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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 language | English |
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Article number | 112467 |
Number of pages | 12 |
Journal | European Journal of Medicinal Chemistry |
Volume | 200 |
Early online date | 18 May 2020 |
DOIs | |
Publication status | Published - 15 Aug 2020 |
Keywords
- Diiodoquinazolinone
- Docking
- NQO1
- Nrf2
- Oxidative stress
- Radiomodulatory
- Sulfonamide
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry
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Dive into the research topics of 'Radiomodulatory effect of a non-electrophilic NQO1 inducer identified in a screen of new 6, 8-diiodoquinazolin-4(3H)-ones carrying a sulfonamide moiety'. Together they form a unique fingerprint.Projects
- 1 Finished
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The Role of the Keap1/Nrf2 Pathway in Tumour Metabolic Adaptation (Joint with University of Cambridge and University College London)
Dinkova-Kostova, A. (Investigator)
1/06/15 → 30/04/21
Project: Research