NAD(P)H: Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives

Mostafa M. Ghorab, Mansour S. Alsaid, Maureen Higgins, Albena T. Dinkova-Kostova, Abdelaaty A. Shahat, Nehal H. Elghazawy, Reem K. Arafa

Research output: Contribution to journalArticle

Abstract

The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements pathway enables cells to survive oxidative stress conditions through regulating the expression of cytoprotective enzymes such as NAD(P)H:quinone oxidoreductase 1 (NQO1). This work presents the design and synthesis of novel anilinoquinazoline derivatives (2–16a) and evaluation of their NQO1 inducer activity in murine cells. Molecular docking of the new compounds was performed to assess their ability to inhibit Keap1–Nrf2 protein–protein interaction through occupying the Keap1–Nrf2-binding domain, which leads to Nrf2 accumulation and enhanced gene expression of NQO1. Docking results showed that all compounds can potentially interact with Keap1; however, 1, 5-dimethyl-2-phenyl-4-(2-phenylquinazolin-4-ylamino)-1, 2-dihydropyrazol-3-one (9), the most potent inducer, showed the largest number of interactions with key amino acids in the binding pocket (Arg483, Tyr525, and Phe478) compared to the native ligand or any other compound in this series.

Original languageEnglish (US)
Pages (from-to)2515-2524
Number of pages10
JournalDrug Design, Development and Therapy
Volume10
DOIs
StatePublished - Aug 8 2016

Fingerprint

NAD
Oxidoreductases
Antioxidant Response Elements
Oxidative Stress
Ligands
Gene Expression
Amino Acids
Enzymes
Kelch-Like ECH-Associated Protein 1
benzoquinone

Keywords

  • Cytoprotection
  • Keap1/Nrf2
  • Kelch domain
  • Molecular modeling
  • NQO1 induction

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Ghorab, M. M., Alsaid, M. S., Higgins, M., Dinkova-Kostova, A. T., Shahat, A. A., Elghazawy, N. H., & Arafa, R. K. (2016). NAD(P)H: Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives. Drug Design, Development and Therapy, 10, 2515-2524. https://doi.org/10.2147/DDDT.S105423

NAD(P)H : Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives. / Ghorab, Mostafa M.; Alsaid, Mansour S.; Higgins, Maureen; Dinkova-Kostova, Albena T.; Shahat, Abdelaaty A.; Elghazawy, Nehal H.; Arafa, Reem K.

In: Drug Design, Development and Therapy, Vol. 10, 08.08.2016, p. 2515-2524.

Research output: Contribution to journalArticle

Ghorab, MM, Alsaid, MS, Higgins, M, Dinkova-Kostova, AT, Shahat, AA, Elghazawy, NH & Arafa, RK 2016, 'NAD(P)H: Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives', Drug Design, Development and Therapy, vol. 10, pp. 2515-2524. https://doi.org/10.2147/DDDT.S105423
Ghorab MM, Alsaid MS, Higgins M, Dinkova-Kostova AT, Shahat AA, Elghazawy NH et al. NAD(P)H: Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives. Drug Design, Development and Therapy. 2016 Aug 8;10:2515-2524. https://doi.org/10.2147/DDDT.S105423
Ghorab, Mostafa M. ; Alsaid, Mansour S. ; Higgins, Maureen ; Dinkova-Kostova, Albena T. ; Shahat, Abdelaaty A. ; Elghazawy, Nehal H. ; Arafa, Reem K. / NAD(P)H : Quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives. In: Drug Design, Development and Therapy. 2016 ; Vol. 10. pp. 2515-2524.
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