Rational design of central selective acetylcholinesterase inhibitors by means of a 'bio-oxidisable prodrug' strategy
| Autor: | Guillaume Hagues, Nicolas Le Fur, Nicolas Torquet, Cyril Papamicaël, Jean Costentin, Pierre Bohn, Vincent Levacher, Francis Marsais |
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| Přispěvatelé: | Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Asymétrie, hétérocycles, hétérochimie et bio-organique (AHHBO), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Neuropsycho-pharmacologie expérimentale, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Breton, Céline, Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2009 |
| Předmět: |
MESH: Oxidation-Reduction
Stereochemistry Phenylcarbamates Rivastigmine MESH: Drug Design 01 natural sciences Biochemistry Substrate Specificity MESH: Blood-Brain Barrier 03 medical and health sciences chemistry.chemical_compound Inhibitory Concentration 50 0302 clinical medicine MESH: Phenylcarbamates In vivo medicine Humans Prodrugs Physical and Theoretical Chemistry MESH: Inhibitory Concentration 50 chemistry.chemical_classification MESH: Humans 010405 organic chemistry Organic Chemistry Quinoline In vitro toxicology Rational design MESH: Acetylcholinesterase Prodrug Acetylcholinesterase 0104 chemical sciences Enzyme chemistry Blood-Brain Barrier Drug Design Quinolines MESH: Substrate Specificity Cholinesterase Inhibitors MESH: Prodrugs MESH: Cholinesterase Inhibitors Oxidation-Reduction MESH: Quinolines 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Organic and Biomolecular Chemistry Organic and Biomolecular Chemistry, Royal Society of Chemistry, 2009, 7 (12), pp.2612-8. ⟨10.1039/b903041g⟩ Organic & Biomolecular Chemistry Organic & Biomolecular Chemistry, 2009, 7 (12), pp.2612-8. ⟨10.1039/b903041g⟩ |
| ISSN: | 1477-0539 1477-0520 |
| DOI: | 10.1039/b903041g⟩ |
| Popis: | International audience; This work deals with the design of a bio-oxidisable prodrug strategy for the development of new central selective acetylcholinesterase inhibitors. This prodrug approach is expected to reduce peripheral anticholinesterase activity responsible for various side effects observed with presently marketed AChE inhibitors. The design of these new AChE inhibitors in quinoline series is roughly based on cyclic analogues of rivastigmine. The key activation step of the prodrug involves an oxidation of an N-alkyl-1,4-dihydroquinoline 1 to the corresponding quinolinium salt 2 unmasking the positive charge required for binding to the catalytic anionic site of the enzyme. The synthesis of a set of 1,4-dihydroquinolines 1 and their corresponding quinolinium salts 2 is presented. An in vitro biological evaluation revealed that while all reduced forms 1 were unable to exhibit any anticholinesterase activity (IC50 > 10(6) nM), most of the quinolinium salts 2 displayed high AChE inhibitory activity (IC50 ranging from 6 microM to 7 nM). These preliminary in vitro assays validate the use of these cyclic analogues of rivastigmine in quinoline series as appealing chemical tools for further in vivo development of this bio-oxidisable prodrug approach. |
| Databáze: | OpenAIRE |
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