Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F23%3A50021130" target="_blank" >RIV/62690094:18470/23:50021130 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.3c00355" target="_blank" >https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.3c00355</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acsmedchemlett.3c00355" target="_blank" >10.1021/acsmedchemlett.3c00355</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity

Popis výsledku v původním jazyce

Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer’s disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16). © 2023 American Chemical Society.

Název v anglickém jazyce

Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity

Popis výsledku anglicky

Multifunctional mitochondrial enzyme 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is a potential drug target for the treatment of various pathologies. The most discussed is the pathology associated with Alzheimer’s disease (AD), where 17β-HSD10 overexpression and its interaction with amyloid-β peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17β-HSD10 inhibitors were designed based on the structure-activity relationship analysis of formerly published inhibitors. A set of enzyme-based and cell-based methods were used to evaluate the inhibitory potency of new compounds, their interaction with the enzyme, and their cytotoxicity. Most compounds exhibited significantly a higher inhibitory potential compared to published benzothiazolyl ureas and good target engagement in a cellular environment accompanied by low cytotoxicity. The best hits displayed mixed-type inhibition with half maximal inhibitory concentration (IC50) values in the nanomolar range for the purified enzyme (3-7, 15) and/or low micromolar IC50 values in the cell-based assay (6, 13-16). © 2023 American Chemical Society.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

<a href="/cs/project/EF19_073%2F0016949" target="_blank" >EF19_073/0016949: Rozvoj interní grantové agentury Univerzity Hradec Králové</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

ACS Medicinal Chemistry Letters

ISSN

1948-5875

e-ISSN

—

Svazek periodika

14

Číslo periodika v rámci svazku

12

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

1724-1732

Kód UT WoS článku

001142988400001

EID výsledku v databázi Scopus

2-s2.0-85178113789