Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer's disease treatment.

Abstract

Amyloid-beta peptide (Aβ) has been recognized to interact with numerous proteins, which may lead to pathological changes in cell metabolism of Alzheimer's disease (AD) patients. One such known metabolic enzyme is mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), also known as 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10). Altered enzyme function caused by the Aβ-ABAD interaction, was previously shown to cause mitochondrial distress and a consequent cytotoxic effect, therefore providing a feasible target in AD drug development. Based on previous frentizole derivatives studies, we report two novel series of benzothiazolyl ureas along with novel insights into the structure and activity relationships for inhibition of ABAD. Two compounds (37, 39) were identified as potent ABAD inhibitors, where compound 39 exhibited comparable cytotoxicity with the frentizole standard; however, one-fold higher cytotoxicity than the parent riluzole standard. The calculated and experimental physical chemical properties of the most potent compounds showed promising features for blood-brain barrier penetration.

• Authors: Lukas Hroch, Ondrej Benek, Patrick Guest, Laura Aitken, Ondrej Soukup, Jana Janockova, Karel Musil, Vlastimil Dohnal, Rafael Dolezal, Kamil Kuca, Terry K Smith, Frank Gunn-Moore, Kamil Musilek
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 15 Pg. 3675-8 (08 01 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27287370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Benzothiazoles
• Enzyme Inhibitors
• Urea
• 3-Hydroxyacyl CoA Dehydrogenases
• HSD17B10 protein, human
• benzothiazole

Topics

• 3-Hydroxyacyl CoA Dehydrogenases (antagonists & inhibitors, metabolism)
• Alzheimer Disease (drug therapy)
• Animals
• Benzothiazoles (chemistry, pharmacology)
• CHO Cells
• Cell Survival (drug effects)
• Cricetulus
• Dose-Response Relationship, Drug
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Molecular Structure
• Structure-Activity Relationship
• Urea (analogs & derivatives, chemistry, pharmacology)