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

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 1; pp. 122 - 133
• Main Authors: Samadi, Abdelouahid, Valderas, Carolina, Ríos, Cristóbal de los, Bastida, Agatha, Chioua, Mourad, González-Lafuente, Laura, Colmena, Inés, Gandía, Luis, Romero, Alejandro, Barrio, Laura del, Martín-de-Saavedra, María D., López, Manuela G., Villarroya, Mercedes, Marco-Contelles, José
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-01-2011; Elsevier
• Subjects: 2-Aminopyridin-3-carbonitriles; Acetylcholinesterase - drug effects; AChE; active sites; Alzheimer Disease - drug therapy; Alzheimer’s disease; Biological and medical sciences; biological assessment; BuChE; calcium; cattle; cell death; Cell Line, Tumor; cerebrovascular disorders; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - therapeutic use; chromaffin cells; drugs; Humans; Inhibition mechanism; inhibitory concentration 50; Kinetics; Medical sciences; Models, Molecular; Molecular modelling; Neuronal cerebrovascular diseases; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - therapeutic use; Nitriles - chemistry; okadaic acid; oxidative stress; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Tacrine - analogs & derivatives; Tacrine analogues; Vascular Diseases - drug therapy; AChE; Neuroprotection; Molecular modelling; Alzheimer’s disease; BuChE; Inhibition mechanism; Neuronal cerebrovascular diseases; Tacrine analogues; 2-Aminopyridin-3-carbonitriles; Nitrile; Alzheimer disease; Molecular dynamics method; Esterases; Acetylcholinesterase; Modeling; Vascular disease; Structure activity relation; Molecular model; Binding mode; Anticholinesterase agent; Chemical synthesis; Alzheimer's disease; Cerebrovascular disease; Tacrine; Enzyme; Enzyme inhibitor; Theoretical study; Neuroprotective agent; Antialzheimer agent; Carboxylic ester hydrolases; Neuron; Hydrolases; Kinetics
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2010.11.040

The structures of tacrine, the 2-aminopyridine-3,5-dicarbonitrile precursors, and the new tacrine analogues.
The synthesis, biological assessment, and molecular modelling of new tacrine analogues 11–22 is described. Compounds 11–22 have been obtained by Friedländer-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: 14nM); IC50 (eqBuChE: 5.2μM]. 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: 64nM); IC50 (eqBuChE: 9.6μM] showed that this compound is a mixed-type inhibitor (Ki=69.2nM) 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.