Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17 beta-HSD10 modulators for Alzheimer's disease treatment

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F16%3A43875626" target="_blank" >RIV/60162694:G44__/16:43875626 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/62690094:18470/16:50004749 RIV/62690094:18450/16:50004749 RIV/00216208:11160/16:10326041 RIV/00179906:_____/16:10326041

Výsledek na webu

<a href="http://www.sciencedirect.com/science/article/pii/S0960894X16305972" target="_blank" >http://www.sciencedirect.com/science/article/pii/S0960894X16305972</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bmcl.2016.05.087" target="_blank" >10.1016/j.bmcl.2016.05.087</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17 beta-HSD10 modulators for Alzheimer's disease treatment

Popis výsledku v původním jazyce

Amyloid-beta peptide (A beta) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10). Altered enzyme function caused by the A beta-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

Název v anglickém jazyce

Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17 beta-HSD10 modulators for Alzheimer's disease treatment

Popis výsledku anglicky

Amyloid-beta peptide (A beta) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10). Altered enzyme function caused by the A beta-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

Druh

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

CEP obor

FR - Farmakologie a lékárnická chemie

OECD FORD obor

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Projekt

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

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Bioorganic and Medicinal Chemistry Letters

ISSN

0960-894X

e-ISSN

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Svazek periodika

26

Číslo periodika v rámci svazku

15

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

4

Strana od-do

3675-3678

Kód UT WoS článku

000380574100058

EID výsledku v databázi Scopus

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