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[b]-Annulated halogen-substituted indoles as potential DYRK1A inhibitors
DOI:
10.3390/molecules24224090
Authors:
Christian
Lechner
(Technische Universität Braunschweig)
,
Maren
Flaßhoff
(Technische Universität Braunschweig)
,
Hannes
Falke
(Technische Universität Braunschweig)
,
Lutz
Preu
(Technische Universität Braunschweig)
,
Nadége
Loaëc
(Faculté de Médecine et des Sciences de la Santé UBO; ManRos Therapeutics & Perha Pharmaceuticals)
,
Laurent
Meijer
(ManRos Therapeutics & Perha Pharmaceuticals)
,
Stefan
Knapp
(Johann Wolfgang Goethe University)
,
Apirat
Chaikuad
(Johann Wolfgang Goethe University)
,
Conrad
Kunick
(Technische Universität Braunschweig)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Molecules
, VOL 24
State:
Published (Approved)
Published:
November 2019
Diamond Proposal Number(s):
8421

Abstract: 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.
Journal Keywords: DYRK1A; indole; molecular docking; protein kinase inhibitor; solubility; nephelometry; X-ray structure analysis
Subject Areas:
Biology and Bio-materials,
Medicine
Instruments:
I04-1-Macromolecular Crystallography (fixed wavelength)
Documents:
molecules-24-04090.pdf