title: Exploring Basic Tail Modifications of Coumarin-Based Dual Acetylcholinesterase-Monoamine Oxidase B Inhibitors: Identification of Water-Soluble, Brain-Permeant Neuroprotective Multitarget Agents.
abstract: Aiming at modulating two key enzymatic targets for Alzheimer's disease (AD), i.e., acetylcholinesterase (AChE) and monoamine oxidase B (MAO B), a series of multitarget ligands was properly designed by linking the 3,4-dimethylcoumarin scaffold to 1,3- and 1,4-substituted piperidine moieties, thus modulating the basicity to improve the hydrophilic/lipophilic balance. After in vitro enzymatic inhibition assays, multipotent inhibitors showing potencies in the nanomolar and in the low micromolar range for hMAO B and eeAChE, respectively, were prioritized and evaluated in human SH-SY5Y cell-based models for their cytotoxicity and neuroprotective effect against oxidative toxins (H2O2, rotenone, and oligomycin-A). The present study led to the identification of a promising multitarget hit compound (5b) exhibiting high hMAO B inhibitory activity (IC50 = 30 nM) and good MAO B/A selectivity (selectivity index, SI = 94) along with a micromolar eeAChE inhibition (IC50 = 1.03 μM). Moreover, 5b behaves as a water-soluble, brain-permeant neuroprotective agent against oxidative insults without interacting with P-gp efflux system.
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: 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: 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: Rosa Maria
authors.initials: RM
authors.lastname: Iacobazzi
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: Saverio
authors.initials: S
authors.lastname: Cellamare
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: 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.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.affiliation: 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: Molecular Discovery Limited 215 Marsh Road, Pinner, Middlesex, London HA5 5NE, U.K.
authors.forename: Lydia
authors.initials: L
authors.lastname: Siragusa
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 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.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D002800:Cholinesterase Inhibitors; D003374:Coumarins; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D014867:Water; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase