6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17 beta-HSD10 and potential drugs for Alzheimer's disease treatment: design, synthesis and in vitro evaluation

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60162694%3AG44__%2F17%3A43875755" target="_blank" >RIV/60162694:G44__/17:43875755 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/62690094:18470/17:50013416 RIV/00216208:11160/17:10360343 RIV/00179906:_____/17:10360343

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>

Jazyk výsledku

angličtina

Název v původním jazyce

6-benzothiazolyl ureas, thioureas and guanidines are potent inhibitors of ABAD/17 beta-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 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) has been connected with the pathogenesis of Alzheimer&apos;s disease (AD). ABAD/17 beta-HSD10 is a binding site for the amyloid-beta peptide (A beta) inside the mitochondrial matrix where it exacerbates A beta toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD&apos;s enzymatic activity is required for mediating A beta 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/17 beta-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 structure-activity 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 mu 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 beta-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 17 beta-hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) has been connected with the pathogenesis of Alzheimer&apos;s disease (AD). ABAD/17 beta-HSD10 is a binding site for the amyloid-beta peptide (A beta) inside the mitochondrial matrix where it exacerbates A beta toxicity. Interaction between these two proteins triggers a series of events leading to mitochondrial dysfunction as seen in AD. Methods: As ABAD&apos;s enzymatic activity is required for mediating A beta 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/17 beta-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 structure-activity 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 mu 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

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

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2017

Kód důvěrnosti údajů

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

Název periodika

Medicinal Chemistry

ISSN

1573-4064

e-ISSN

—

Svazek periodika

13

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

AE - Spojené arabské emiráty

Počet stran výsledku

14

Strana od-do

345-358

Kód UT WoS článku

000402479000004

EID výsledku v databázi Scopus

2-s2.0-85020833089