Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety

Aiten M. Soliman (Lead / Corresponding author), Heba M. Karam, Mai H. Mekkawy, Maureen Higgins, Albena Dinkova-Kostova, Mostafa M. Ghorab (Lead / Corresponding author)

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Abstract

Fifteen new quinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail were synthesized. The structures assigned to the products were concordant with the microanalytical and spectral data. Compounds 4-18 were screened for their ability to induce the antioxidant enzyme NAD(P)H: quinone oxidoreductase 1(NQO1) in cells, a classical target for transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). The 2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio)-N-(3,4,5-trimethoxyphenyl) acetamide 15 showed the most potent NQO1 inducer activity in vitro. Compound 15 had low toxicity in mice (LD50=500 mg/Kg). It also reduced the damaging effects of gamma radiation, as assessed by the levels of Nrf2, NQO1, reactive oxygen species (ROS) and malondialdehyde (MDA) in liver tissues. In addition, compound 15 showed amelioration in the complete blood count of irradiated mice and enhanced survival over a period of 30 days following irradiation. Molecular docking of 15 inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, showed the same binding interactions as that of the co-crystallized ligand considering the binding possibilities and energy scores. These findings suggest that compound 15 could be considered as a promising antioxidant and radiomodulatory agent.
Original languageEnglish
Article number112467
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume200
Early online date18 May 2020
DOIs
Publication statusE-pub ahead of print - 18 May 2020

Keywords

  • Diiodoquinazolinone
  • Docking
  • NQO1
  • Nrf2
  • Oxidative stress
  • Radiomodulatory
  • Sulfonamide

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