Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing
benzenesulfonamide moiety with variable
acetamide tail and evaluation of 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. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)
acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with
free radical scavenging activity (IC50 = 28 µM) and in vivo median lethal dose (LD50) of 500 mg/Kg. The possible radioprotective activity of
compound 17 was evaluated in (7 Gy) irradiated mice.
Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS,
malondialdehyde (MDA) and NQO1 in liver tissues. Moreover,
compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of
Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key
amino acids as those of the co-crystallized
ligand. This study identifies 17 as a novel
antioxidant that protects against the harmful effect of radiation.