2. Academic Validation
  3. Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy

Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy

  • Eur J Med Chem. 2017 Jan 27:126:576-589. doi: 10.1016/j.ejmech.2016.11.050.
Youssef Dgachi 1,  Olga Sokolov 2,  Vincent Luzet 2,  Justyna Godyń 3,  Dawid Panek 3,  Alexandre Bonet 4,  Hélène Martin 4,  Isabel Iriepa 5,  Ignacio Moraleda 5,  Cristina García-Iriepa 6,  Jana Janockova 7,  Lysiane Richert 4,  Ondrej Soukup 7,  Barbara Malawska 3,  Fakher Chabchoub 8,  José Marco-Contelles 9,  Lhassane Ismaili 10
Affiliations

Affiliations

  • 1 Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, 3000 Sfax, Tunisia.
  • 2 Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques, EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, UFR SMP, 19, rue Ambroise Paré, F-25000 Besançon, France.
  • 3 Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9 Street, 30-688 Krakow, Poland.
  • 4 Laboratory of Cell Toxicology, EA 4267, Univ. Bourgogne Franche-Comté, 19 rue Ambroise Paré, F-25030 Besançon Cedex, France.
  • 5 Department of Organic Chemistry and Inorganic Chemistry, School of Biology, Enviromental Sciences and Chemistry, University Alcala, Ctra. Barcelona, Km. 33.6, 28871 Alcala de Henares, Spain.
  • 6 Department of Analytical Chemistry, Physical Chemistry, and Chemical Engineering, School of Biology, Enviromental Sciences and Chemistry, University Alcala, Ctra. Barcelona, Km. 33.6, 28871 Alcala de Henares, Spain.
  • 7 Biomedical Research Center, University Hospital Hradec Kralove, Czechia.
  • 8 Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, B. P 802, 3000 Sfax, Tunisia. Electronic address: fakher.chabchoub@yahoo.fr.
  • 9 Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: iqoc21@iqog.csic.es.
  • 10 Laboratoire de Chimie Organique et Thérapeutique, Neurosciences intégratives et cliniques, EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, UFR SMP, 19, rue Ambroise Paré, F-25000 Besançon, France. Electronic address: lhassane.ismaili@univ-fcomte.fr.
PMID: 27918993 DOI: 10.1016/j.ejmech.2016.11.050
Abstract

Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC50 = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay.

Keywords

Acetylcholinesterase inhibitors; Alzheimer's disease; Antioxidants; Brain blood barrier; Hepatotoxicity; Molecular modeling; Multifunctional agents.

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