title: Structure-Based Design and Optimization of Multitarget-Directed 2H-Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases.
abstract: The multifactorial nature of Alzheimer's disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible N-benzyl-N-alkyloxy coumarins 2-12 showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing meta- and para-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds 21, 24, 37, and 39, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound 37 as a BBB-permeant neuroprotective agent against H2O2-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity.
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Farina
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
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.
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.
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Gadaleta
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
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.
authors.forename: Ramon
authors.initials: R
authors.lastname: Soto-Otero
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.
authors.forename: Estefania
authors.initials: E
authors.lastname: Mendez-Alvarez
authors.affiliation: §School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest Ansermet 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Carolina S
authors.initials: CS
authors.lastname: Passos
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Muncipinto
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Cosimo D
authors.initials: CD
authors.lastname: Altomare
authors.affiliation: §School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest Ansermet 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nurisso
authors.affiliation: §School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest Ansermet 30, CH-1211, Geneva 4, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Carrupt
authors.affiliation: †Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D002802:Cholinesterases / Q000737:chemistry / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D010539:Permeability; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; C030123:coumarin; D008995:Monoamine Oxidase; D002802:Cholinesterases