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Multi-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors

dc.contributor.authorReis J.
dc.contributor.authorCagide F.
dc.contributor.authorValencia M.E.
dc.contributor.authorTeixeira J.
dc.contributor.authorBagetta D.
dc.contributor.authorPérez C.
dc.contributor.authorUriarte E.
dc.contributor.authorOliveira P.J.
dc.contributor.authorOrtuso F.
dc.contributor.authorAlcaro S.
dc.contributor.authorRodríguez-Franco M.I.
dc.contributor.authorBorges F.
dc.date.accessioned2020-09-02T22:27:03Z
dc.date.available2020-09-02T22:27:03Z
dc.date.issued2018
dc.identifier10.1016/j.ejmech.2018.07.056
dc.identifier.citation158, , 781-800
dc.identifier.issn02235234
dc.identifier.urihttps://hdl.handle.net/20.500.12728/6037
dc.descriptionThere has been a substantial research effort to design multi-target ligands for the treatment of Alzheimer's disease (AD), an approach that is moved by the knowledge that AD is a complex and multifactorial disease affecting many linked to pathological pathways. Accordingly, we have devoted efforts to develop multi-target ligands based on the chromone scaffold. As a result, a small library of chromone derivatives was synthesized and screened towards human cholinesterases and monoamine oxidases. Compounds 2-(dimethylamino)ethyl (E)-3-(4-oxo-2-(p-methylphenlcarbamoyl)-4H-chromen-6-yl)acrylate (9a) and 2-(dimethylamino)ethyl (E)-3-(4-oxo-3-(phenylcarbamoyl)-4H-chromen-6-yl)acrylate (23a) were identified as the most promising multi-target inhibitors of the series. Compound 9a acted as a potent, selective and bifunctional AChEI (IC50 = 0.21 μM, Ki = 0.19 μM) and displayed dual hMAO inhibitory activity (hMAO-A IC50 = 0.94 μM, Ki = 0.057 μM and hMAO-B IC50 = 3.81 μM, Ki = 0.48 μM). Compound 23a acted as a selective IMAO-B (IC50 = 0.63 μM, Ki = 0.34 μM) while still displaying hChE inhibitory and bifunctional activity in the low micromolar range. Overall, these two compounds stand out as reversible multi-target inhibitors with favourable permeability, toxicological and drug-like profiles, thus being valid candidates for subsequent optimization and pre-clinical studies. © 2018
dc.language.isoen
dc.publisherElsevier Masson SAS
dc.subjectAChE inhibitors
dc.subjectAlzheimer's disease
dc.subjectChromone
dc.subjectMAO-B inhibitors
dc.subjectMulti-target-directed ligands
dc.subjectNew chemical entities
dc.subject2 (dimethylamino)ethyl (e) 3 [4 oxo 2 (4 methylphenlcarbamoyl) 4h chromen 6 yl]acrylate
dc.subject2 (dimethylamino)ethyl (e) 3 [4 oxo 3 (phenylcarbamoyl) 4h chromen 6 yl]acrylate
dc.subjectcholinesterase inhibitor
dc.subjectchromone derivative
dc.subjectmonoamine oxidase inhibitor
dc.subjectunclassified drug
dc.subjectamine oxidase (flavin containing)
dc.subjectcholinesterase
dc.subjectcholinesterase inhibitor
dc.subjectchromone derivative
dc.subjectligand
dc.subjectmonoamine oxidase inhibitor
dc.subjectAlzheimer disease
dc.subjectArticle
dc.subjectdrug structure
dc.subjectdrug synthesis
dc.subjectenzyme inhibition
dc.subjectIC50
dc.subjectAlzheimer disease
dc.subjectblood brain barrier
dc.subjectchemistry
dc.subjectdrug design
dc.subjectHep-G2 cell line
dc.subjecthuman
dc.subjectmetabolism
dc.subjectmolecular docking
dc.subjectmolecularly targeted therapy
dc.subjectAlzheimer Disease
dc.subjectBlood-Brain Barrier
dc.subjectCholinesterase Inhibitors
dc.subjectCholinesterases
dc.subjectChromones
dc.subjectDrug Design
dc.subjectHep G2 Cells
dc.subjectHumans
dc.subjectLigands
dc.subjectMolecular Docking Simulation
dc.subjectMolecular Targeted Therapy
dc.subjectMonoamine Oxidase
dc.subjectMonoamine Oxidase Inhibitors
dc.titleMulti-target-directed ligands for Alzheimer's disease: Discovery of chromone-based monoamine oxidase/cholinesterase inhibitors
dc.typeArticle


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