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

Abstract

Inhibition of IKK-beta (inhibitor of nuclear factor kappa-B kinase subunit beta) has been broadly documented as 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-beta. 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-beta 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-beta potential modulators. Successfully, new IKK-beta 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-beta (K-inact 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-beta.