title: Searching for Multi-Targeting Neurotherapeutics against Alzheimer's: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif.
abstract: The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer's disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam.
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. leonardo.pisani@uniba.it.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pisani
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. roberta.farina@uniba.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Farina
authors.affiliation: Grupo de Neuroquimica, Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, San Francisco I, E-15782 Santiago de Compostela, Spain. ramon.soto@usc.es.
authors.forename: Ramon
authors.initials: R
authors.lastname: Soto-Otero
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. nunzio.denora@uniba.it.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. giuseppe.mangiatordi@uniba.it.
authors.forename: Giuseppe Felice
authors.initials: GF
authors.lastname: Mangiatordi
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. orazio.nicolotti@uniba.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: Grupo de Neuroquimica, Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, San Francisco I, E-15782 Santiago de Compostela, Spain. estefania.mendez@usc.es.
authors.forename: Estefania
authors.initials: E
authors.lastname: Mendez-Alvarez
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. cosimodamiano.altomare@uniba.it.
authors.forename: Cosimo Damiano
authors.initials: CD
authors.lastname: Altomare
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. marco.catto@uniba.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Catto
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", via E. Orabona, 4, I-70125 Bari, Italy. angelo.carotti@uniba.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors
keywords: Alzheimer’s disease; MAO inhibitors; cholinesterase inhibitors; coumarins; multi-target-directed ligands