Nanomolar Benzothiazole-Based Inhibitors of 17ß-HSD10 with Cellular Bioactivity.
ACS Med Chem Lett
; 14(12): 1724-1732, 2023 Dec 14.
Article
in En
| MEDLINE
| ID: mdl-38116418
ABSTRACT
Multifunctional mitochondrial enzyme 17ß-hydroxysteroid dehydrogenase type 10 (17ß-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 17ß-HSD10 overexpression and its interaction with amyloid-ß peptide contribute to mitochondrial dysfunction and neuronal stress. In this work, a series of new benzothiazole-derived 17ß-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).
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01-internacional
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MEDLINE
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En
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ACS Med Chem Lett
/
ACS medicinal chemistry letters
Year:
2023
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Article
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