Synthesis, anticancer activity and molecular modeling of new NSAIDs-Ebselen derivatives as potential TrxR1 inhibitor

Thioredoxin reductase 1 (TrxR1) is a key anticancer drug target whose inhibition can trigger reactive oxygen species (ROS)-mediated apoptosis in human cancer cells. In this study, a series of NSAID-Ebselen derivatives ( 5a-j ) were rationally designed using representative NSAID scaffolds because of their well-documented anti-inflammatory and anticancer properties, as well as the presence of functional groups that allow efficient conjugation with Ebselen. The structures of the new compounds were confirmed by 1 HNMR, 13 C NMR and MS. Compound 5e showed potent antiproliferative activity with IC₅₀ values of 2.4 μM (MCF-7) and 1.4 μM (HeLa), markedly lower than those of the reference drug 5-fluorouracil (12.4 and 14.5 μM, respectively).Antioxidant capacities were assessed using complementary biochemical assays, including DPPH radical scavenging, bleomycin-mediated DNA cleavage, and glutathione peroxidase (GPx)-like activity assays. TrxR1 inhibition experiments and molecular docking analyses further confirmed that these NSAID-Ebselen hybrids are promising TrxR1 inhibitors.