NQO1 induction and radiation-based biodistribution study of a new quinoline derivative identified in a screen of 6,8-diiodoquinazolinone sulfonamide conjugates.

A series of quinazoline derivatives 10-23 incorporating benzenesulfonamide and various aliphatic, aromatic and heterocyclic acetamide tails were designed, synthesized, and in vitro evaluated for their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. Compounds 13 and 20 exhibited the highest potency among this series, with CD values 14 and 3 μM, respectively. The quinoline derivative 20 was subjected to radiolabeling. The radio-synthesized derivative was assessed for its biodistribution in normal and tumor-bearing animal models, where it displayed high in vivo stability and selectivity toward tumor cells. Molecular docking of 20 within the Nrf2-binding site of Kelch-like ECH-associated protein 1 (Keap1) predicted the highest binding affinity -8.76 kcal/mol with the least RMSD value 1.01 Å. It showed a stable binding confirmed by RMSF compared to the co-crystallized ligand. This study identifies compound 20 as a promising antioxidant for continued optimization in redox-modulating research.