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

• Published in: European journal of medicinal chemistry Vol. 197; p. 112282
• Main Authors: Košak, Urban, Strašek, Nika, Knez, Damijan, Jukič, Marko, Žakelj, Simon, Zahirović, Abida, Pišlar, Anja, Brazzolotto, Xavier, Nachon, Florian, Kos, Janko, Gobec, Stanislav
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.07.2020; Elsevier
• Subjects: Acetylcholinesterase; Alzheimer’s disease; Butyrylcholinesterase; Chemistry, Medicinal; Life Sciences & Biomedicine; Monoamine oxidase; Multi-target-directed ligands; N-Alkylpiperidine carbamates; Pharmacology & Pharmacy; Science & Technology; N-Alkylpiperidine carbamates; Monoamine oxidase; Multi-target-directed ligands; Alzheimer’s disease; Acetylcholinesterase; Butyrylcholinesterase; CRYSTAL-STRUCTURE; DRUG DESIGN; DISEASE; MONOAMINE-OXIDASE-B; THERAPEUTIC STRATEGIES; INHIBITORS; CHOLINESTERASES; Alzheimer's disease; AGGREGATION
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112282

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. [Display omitted] •Novel N-alkylpiperidine carbamates were designed, synthesized and bioevaluated.•Compound 10 inhibits cholinesterases, monoamine oxidase B and is neuroprotective.•Compound 13 is a potent selective butyrycholinesterase inhibitor.•Neuroprotective compound 16 inhibits monoamine oxidase B and amyloid β aggregation.•Compound 22 inhibits both acetylcholinesterase and butyrylcholinesterase.