Article Metrics


Online attention

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

DOI: 10.3390/molecules24224090 DOI Help

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

Open Access Open Access

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, Chemistry

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 21/11/2019 14:18


Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)