Details

Autor(en) / Beteiligte

• Hanzlova, Michaela
• Miskerikova, Marketa Sedlacek
• Rotterova, Aneta
• Chalupova, Katarina
• Jurkova, Katarina
• Hamsikova, Marie
• Andrys, Rudolf
• Haleckova, Annamaria
• Svobodova, Jana
• Schmidt, Monika
• Benek, Ondrej
• Musilek, Kamil

Titel

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

Ist Teil von

• ACS medicinal chemistry letters, 2023-12, Vol.14 (12), p.1724-1732

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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).