Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F17%3A50005605" target="_blank" >RIV/62690094:18470/17:50005605 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11160/17:10359065 RIV/00179906:_____/17:10359065

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0968089616314523" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0968089616314523</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmc.2016.12.029" target="_blank" >10.1016/j.bmc.2016.12.029</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment

Popis výsledku v původním jazyce

Alzheimer&apos;s disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (A beta). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34 mu M and 030 mu M, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex (TM) Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

Název v anglickém jazyce

Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment

Popis výsledku anglicky

Alzheimer&apos;s disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (A beta). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34 mu M and 030 mu M, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex (TM) Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/NV15-28967A" target="_blank" >NV15-28967A: Modulátory mitochondriálních enzymů k léčbě neurodegenerativních onemocnění</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Bioorganic and medicinal chemistry

ISSN

0968-0896

e-ISSN

—

Svazek periodika

25

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

10

Strana od-do

1143-1152

Kód UT WoS článku

000394201900031

EID výsledku v databázi Scopus

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