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

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Date
01/08/2016
Author
Hroch, Lukas
Benek, Ondrej
Guest, Patrick
Aitken, Laura
Soukup, Ondrej
Janockova, Jana
Musil, Karel
Dohnal, Vlastimil
Dolezal, Rafael
Kuca, Kamil
Smith, Terry K
Gunn-Moore, Frank J
Musilek, K
Keywords
Alzheimer's disease (AD)
Amyloid-beta peptide (Aβ)
Mitochondria
Amyloid binding alcohol dehydrogenase (ABAD)
17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10)
Benzothiazole
Riluzole
R Medicine (General)
QR Microbiology
NDAS
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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.
Citation
Hroch , L , Benek , O , Guest , P , Aitken , L , Soukup , O , Janockova , J , Musil , K , Dohnal , V , Dolezal , R , Kuca , K , Smith , T K , Gunn-Moore , F J & Musilek , K 2016 , ' Design, synthesis and in vitro evaluation of benzothiazole-based ureas as potential ABAD/17β-HSD10 modulators for Alzheimer’s disease treatment ' , Bioorganic and Medicinal Chemistry Letters , vol. 26 , no. 15 , pp. 3675-3678 . https://doi.org/10.1016/j.bmcl.2016.05.087
Publication
Bioorganic and Medicinal Chemistry Letters
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.bmcl.2016.05.087
ISSN
0960-894X
Type
Journal item
Rights
© 2016 Elsevier Ltd. All rights reserved. This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at https://dx.doi.org/10.1016/j.bmcl.2016.05.087
Description
This work was supported by the Ministry of Health of the Czech Republic (no. NV15-28967A), Charles University in Prague (no. GAUK B-CH/992214, SVV 260 291) and the Alzheimer’s Society (specifically The Barcopel Foundation). This research is part-funded by the MSD Scottish Life Sciences fund.
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/11451

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