Chromone Derivatives as a Novel NOX4 Inhibitor: Design, Synthesis, and Regulation of ROS in Renal Fibroblast

Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) has emerged as a promising target for developing drugs to tackle renal fibrosis. In this study, a series of chromone derivatives were designed and synthesized. Additionally, we established a NOX4 overexpression model using the NRK-49F rat renal fibroblasts cell line and identified compound 14m as highly active through the assessment of intracellular reactive oxygen species (ROS) levels in this model. The drug affinity responsive target stability (DARTS) assay illuminated the robust binding stability of 14m with NOX4. Mechanistic studies further substantiated its efficacy in ameliorating fibrosis and inflammation. This investigation positions 14m as a noteworthy NOX4 inhibitor, shedding light on its regulatory role in renal fibroblasts. Importantly, it diversifies the structural landscape of NOX4 inhibitors, offering novel lead compounds for future development.