title: New cholinesterase inhibitors for Alzheimer's disease: Structure Activity Studies (SARs) and molecular docking of isoquinolone and azepanone derivatives.
abstract: A library of isoquinolinone and azepanone derivatives were screened for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. The strategy adopted included (a) in vitro biological assays, against eel AChE (EeAChE) and equine serum BuChE (EqBuChE) in order to determine the compounds IC50 and their dose-response activity, consolidated by (b) molecular docking studies to evaluate the docking poses and interatomic interactions in the case of the hit compounds, validated by STD-NMR studies. Compound (1f) was identified as one of these hits with an IC50 of 89.5μM for EeAChE and 153.8μM for EqBuChE, (2a) was identified as a second hit with an IC50 of 108.4μM (EeAChE) and 277.8μM (EqBuChE). In order to gain insights into the binding mode and principle active site interactions of these molecules, (R)-(1f) along with 3 other analogues (also as the R-enantiomer) were docked into both RhAChE and hBuChE models. Galantamine was used as the benchmark. The docking study was validated by performing an STD-NMR study of (1f) with EeAChE using galantamine as the benchmark.
authors.affiliation: ICAAM-Instituto de Ciências Agrárias e Ambientais Mediterrânicas, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Ap. 94, 7002-554 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: Patrícia
authors.initials: P
authors.lastname: Bacalhau
authors.affiliation: Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Amor A
authors.initials: AA
authors.lastname: San Juan
authors.affiliation: Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Marques
authors.affiliation: Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Peixoto
authors.affiliation: Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal.
authors.forename: Albertino
authors.initials: A
authors.lastname: Goth
authors.affiliation: Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Guarda
authors.affiliation: Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: Mara
authors.initials: M
authors.lastname: Silva
authors.affiliation: ICAAM-Instituto de Ciências Agrárias e Ambientais Mediterrânicas, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Ap. 94, 7002-554 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Arantes
authors.affiliation: Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: A Teresa
authors.initials: AT
authors.lastname: Caldeira
authors.affiliation: Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal; ICAAM-Instituto de Ciências Agrárias e Ambientais Mediterrânicas, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Ap. 94, 7002-554 Évora, Portugal; Laboratório HERCULES, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Palácio do Vimioso, Largo Marquês de Marialva, 8, 7000-809 Évora, Portugal.
authors.forename: Rosário
authors.initials: R
authors.lastname: Martins
authors.affiliation: Departamento de Química, Escola de Ciências e Tecnologia, Universidade de Évora, Rua Romão Ramalho 59, 7000-671 Évora, Portugal; Centro de Química de Évora, Institute for Research and Advanced Studies (IIFA), Universidade de Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal. Electronic address: ajb@uevera.pt.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Burke
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D002800:Cholinesterase Inhibitors; D007546:Isoquinolines; D002802:Cholinesterases