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

Inhibition of IKK-β (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-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 (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-β.