Design, synthesis and biological evaluation of novel thiazolidinedione derivatives as irreversible allosteric IKK-β modulators

Abstract

The kinase known as IKK-β activates NF-κB signaling pathway leading to expression of several genes contributing to inflammation, immune response, and cell proliferation. Modulation of IKK-β kinase activity could be useful for treatment and management of such diseases. Starting from a discovered weakly active hit compound, twenty four thiazolidinedione-scaffold based chemical entities belonging to five series have been designed, synthesized and evaluated as potential IKK-β modulators. Among them, compounds 6q, 6r and 6u showed low micromolar IC₅₀ values while compounds 6v, 6w, and 6x elicited submicromolar IC₅₀ values equal to 0.4, 0.7 and 0.9 μM respectively. These submicromolar IC₅₀ values are 243, 139 and 105 folds the value of the reported IC₅₀ of the starting hit compound. Kinetic study of compounds 6v and 6w confirmed this class of modulators as irreversible inhibitors. LPS-treated RAW 264.7 macrophages proved the anti-inflammatory activity of compounds 6q and 6v. Assay of hERG inhibition demonstrated a safe profile of compound 6q suggesting it as a lead for further development of IKK-β modulators.

Keywords: Allosteric modulation; IKK-β modulators; NF-κB signaling pathway; Thiazolidinediones.