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
  • 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: [email protected].
  • 9. Laboratory of Medicinal Chemistry (IQOG, CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: [email protected].
  • 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: [email protected].
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.