Novel Antioxidant Quinazoline Sulfonamide Derivatives Acting Through NQO1 Induction and Their Radiation‐Based Biodistribution Studies

A series of quinazoline derivatives 5-19 bearing a benzenesulfonamide moiety and different acetamide side chains, including aromatic and heterocyclic groups, were designed, synthesized and confirmed structurally by microanalytical and spectral data. The obtained compounds were evaluated in vitro for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) through induction of NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 15 and 18 exhibited the highest potency with CD values of 2.5 and 5 µM, respectively. The most potent derivatives (15 and 18) were further evaluated for their antioxidant potential using DPPH, with compound 18 demonstrating the highest radical scavenging activity. A radiation-based biodistribution study was conducted using 18 and displayed marked selectivity toward tumor cells over normal cells. Molecular docking studies and molecular dynamics simulations demonstrated that 18 exhibits a strong binding affinity and forms key stabilizing interactions within the Nrf2-binding domain of Kelch-like ECH-associated protein 1 (Keap1). These results demonstrate that quinazoline sulfonamide derivatives are promising oxidative stress modulators with tumor targeting ability.