhibitor 10, dual AChE (IC₅₀ = 2.25 μM) and BChE (IC₅₀ = 0.81 μM) inhibitor 22, selective BChE (IC₅₀ = 0.06 μM) inhibitor 13, and selective MAO-B (IC₅₀ = 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.

Keywords: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Monoamine oxidase; Multi-target-directed ligands; N-Alkylpiperidine carbamates.