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, Mansour S. Alsaid, Marwa G. El-Gazzar, Maureen Higgins, Albena T. Dinkova-Kostova, Abdelaaty A. Shahat

Research output: Contribution to journalArticle

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, 1H-NMR, 13C-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 (US)
Pages (from-to)1-6
Number of pages6
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
DOIs
StateAccepted/In press - Mar 23 2016

Fingerprint

Quinazolines
Biological Assay
NAD
Amines
Oxidoreductases
Binding Sites
Databases
Enzymes
Proteins
Proton Magnetic Resonance Spectroscopy
benzoquinone
2-phenylquinazoline
Kelch Repeat
Carbon-13 Magnetic Resonance Spectroscopy

Keywords

  • NAD(P)H
  • quinazoline
  • synthesis

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

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. / Ghorab, Mostafa M.; Alsaid, Mansour S.; El-Gazzar, Marwa G.; Higgins, Maureen; Dinkova-Kostova, Albena T.; Shahat, Abdelaaty A.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, 23.03.2016, p. 1-6.

Research output: Contribution to journalArticle

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