Imidazo[4,5-b]pyridine derived tubulin polymerization inhibitors: Design, synthesis, biological activity in vitro and computational analysis

Bioorg Chem. 2022 Oct:127:106032. doi: 10.1016/j.bioorg.2022.106032. Epub 2022 Jul 16.


Imidazo[4,5-b]pyridine derived acrylonitriles were synthesized and explored for their in vitro antiproliferative effect on a diverse human cancer cell line panel. Three compounds, 20, 21 and 33, showed strong activity in the submicromolar range (IC50 0.2-0.6 μM), and were chosen for further biological experiments. Immunofluorescence staining and tubulin polymerization assays confirmed tubulin as the main target, but excluded its colchicine-binding site as a potential interacting unit. This was supported by the computational analysis, which revealed that the most potent ligands act on the extended colchicine site on the surface between interacting tubulin subunits, where they interfere with their polymerization and reveal pronounced antitumor properties. In addition, lead molecule 21 potently inhibited cancer cell migration, while it did not affect the viability of normal cells even at the highest concentration tested (100 µM).

Keywords: 5-b]pyridine; Acrylonitriles; Amination; Antiproliferative activity in vitro; Docking simulations; Imidazo[4; Molecular dynamic simulations; Tubulin polymerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Cell Line, Tumor
  • Cell Proliferation
  • Colchicine / pharmacology
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Neoplasms*
  • Polymerization
  • Pyridines / chemistry
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Tubulin Modulators


  • Antineoplastic Agents
  • Pyridines
  • Tubulin
  • Tubulin Modulators
  • Colchicine