1. Academic Validation
  2. N-alkylpiperidine carbamates as potential anti-Alzheimer's agents

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

  • Eur J Med Chem. 2020 Jul 1;197:112282. doi: 10.1016/j.ejmech.2020.112282.
Urban Košak 1 Nika Strašek 1 Damijan Knez 1 Marko Jukič 1 Simon Žakelj 1 Abida Zahirović 1 Anja Pišlar 1 Xavier Brazzolotto 2 Florian Nachon 2 Janko Kos 1 Stanislav Gobec 3
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia.
  • 2 Institut de Recherche Biomédicale des Armées, 91223, Brétigny-sur-Orge, France.
  • 3 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000, Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa.uni-lj.si.
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 β1-42 (Aβ1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Aβ1-42 anti-aggregation effects.

Keywords

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

Figures
Products