[b]-annulated halogen-substituted indoles as potential DYRK1A inhibitors

  • Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer’s disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.

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Author:Christian Lechner, Maren Flaßhof, Hannes Falke, Lutz Preu, Nadége Loaëc, Laurent Meijer, Stefan KnappORCiD, Apirat ChaikuadORCiD, Conrad Kunick
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31766108
Parent Title (English):Molecules
Place of publication:Basel
Contributor(s):David St. Clair Black
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/11/13
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/02/05
Tag:DYRK1A; X-ray structure analysis; indole; molecular docking; nephelometry; protein kinase inhibitor; solubility
Issue:22, Art. 4090
Page Number:19
First Page:1
Last Page:19
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0