Design, synthesis and evaluation of small molecule imidazo[2,1-b][1,3,4]thiadiazoles as inhibitors of transforming growth factor-β type-I receptor kinase (ALK5)

• Synthesis and in vitro ALK5 inhibitory activity of a novel imidazo [2,1-b][1,3,4] thiadiazoles evaluated.
• Characterized by IR, 1H NMR, 13C NMR, HRMS technique.
• The title compound 6d shown promising ALK5 inhibitory activity.

A new series of imidazo[2,1-b][1,3,4]thiadiazoles 5(a–g), 6(a–g), 9(a–i) and 12(a–h) were synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d, 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC50 = 0.0012 μM) and elective inhibition (91%) against the P38αkinase at10 μM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

A novel series of imidazo[2,1-b][1,3,4]thiadiazoles were synthesized and evaluated for in vitro ALK5 inhibitory activity.Figure optionsDownload as PowerPoint slide