Optimization study towards more potent thiazolidine-2,4-dione IKK-β modulator: Synthesis, biological evaluation and in silico docking simulation

Bioorg Chem. 2019 Nov;92:103261. doi: 10.1016/j.bioorg.2019.103261. Epub 2019 Sep 7.

Abstract

Inhibition of IKK-β (inhibitor of nuclear factor kappa-B kinase subunit beta) has been broadly documentedas a promising approach for treatment of acute and chronic inflammatory diseases, cancer, and autoimmune diseases. Recently, we have identified a novel class of thiazolidine-2,4-diones as structurally novel modulators for IKK-β. Herein, we report a hit optimization study via analog synthesis strategy aiming to acquire more potent derivative(s), probe the structure activity relationship (SAR), and get reasonable explanations for the elicited IKK-β inhibitory activities though an in silico docking simulation study. Accordingly, a new series of eighteen thiazolidine-2,4-dione derivatives was rationally designed, synthesized, identified with different spectroscopic techniques and biologically evaluated as noteworthy IKK-β potential modulators. Successfully, new IKK-β potent modulators were obtained, including the most potent analog up-to-date 7m with IC50 value of 260 nM. A detailed structure activity relationship (SAR) was discussed and a mechanistic study for 7m was carried out indicating its irreversible inhibition mode with IKK-β (Kinact value = 0.01 (min-1). Furthermore, the conducted in silico simulation study provided new insights for the binding modes of this novel class of modulators with IKK-β.

Keywords: IKK-β modulator; Molecular docking; NF-κB signaling pathway; Thiazolidine-2,4-dione.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Molecular Docking Simulation*
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*

Substances

  • Protein Kinase Inhibitors
  • Thiazolidinediones
  • thiazolidine-2,4-dione
  • I-kappa B Kinase