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

Molecules. 2019 Nov 13;24(22):4090. doi: 10.3390/molecules24224090.

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.

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

MeSH terms

  • Drug Design
  • Dyrk Kinases
  • Halogens / chemistry*
  • Humans
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / chemistry*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / chemistry*
  • Solubility
  • Spectrum Analysis
  • Structure-Activity Relationship

Substances

  • Halogens
  • Indoles
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases