6-Benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023752%3A_____%2F17%3A43915455" target="_blank" >RIV/00023752:_____/17:43915455 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/00007064:K13__/17:N0000036
Výsledek na webu
<a href="http://www.eurekaselect.com/149078/article" target="_blank" >http://www.eurekaselect.com/149078/article</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.2174/1573406413666170109142725" target="_blank" >10.2174/1573406413666170109142725</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
6-Benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation
Popis výsledku v původním jazyce
Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer’s disease (AD). ABAD/17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβtoxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD’s enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structureactivity relationship QSAR and pharmacophore studies have been performed. Results and Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40 µ M) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.
Název v anglickém jazyce
6-Benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17-HSD10 and potential drugs for Alzheimer's disease treatment: Design, synthesis and in vitro evaluation
Popis výsledku anglicky
Background: The mitochondrial enzyme amyloid beta-binding alcohol dehydrogenase (ABAD) also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) has been connected with the pathogenesis of Alzheimer’s disease (AD). ABAD/17β-HSD10 is a binding site for the amyloid-beta peptide (Aβ) inside the mitochondrial matrix where it exacerbates Aβtoxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD’s enzymatic activity is required for mediating Aβ toxicity, its inhibition presents a promising strategy for AD treatment. In this study, a series of new benzothiazolylurea analogues have been prepared and evaluated in vitro for their potency to inhibit ABAD/17β-HSD10 enzymatic activity. The most potent compounds have also been tested for their cytotoxic properties and their ability to permeate through blood-brain barrier has been predicted. To explain the structureactivity relationship QSAR and pharmacophore studies have been performed. Results and Conclusion: Compound 12 was identified being the most promising hit compound with good inhibitory activity (IC50 = 3.06 ± 0.40 µ M) and acceptable cytotoxicity profile comparable to the parent compound of frentizole. The satisfactory physical-chemical properties suggesting its capability to permeate through BBB make compound 12 a novel lead structure for further development and biological assessment.
Klasifikace
Druh
J<sub>imp</sub> - Článek v periodiku v databázi Web of Science
CEP obor
—
OECD FORD obor
30107 - Medicinal chemistry
Návaznosti výsledku
Projekt
<a href="/cs/project/LO1611" target="_blank" >LO1611: Udržitelnost pro Národní ústav duševního zdraví</a><br>
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2017
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Medicinal Chemistry
ISSN
1573-4064
e-ISSN
—
Svazek periodika
13
Číslo periodika v rámci svazku
4
Stát vydavatele periodika
NL - Nizozemsko
Počet stran výsledku
14
Strana od-do
345-358
Kód UT WoS článku
000402479000004
EID výsledku v databázi Scopus
2-s2.0-85020833089