Synthesis, biological evaluation and molecular modeling studies of imidazo[1,2-a]pyridines derivatives as protein kinase inhibitors

• Published in: European journal of medicinal chemistry 2016-11, Vol.123, p.105-114
• Main Authors: Lawson, Marie, Rodrigo, Jordi, Baratte, Blandine, Robert, Thomas, Delehouzé, Claire, Lozach, Olivier, Ruchaud, Sandrine, Bach, Stéphane, Brion, Jean-Daniel, Alami, Mouad, Hamze, Abdallah
• Format: Article
• Language: English
• Subjects: Chemical Sciences; Cheminformatics; CLK1; Dyrk Kinases; DYRK1A; Humans; Imidazo[1,2-a]pyridines; Kinase inhibitors; Life Sciences; Models, Molecular; Molecular Docking Simulation; Organic chemistry; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.07.040

We report here the synthesis, the biological evaluation and the molecular modeling studies of new imidazo[1,2-a]pyridines derivatives designed as potent kinase inhibitors. This collection was obtained from 2-aminopyridines and 2-bromoacetophenone which afforded final compound in only one step. The bioactivity of this family of new compounds was tested using protein kinase and ATP competition assays. The structure-activity relationship (SAR) revealed that six compounds inhibit DYRK1A and CLK1 at a micromolar range. Docking studies provided possible explanations that correlate with the SAR data. The most active compound 4c inhibits CLK1 (IC50 of 0.7 μM) and DYRK1A (IC50 of 2.6 μM). [Display omitted] •Imidazo[1,2-a]pyridines 4 were synthesized in one step from 2-aminopyridines and 2-bromoacephenones in good yield.•Six imidazo[1,2-a]pyridines derivatives were active on kinases with micromolar IC50. (0.7–8.9 μM).•The most active imidazo[1,2-a]pyridines derivative 4c inhibits kinases with a IC50 of 0.7 μM (CLK1) and 2.6 μM (DYRKA1).•Docking studies indicate that 4c good binding mode on CLK1 and DYRKA1.