Chromenones as Multineurotargeting Inhibitors of Human Enzymes
- The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 μM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
Document Type: | Article |
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Language: | English |
Author: | Carina Lemke, Joscha Christmann, Jiafei Yin, José M. Alonso, Estefanía Serrano, Mourad Chioua, Lhassane Ismaili, María Angeles Martínez-Grau, Christopher D. Beadle, Tatiana Vetman, Florian M. Dato, Ulrike Bartz, Paul W. Elsinghorst, Markus Pietsch, Christa E. Müller, Isabel Iriepa, Timo Wille, José Marco-Contelles, Michael Gütschow |
Parent Title (English): | ACS Omega |
Volume: | 4 |
Issue: | 26 |
First Page: | 22161 |
Last Page: | 22168 |
ISSN: | 2470-1343 |
URN: | urn:nbn:de:hbz:1044-opus-47081 |
DOI: | https://doi.org/10.1021/acsomega.9b03409 |
PMID: | https://pubmed.ncbi.nlm.nih.gov/31891098 |
Publisher: | American Chemical Society (ACS) |
Publishing Institution: | Hochschule Bonn-Rhein-Sieg |
Date of first publication: | 2019/12/11 |
Copyright: | © 2019 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
Funding: | J.M.C. thanks MINECO (grant SAF2015-65586-R), UCJC (grants 2015-12, 2014-35, and 2015-21), and EU (COST Action CA15135) for support. |
Departments, institutes and facilities: | Fachbereich Angewandte Naturwissenschaften |
Dewey Decimal Classification (DDC): | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Entry in this database: | 2019/12/14 |
Licence (English): | ACS AuthorChoice/Editors’ Choice License |