Exploration of the imidazo[1,2-b]pyridazine scaffold as a protein kinase inhibitor

Eur J Med Chem. 2017 Jan 5:125:696-709. doi: 10.1016/j.ejmech.2016.09.064. Epub 2016 Sep 22.

Abstract

3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives were synthesized to identify new inhibitors of various eukaryotic kinases, including mammalian and protozoan kinases. Among the imidazo[1,2-b]pyridazines tested as kinase inhibitors, several derivatives were selective for DYRKs and CLKs, with IC50 < 100 nM. The characterization of the kinome of several parasites, such as Plasmodium and Leishmania, has pointed out profound divergences between protein kinases of the parasites and those of the host. This led us to investigate the activities of the prepared compounds against 11 parasitic kinases. 3,6-Disubstituted imidazo[1,2-b]pyridazines showed potent inhibition of Plasmodium falciparum CLK1 (PfCLK1). Compound 20a was found to be the most selective product against CLK1 (IC50 = 82 nM), CLK4 (IC50 = 44 nM), DYRK1A (IC50 = 50 nM), and PfCLK1 (IC50 = 32 nM). The compounds were also tested against Leishmania amazonensis. Several compounds showed anti-leishmanial activity at rather high (10 μM) concentration, but were not toxic at 1 μM or 10 μM, as judged by viability assays carried out using a neuroblastoma cell line.

Keywords: CLKs; Imidazo[1,2-b]pyridazine; Kinase inhibitor; Leishmania, DYRK1A; Unicellular parasites.

MeSH terms

  • Antiparasitic Agents / chemical synthesis
  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / pharmacology
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Eukaryota / drug effects
  • Inhibitory Concentration 50
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*

Substances

  • Antiparasitic Agents
  • Protein Kinase Inhibitors
  • Pyridazines