A thioridazine-derived molecule exhibits potential anti-inflammatory activity through IKK inhibition.

Chronic inflammatory diseases are leading causes of morbidity and mortality, necessitating the development of targeted therapeutics with improved safety. Many drugs have been withdrawn from the market because of their off-target effects, particularly hERG inhibition, which leads to severe cardiotoxicity. The NF-κB pathway plays a critical role in inflammation and immune response, making IKKβ an attractive therapeutic target. Thioridazine, a known inhibitor of IKKβ, has demonstrated potential anti-inflammatory effects. However, its clinical utility is severely limited by the strong inhibition of the hERG potassium channel, which increases the risk of cardiac arrhythmias. Therefore, it is necessary to develop safer IKKβ inhibitors using rational drug design approaches. By leveraging a similar compound library and in silico techniques, we aimed to retain the original therapeutic potential of thioridazine, while minimising its drawbacks. A library of thioridazine derivatives was computationally designed and screened by molecular docking and simulations. The selected compounds were subjected to patch-clamp analysis, confocal microscopy, western blotting, and qRT-PCR to evaluate their anti-inflammatory potential and hERG affinity, respectively. TDZ-D2{10-(2-oxo-2-pyrrolidin-1-ylethyl)acridin-9-one}, a thioridazine derivative, displayed significantly lower hERG binding while maintaining strong IKKβ inhibition, preserving IκBα stability, reducing NF-κB p65 translocation, and suppressing pro-inflammatory cytokine expression. This study highlights the potential of ligand-based lead optimisation techniques for mitigating off-target effects, thereby offering a safer anti-inflammatory therapeutic candidate. By overcoming the cardiotoxicity associated with thioridazine, TDZ-D2 presents a promising avenue for drug development for inflammatory diseases.