title: 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.
abstract: 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) [IC(50) (EeAChE: 14nM); IC(50) (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) [IC(50) (EeAChE: 64nM); IC(50) (eqBuChE: 9.6μM] showed that this compound is a mixed-type inhibitor (K(i)=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.
authors.affiliation: Laboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Carolina
authors.initials: C
authors.lastname: Valderas
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: Agatha
authors.initials: A
authors.lastname: Bastida
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Laura
authors.initials: L
authors.lastname: González-Lafuente
authors.forename: Inés
authors.initials: I
authors.lastname: Colmena
authors.forename: Luis
authors.initials: L
authors.lastname: Gandía
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Laura
authors.initials: L
authors.lastname: Del Barrio
authors.forename: María D
authors.initials: MD
authors.lastname: Martín-de-Saavedra
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D009570:Nitriles / Q000737:chemistry*; D013619:Tacrine / Q000031:analogs & derivatives*; D014652:Vascular Diseases / Q000188:drug therapy*
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; D013619:Tacrine; D000110:Acetylcholinesterase