Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity

Bioorg Chem. 2018 Oct:80:565-576. doi: 10.1016/j.bioorg.2018.07.006. Epub 2018 Jul 6.

Abstract

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC50 = 0.63-1.32 μM) relative to sorafenib (IC50 = 0.76 μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C).

Keywords: Anticancer; CDK9; HCT116; Imidazo[4,5-b]pyridines; MCF-7.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 9 / metabolism
  • Drug Design
  • Drug Screening Assays, Antitumor
  • HCT116 Cells
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry*
  • Imidazoles / pharmacology*
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry*
  • Pyridines / pharmacology*

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Protein Kinase Inhibitors
  • Pyridines
  • imidazopyridine
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9