Sultams as Dual Inhibitors of Human Carbonic Anhydrase and Thioredoxin Reductase

Cancer remains a leading cause of mortality, often complicated by drug resistance arising from single-target therapies. Dual inhibitors that simultaneously target multiple cancer-related defense mechanisms offer a promising strategy to overcome these limitations. Herein, we report the design, synthesis, and biological evaluation of a series of sultam-based N-acyl derivatives (8a-k and 9a-k) as potential dual inhibitors of thioredoxin reductase (TrxR1) and tumor-associated carbonic anhydrases (CA IX and XII). TrxR1 screening identified a few active compounds, with inhibitory potency strongly influenced by the type and orientation of substituents. CA inhibition assays revealed pronounced selectivity for CA IX/XII, while off-target isoforms CA I and CA II remained unaffected. These findings highlight the potential of sultam derivatives as dual-targeting anticancer agents and provide a foundation for further optimization toward selective, multi-pathway cancer therapy.