title: NAD(P)H:quinone oxidoreductase 1 inducer activity of some novel anilinoquinazoline derivatives.
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
  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.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; Department of Drug Radiation Research, National Center for Radiation Research & Technology, Atomic Energy Authority, Cairo, Egypt.
authors.forename: Mostafa M
authors.initials: MM
authors.lastname: Ghorab
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Mansour S
authors.initials: MS
authors.lastname: Alsaid
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK.
authors.forename: Maureen
authors.initials: M
authors.lastname: Higgins
authors.affiliation: Jacqui Wood Cancer Centre, Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, UK; Department of Medicine; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Albena T
authors.initials: AT
authors.lastname: Dinkova-Kostova
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; Phytochemistry Department, National Research Center, Dokki, Giza.
authors.forename: Abdelaaty A
authors.initials: AA
authors.lastname: Shahat
authors.affiliation: Zewail City of Science and Technology.
authors.forename: Nehal H
authors.initials: NH
authors.lastname: Elghazawy
authors.affiliation: Zewail City of Science and Technology; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
authors.forename: Reem K
authors.initials: RK
authors.lastname: Arafa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009243:NAD / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011799:Quinazolines; D009243:NAD; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse
keywords: Keap1/Nrf2; Kelch domain; NQO1 induction; cytoprotection; molecular modeling