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

GND
120610631X
Affiliation
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Lechner, Christian;
GND
1206106212
Affiliation
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Flaßhoff, Maren;
GND
1151475025
Affiliation
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Falke, Hannes;
GND
1132100763
Affiliation
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Preu, Lutz;
Affiliation
Faculté de Médecine et des Sciences de la Santé UBO, 22 avenue Camille Desmoulins, 29200-Brest, France.
Loaëc, Nadége;
ORCID
0000-0003-3511-4916
Affiliation
ManRos Therapeutics & Perha Pharmaceuticals, Perharidy Research Center, 29680 Roscoff, France.
Meijer, Laurent;
ORCID
0000-0001-5995-6494
Affiliation
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.
Knapp, Stefan;
ORCID
0000-0003-1120-2209
Affiliation
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.
Chaikuad, Apirat;
ORCID
0000-0001-7041-5322
Affiliation
Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.
Kunick, Conrad

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.

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