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

Mostafa M Ghorab (Lead / Corresponding author), Mansour S Alsaid, Maureen Higgins, Albena T Dinkova-Kostova, Abdelaaty A Shahat, Nehal H Elghazawy, Reem K Arafa

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    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
    Pages (from-to)2515-2524
    Number of pages10
    JournalDrug Design, Development and Therapy
    Volume10
    DOIs
    Publication statusPublished - 8 Aug 2016

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    Keywords

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

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