title: Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting β-amyloid, tau, and cholinesterase pathologies.
abstract: Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Ornella
authors.initials: O
authors.lastname: Di Pietro
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Pérez-Areales
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia (Campus Torribera), and IBUB, Universitat de Barcelona, Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Juárez-Jiménez
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN(2)UB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Espargaró
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain.
authors.forename: M Victòria
authors.initials: MV
authors.lastname: Clos
authors.affiliation: Departament de Farmacologia, de Terapèutica i de Toxicologia, Institut de Neurociències, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Barcelona, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Pérez
authors.affiliation: Laboratori de Química Orgànica, Facultat de Farmàcia, Universitat de Barcelona, and Barcelona Science Park, Baldiri Reixac 10-12, E-08028 Barcelona, Spain.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Lavilla
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia, and Institut de Nanociència i Nanotecnologia (IN(2)UB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.
authors.forename: Raimon
authors.initials: R
authors.lastname: Sabaté
authors.affiliation: Departament de Fisicoquímica, Facultat de Farmàcia (Campus Torribera), and IBUB, Universitat de Barcelona, Prat de la Riba 171, E-08921 Santa Coloma de Gramenet, Spain. Electronic address: fjluque@ub.edu.
authors.forename: F Javier
authors.initials: FJ
authors.lastname: Luque
authors.affiliation: Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain. Electronic address: dmunoztorrero@ub.edu.
authors.forename: Diego
authors.initials: D
authors.lastname: Muñoz-Torrero
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; C000596755:N-(3-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)propyl)-5-(4-chlorophenyl)-1,2,3,4-tetrahydrobenzo(h)(1,6)naphthyridine-9-carboxamide; D009287:Naphthyridines; D016875:tau Proteins; D013619:Tacrine; D002802:Cholinesterases
keywords: Aβ aggregation inhibitors; Dual binding site AChE inhibitors; Multitarget compounds; Tau aggregation inhibitors; Tetrahydrobenzo[h][1,6]naphthyridines