title: Synthesis, biological assessment and molecular modeling of new multipotent MAO and cholinesterase inhibitors as potential drugs for the treatment of Alzheimer's disease.
abstract: The synthesis, biological evaluation and molecular modeling of new multipotent inhibitors of type I and type II, able to simultaneously inhibit monoamine oxidases (MAO) as well as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), is described. Compounds of type I were prepared by sequential reaction of 2,6-dichloro-4-phenylpyridine-3,5-dicarbonitrile (14) [or 2,6-dichloropyridine-3,5-dicarbonitrile (15)] with prop-2-yn-1-amine (or N-methylprop-2-yn-1-amine) and 2-(1-benzyl-piperidin-4-yl)alkylamines 22-25. Compounds of type II were prepared by Friedländer type reaction of 6-amino-5-formyl-2-(methyl(prop-2-yn-1-yl)amino)nicotinonitriles 32 and 33 with 4-(1-benzylpiperidin-4-yl)butan-2-one (31). The biological evaluation of molecules 1-11 showed that most of these compounds are potent, in the nanomolar range, and selective AChEI, with moderate and equipotent selectivity for MAO-A and MAO-B inhibition. Kinetic studies of compound 8 proved that this is a EeAChE mixed type inhibitor (IC(50) = 16 ± 2; Ki = 12 ± 3 nM). Molecular modeling investigation on compound 8 confirmed its dual AChE inhibitory profile, binding simultaneously at the catalytic active site (CAS) and at the peripheric anionic site (PAS). In overall, compound 11, as a potent and selective dual AChEI, showing a moderate and selective MAO-A inhibitory profile, can be considered as an attractive multipotent drug for further development on two key pharmacological targets playing key roles in the therapy of Alzheimer's disease.
authors.affiliation: Laboratorio de Radicales Libres y Química Computacional , 28006 Madrid, Spain. samadi@iqog.csic.es
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Irene
authors.initials: I
authors.lastname: Bolea
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de Los Ríos
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.forename: Agatha
authors.initials: A
authors.lastname: Bastida
authors.forename: Gerard
authors.initials: G
authors.lastname: Esteban
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.forename: Enrique
authors.initials: E
authors.lastname: Gálvez
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008958:Models, Molecular; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors