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N-alkylpiperidine carbamates as potential anti-Alzheimer's agentsKošak, Urban ...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 [micro]M), BChE (IC50 = 0.56 [micro]M) and MAO-B (IC50 = 26.1 [micro]M) inhibitor 10, dual AChE (IC50 = 2.25 [micro]M) and BChE (IC50 = 0.81 [micro]M) inhibitor 22, selective BChE (IC50 = 0.06 [micro]M) inhibitor 13, and selective MAO-B (IC50 = 0.18 [micro]M) 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 [beta]1-42 (A[beta]1-42)-induced neuronal cell death. The neuroprotective effects of compound 16 could be the result of its A[beta]1[beta]42 anti-aggregation effects.Source: European journal of medicinal chemistry. - ISSN 0223-5234 (Vol. 197, 2020, str. 1-24)Type of material - article, component part ; adult, seriousPublish date - 2020Language - englishCOBISS.SI-ID - 15755267
Author
Košak, Urban |
Strašek Benedik, Nika |
Knez, Damijan, farmacevt |
Jukič, Marko |
Žakelj, Simon |
Zahirović, Abida |
Pišlar, Anja |
Brazzolotto, Xavier |
Nachon, Florian |
Kos, Janko, 1959- |
Gobec, Stanislav, 1970-
Topics
Alzheimerjeva bolezen |
Nevrodegenerativne bolezni |
Alzheimer's disease |
acetylcholinesterase |
butyrylcholinesterase |
monoamine oxidase |
multi-target-directed ligands |
N-Alkylpiperidine carbamates |
zaviralci holinesteraze |
monoaminooksidaze |
butirilholin-esteraza |
ligandi
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Košak, Urban | 33908 |
Strašek Benedik, Nika | 52378 |
Knez, Damijan, farmacevt | 36438 |
Jukič, Marko | 32587 |
Žakelj, Simon | 22659 |
Zahirović, Abida | 52419 |
Pišlar, Anja | 32035 |
Brazzolotto, Xavier | |
Nachon, Florian | |
Kos, Janko, 1959- | 04648 |
Gobec, Stanislav, 1970- | 15284 |
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