Design, synthesis and in vitro evaluation of indolotacrine analogues as multitarget-directed ligands for the treatment of Alzheimer's disease

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F16%3A43915050" target="_blank" >RIV/00023752:_____/16:43915050 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/60162694:G44__/16:43875619 RIV/62690094:18470/16:50004736 RIV/00216208:11160/16:10324912 RIV/00179906:_____/16:10324912

Výsledek na webu

<a href="http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500383/abstract" target="_blank" >http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201500383/abstract</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cmdc.201500383" target="_blank" >10.1002/cmdc.201500383</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, synthesis and in vitro evaluation of indolotacrine analogues as multitarget-directed ligands for the treatment of Alzheimer's disease

Popis výsledku v původním jazyce

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50: 1.5 mu m), butyrylcholinesterase (BChE IC50: 2.4 mu m) and MAO A (IC50: 0.49 mu m), and it is also a weak inhibitor of MAO B (IC50: 53.9 mu m). Although its cytotoxic (IC50: 5.5 +/- 0.4 mu m) and hepatotoxic (IC50: 1.22 +/- 0.11 mu m) profiles are not as good as those of the standard 7-methoxytacrine (IC50: 63 +/- 4 and 11.50 +/- 0.77 mu m, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9b a promising lead compound for further development and investigation.

Název v anglickém jazyce

Design, synthesis and in vitro evaluation of indolotacrine analogues as multitarget-directed ligands for the treatment of Alzheimer's disease

Popis výsledku anglicky

Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50: 1.5 mu m), butyrylcholinesterase (BChE IC50: 2.4 mu m) and MAO A (IC50: 0.49 mu m), and it is also a weak inhibitor of MAO B (IC50: 53.9 mu m). Although its cytotoxic (IC50: 5.5 +/- 0.4 mu m) and hepatotoxic (IC50: 1.22 +/- 0.11 mu m) profiles are not as good as those of the standard 7-methoxytacrine (IC50: 63 +/- 4 and 11.50 +/- 0.77 mu m, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9b a promising lead compound for further development and investigation.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FH - Neurologie, neurochirurgie, neurovědy

OECD FORD obor

—

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2016

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemMedChem

ISSN

1860-7179

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

6

Strana od-do

1264-1269

Kód UT WoS článku

000380024300010

EID výsledku v databázi Scopus

2-s2.0-84978757630