title: Multipotent MAO and cholinesterase inhibitors for the treatment of Alzheimer's disease: synthesis, pharmacological analysis and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amine.
abstract: The synthesis, pharmacological evaluation and molecular modeling of heterocyclic substituted alkyl and cycloalkyl propargyl amines 1-7 of type I, and 9-12 of type II, designed as multipotent inhibitors able to simultaneously inhibit monoamine oxidases (MAO-A/B) as well as cholinesterase (AChE/BuChE) enzymes, as potential drugs for the treatment of Alzheimer's disease, are described. Indole derivatives 1-7 of type I are well known MAO inhibitors whose capacity to inhibit AChE and BuChE was here investigated for the first time. As a result, compound 7 was identified as a MAO-B inhibitor (IC(50) = 31 ± 2 nM) and a moderately selective eqBuChE inhibitor (IC(50) = 4.7 ± 0.2 μM). Conversely, the new and readily available 5-amino-7-(prop-2-yn-1-yl)-6,7,8,9-tetrahydropyrido[2,3-b][1,6]naphthyridine derivatives 9-13 of type II are poor MAO inhibitors, but showed AChE selective inhibition, compound 12 being the most attractive as it acts as a non-competitive inhibitor on EeAChE (IC(50) = 25 ± 3 nM, K(i) = 65 nM). The ability of this compound to interact with the AChE peripheral binding site was confirmed by kinetic studies and by molecular modeling investigation. Studies on human ChEs confirmed that 12 is a selective AChE inhibitor with inhibitory potency in the submicromolar range. Moreover, in agreement with its mode of action, 12 was shown to be able to inhibit Aβ aggregation induced by hAChE by 30.6%.
authors.affiliation: Laboratorio de Radicales Libres y Química Computacional (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain. samadi@iqog.csic.es
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: Cristóbal
authors.initials: C
authors.lastname: de los Ríos
authors.forename: Irene
authors.initials: I
authors.lastname: Bolea
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.forename: Isabel
authors.initials: I
authors.lastname: Iriepa
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraleda
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Enrique
authors.initials: E
authors.lastname: Gálvez
authors.forename: Carolina
authors.initials: C
authors.lastname: Valderas
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism*; D004593:Electrophorus; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010293:Pargyline / Q000031:analogs & derivatives* / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry; D011437:Propylamines / Q000737:chemistry*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D006571:Heterocyclic Compounds; D008996:Monoamine Oxidase Inhibitors; D010446:Peptide Fragments; D011437:Propylamines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C009054:propargylamine; D010293:Pargyline; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases