[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors

Institute for Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany

Author to whom correspondence should be addressed.

Academic Editor: David StC Black

Molecules 2019, 24(22), 4090; https://doi.org/10.3390/molecules24224090

Received: 12 September 2019 / Revised: 5 November 2019 / Accepted: 7 November 2019 / Published: 13 November 2019

(This article belongs to the Special Issue Indole Derivatives: Synthesis and Application)

View Full-Text Download PDF

Browse Figures

Citation Export

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. View Full-Text

Keywords: DYRK1A; indole; molecular docking; protein kinase inhibitor; solubility; nephelometry; X-ray structure analysis

▼ Show Figures

Figure 1

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

Supplementary Material

Supplementary File 1:
PDF-Document (PDF, 1394 KiB)

Share and Cite

MDPI and ACS Style

Lechner, C.; Flaßhoff, M.; Falke, H.; Preu, L.; Loaëc, N.; Meijer, L.; Knapp, S.; Chaikuad, A.; Kunick, C. [b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors. Molecules 2019, 24, 4090. https://doi.org/10.3390/molecules24224090

AMA Style

Lechner C, Flaßhoff M, Falke H, Preu L, Loaëc N, Meijer L, Knapp S, Chaikuad A, Kunick C. [b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors. Molecules. 2019; 24(22):4090. https://doi.org/10.3390/molecules24224090

Chicago/Turabian Style

Lechner, Christian, Maren Flaßhoff, Hannes Falke, Lutz Preu, Nadége Loaëc, Laurent Meijer, Stefan Knapp, Apirat Chaikuad, and Conrad Kunick. 2019. "[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors" Molecules 24, no. 22: 4090. https://doi.org/10.3390/molecules24224090

Find Other Styles

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Abstract views Pdf views Html views

Article Menu

[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors

Abstract

Supplementary Material

Share and Cite

Article Metrics

Article Access Statistics

Article Access Map by Country/Region

Further Information

Guidelines

MDPI Initiatives

Follow MDPI