Novel Benzothiazole-based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer's Disease Treatment

Molecules. 2019 Jul 29;24(15):2757. doi: 10.3390/molecules24152757.


: It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.

Keywords: 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), amyloid binding alcohol dehydrogenase (ABAD), benzothiazole; Alzheimer’s disease (AD), amyloid-beta peptide (Aβ), mitochondria.

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
  • 17-Hydroxysteroid Dehydrogenases / chemistry*
  • Alzheimer Disease / drug therapy
  • Amyloid beta-Peptides / metabolism
  • Benzothiazoles / chemistry*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Mitochondria / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Urea / chemistry*


  • Amyloid beta-Peptides
  • Benzothiazoles
  • Urea
  • 17-Hydroxysteroid Dehydrogenases