Cholinergic and neuroprotective drugs for the treatment of Alzheimer and neuronal vascular diseases. II. Synthesis, biological assessment, and molecular modelling of new tacrine analogues from highly substituted 2-aminopyridine-3-carbonitriles
| Autor: | José Marco-Contelles, Laura González-Lafuente, Maria Dolores Martin-de-Saavedra, Abdelouahid Samadi, Mourad Chioua, Agatha Bastida, Mercedes Villarroya, Laura del Barrio, Cristóbal de los Ríos, Luis Gandía, Inés Colmena, Carolina Valderas, Manuela G. López, Alejandro Romero |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Clinical Biochemistry Pharmaceutical Science Biochemistry Chemical synthesis Neuroprotection chemistry.chemical_compound Alzheimer Disease Cell Line Tumor Nitriles Drug Discovery medicine Humans Vascular Diseases Molecular Biology IC50 biology Organic Chemistry Okadaic acid Acetylcholinesterase Kinetics Neuroprotective Agents chemistry Enzyme inhibitor Tacrine biology.protein Molecular Medicine Cholinergic Cholinesterase Inhibitors medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 19:122-133 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2010.11.040 |
| Popis: | The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11–22 is described. Compounds 11–22 have been obtained by Friedlander-type reaction of 2-aminopyridine-3-carbonitriles 1–10 with cyclohexanone or 1-benzyl-4-piperidone. The biological evaluation showed that some of these molecules were good AChE inhibitors, in the nanomolar range, and quite selective regarding the inhibition of BuChE, the most potent being 5-amino-2-(dimethylamino)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (11) [IC50 (EeAChE: 14 nM); IC50 (eqBuChE: 5.2 μM]. Kinetic studies on the easily available and potent anticholinesterasic compound 5-amino-2-(methoxy)-6,7,8,9-tetrahydrobenzo[1,8-b]-naphthyridine-3-carbonitrile (16) [IC50 (EeAChE: 64 nM); IC50 (eqBuChE: 9.6 μM] showed that this compound is a mixed-type inhibitor (Ki = 69.2 nM) of EeAChE. Molecular modelling on inhibitor 16 confirms that this compound, as expected and similarly to tacrine, binds at the catalytic active site of EeAChE. The neuroprotective profile of molecules 11–22 has been investigated in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone. Compound 16 was also able to rescue by 50% cell death induced by okadaic acid in SH-SY5Y cells. From these results we conclude that the neuroprotective profile of these molecules is moderate, the most potent being compounds 12 and 17 which reduced cell death by 29%. Compound 16 does not affect ACh- nor K+-induced calcium signals in bovine chromaffin cells. Consequently, tacrine analogues 11–22 can be considered attractive therapeutic molecules on two key pharmacological targets playing key roles in the progression of Alzheimer, that is, cholinergic dysfunction and oxidative stress, as well as in neuronal cerebrovascular diseases. |
| Databáze: | OpenAIRE |
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