Academic Journal
Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies
| العنوان: | Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies |
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| المؤلفون: | Ţînţaş, Mihaela-Liliana, Gembus, Vincent, Alix, Florent, Barré, Anaïs, Coadou, Gaël, Truong, Lina, Sebban, Muriel, Papamicaël, Cyril, Oulyadi, Hassan, Levacher, Vincent |
| المساهمون: | VFP Therapies Drugs : Highway to the Brain, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Université de Rouen Normandie (UNIROUEN), 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)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), 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)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011) |
| المصدر: | ISSN: 0223-5234. |
| بيانات النشر: | HAL CCSD Elsevier |
| سنة النشر: | 2018 |
| المجموعة: | Normandie Université: HAL |
| مصطلحات موضوعية: | Dual-binding site inhibitor, Alzheimer, Acetylcholine esterase inhibitors, [CHIM]Chemical Sciences |
| الوصف: | International audience ; Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | hal-03134356; https://hal.science/hal-03134356; https://hal.science/hal-03134356/document; https://hal.science/hal-03134356/file/Eur%20J%20Med%20Chem%202016.pdf |
| DOI: | 10.1016/j.ejmech.2018.05.057 |
| الاتاحة: | https://hal.science/hal-03134356 https://hal.science/hal-03134356/document https://hal.science/hal-03134356/file/Eur%20J%20Med%20Chem%202016.pdf https://doi.org/10.1016/j.ejmech.2018.05.057 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.4DF77B21 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ejmech.2018.05.057 |
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