TY  - JOUR
A1  - Lechner, Christian
A1  - Flaßhof, Maren
A1  - Falke, Hannes
A1  - Preu, Lutz
A1  - Loaëc, Nadége
A1  - Meijer, Laurent
A1  - Knapp, Stefan
A1  - Chaikuad, Apirat
A1  - Kunick, Conrad
T1  - [b]-annulated halogen-substituted indoles as potential DYRK1A inhibitors
T2  - Molecules
N2  - 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.
KW  - DYRK1A
KW  - indole
KW  - molecular docking
KW  - protein kinase inhibitor
KW  - solubility
KW  - nephelometry
KW  - X-ray structure analysis
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51829
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-518299
SN  - 1420-3049
N1  - 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
VL  - 24
IS  - 22, Art. 4090
SP  - 1
EP  - 19
PB  - MDPI
CY  - Basel
ER  -