Title : N-alkylpiperidine carbamates as potential anti-Alzheimer's agents - Kosak_2020_Eur.J.Med.Chem_197_112282 |
Author(s) : Kosak U , Strasek N , Knez N , Jukic M , Zakelj S , Zahirovic A , Pislar A , Brazzolotto X , Nachon F , Kos J , Gobec S , Knez D |
Ref : Eur Journal of Medicinal Chemistry , 197 :112282 , 2020 |
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 muM), BChE (IC50 = 0.56 muM) and MAO-B (IC50 = 26.1 muM) inhibitor 10, dual AChE (IC50 = 2.25 muM) and BChE (IC50 = 0.81 muM) inhibitor 22, selective BChE (IC50 = 0.06 muM) inhibitor 13, and selective MAO-B (IC50 = 0.18 muM) 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 beta1-42 (Abeta1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its Abeta1-42 anti-aggregation effects. |
PubMedSearch : Kosak_2020_Eur.J.Med.Chem_197_112282 |
PubMedID: 32380361 |
Gene_locus related to this paper: human-BCHE |
Inhibitor | 6SAM-cpd13 |
Gene_locus | human-BCHE |
Structure | 6SAM |
Kosak U, Strasek N, Knez N, Jukic M, Zakelj S, Zahirovic A, Pislar A, Brazzolotto X, Nachon F, Kos J, Gobec S, Knez D (2020)
N-alkylpiperidine carbamates as potential anti-Alzheimer's agents
Eur Journal of Medicinal Chemistry
197 :112282
Kosak U, Strasek N, Knez N, Jukic M, Zakelj S, Zahirovic A, Pislar A, Brazzolotto X, Nachon F, Kos J, Gobec S, Knez D (2020)
Eur Journal of Medicinal Chemistry
197 :112282