Synthesis and biological evaluation of novel 2-phenylquinazoline-4-amine derivatives: identification of 6-phenyl-8H-benzo[g]quinazolino[4,3-b]quinazolin-8-one as a highly potent inducer of NAD(P)H quinone oxidoreductase 1

Mostafa M. Ghorab (Lead / Corresponding author), Mansour S. Alsaid, Marwa G. El-Gazzar, Maureen Higgins, Albena T. Dinkova-Kostova, Abdelaaty A. Shahat

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    Abstract

    A novel series of quinazoline compounds (2-14) incorporating biologically active heterocyclic moieties were designed and synthesized. The structure of the newly synthesized compounds was recognized on the basis of elemental analyses, IR, (1)H-NMR, (13)C-NMR and mass spectral data. All compounds were evaluated for their ability to induce the cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) using a quantitative bioassay and a docking study was performed in the Kelch domain of Keap1 obtained from the Protein Data Bank (PDB ID: 4IQK) to explore the ability of the synthesized compounds to block the Nrf2-binding site of Keap1. All of the synthesized compounds showed concentration-dependent inducer activity with potencies in the low- or sub-micromolar range. Compound 12 was the most potent inducer in this new series, with a concentration that doubles the specific activity of NQO1 (CD value) of 70 nM. The identification of this compound offers a new chemical scaffold for future development of highly potent inducers.

    Original languageEnglish
    Pages (from-to)34-49
    Number of pages6
    JournalJournal of Enzyme Inhibition and Medicinal Chemistry
    Volume31
    Issue numberSuppl. 1
    Early online date1 Apr 2016
    DOIs
    Publication statusPublished - 2016

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    Keywords

    • Synthesis
    • quinazoline
    • NAD(P)H

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