Synthesis and evaluation of frentizole-based indolyl thiourea analogues as MAO/ABAD inhibitors for Alzheimer's disease treatment
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
BB/J01446X/1
Biotechnology and Biological Sciences Research Council - United Kingdom
PubMed
28082069
DOI
10.1016/j.bmc.2016.12.029
PII: S0968-0896(16)31452-3
Knihovny.cz E-resources
- Keywords
- 17β-Hydroxysteroid dehydrogenase type 10 (17β-HSD10), Alzheimer's disease (AD), Amyloid-beta peptide (Aβ), Horseradish peroxidase (HRP), Mitochondrial amyloid-binding alcohol dehydrogenase (ABAD), Monoamine oxidase (MAO),
- MeSH
- 3-Hydroxyacyl CoA Dehydrogenases antagonists & inhibitors metabolism MeSH
- Alzheimer Disease drug therapy metabolism MeSH
- Benzothiazoles chemistry pharmacology MeSH
- Phenylurea Compounds chemistry pharmacology MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Molecular Structure MeSH
- Monoamine Oxidase metabolism MeSH
- Thiourea chemical synthesis chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-Hydroxyacyl CoA Dehydrogenases MeSH
- Benzothiazoles MeSH
- Phenylurea Compounds MeSH
- frentizole MeSH Browser
- HSD17B10 protein, human MeSH Browser
- Enzyme Inhibitors MeSH
- Monoamine Oxidase MeSH
- Thiourea MeSH
Alzheimer's disease (AD) is a neurodegenerative disorder associated with an excessive accumulation of amyloid-beta peptide (Aβ). Based on the multifactorial nature of AD, preparation of multi-target-directed ligands presents a viable option to address more pathological events at one time. A novel class of asymmetrical disubstituted indolyl thioureas have been designed and synthesized to interact with monoamine oxidase (MAO) and/or amyloid-binding alcohol dehydrogenase (ABAD). The design combines the features of known MAO inhibitors scaffolds (e.g. rasagiline or ladostigil) and a frentizole moiety with potential to interact with ABAD. Evaluation against MAO identified several compounds that inhibited in the low to moderate micromolar range. The most promising compound (19) inhibited human MAO-A and MAO-B with IC50 values of 6.34μM and 0.30μM, respectively. ABAD activity evaluation did not show any highly potent compound, but the compound series allowed identification of structural features to assist the future development of ABAD inhibitors. Finally, several of the compounds were found to be potent inhibitors of horseradish peroxidase (HRP), preventing the use of the Amplex™ Red assay to detect hydrogen peroxide produced by MAO, highlighting the need for serious precautions when using an enzyme-coupled assay.
References provided by Crossref.org
Nanomolar Benzothiazole-Based Inhibitors of 17β-HSD10 with Cellular Bioactivity
Novel Benzothiazole-based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer's Disease Treatment
