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Open AccessArticle

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

1
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany
2
Zentrum für Pharmaverfahrenstechnik (PVZ), Technische Universität Braunschweig, Franz-Liszt-Straße 35A, 38106 Braunschweig, Germany
3
Faculté de Médecine et des Sciences de la Santé UBO, 22 avenue Camille Desmoulins, 29200-Brest, France
4
ManRos Therapeutics & Perha Pharmaceuticals, Perharidy Research Center, 29680 Roscoff, France
5
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)
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 DYRK1A; indole; molecular docking; protein kinase inhibitor; solubility; nephelometry; X-ray structure analysis
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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; Flaßhoff, Maren; Falke, Hannes; Preu, Lutz; Loaëc, Nadége; Meijer, Laurent; Knapp, Stefan; Chaikuad, Apirat; Kunick, Conrad. 2019. "[b]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors" Molecules 24, no. 22: 4090. https://doi.org/10.3390/molecules24224090

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