Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5919-23. doi: 10.1016/j.bmcl.2012.07.068. Epub 2012 Jul 25.

Abstract

4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.

MeSH terms

  • Crystallography, X-Ray
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 5 / metabolism
  • Dose-Response Relationship, Drug
  • Models, Molecular
  • Molecular Structure
  • Nerve Tissue Proteins / antagonists & inhibitors*
  • Nerve Tissue Proteins / metabolism
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology*
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology*

Substances

  • 4-(1,3-benzothiazol-2-yl)thiophene-2-sulfonamide
  • Nerve Tissue Proteins
  • Protein Kinase Inhibitors
  • Sulfonamides
  • Thiophenes
  • neuronal Cdk5 activator (p25-p35)
  • Cyclin-Dependent Kinase 5