title: In silico design of novel 2H-chromen-2-one derivatives as potent and selective MAO-B inhibitors.
abstract: Inhibition data on rat monoamine oxidase B isoform of a large number of 7-metahalobenzyloxy-2H-chromen-2-one derivatives (67 compounds) carrying at position 4 a variety of substituents differing in steric, electrostatic, lipophilic and H-bonding properties, were modeled by Gaussian field-based 3D-QSAR and docking simulations carried out on rat MAO-B homology model. The computational study combining two different approaches provided easily interpretable binding modes, highlighting the dominant role of the steric effects at position 4, and guided the design of new, potent and selective MAO-B inhibitors. The 4-hydroxyethyl-, 4-chloroethyl-, 4-carboxamidoethyl-coumarin derivatives 70, 71, and 76, respectively, were endowed with high MAO-B inhibitory potency (pIC50 = 8.13, 7.89 and 7.82, respectively) and good selectivity over MAO-A (pIC50 = 5.33, 3% inhibition at 10 μM, and pIC50 = 5.37, respectively). New compounds with moderate to low MAO-B inhibitory activity were also designed and prepared to challenge the predictive power of our docking-based 3D-QSAR model. The good match between predicted and experimental pIC50 values for all the newly designed compounds confirmed the robustness of our model (r(2) = 0.856, RMSE = 0.421) and its transparent rationale in unveiling the main molecular determinants for high potency towards MAO-B.
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: 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: 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: 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 Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV, 3, I-16132 Genova, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Di Braccio
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: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona, 4, I-70125 Bari, Italy. Electronic address: carotti_angelo@hotmail.com.
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D000818:Animals; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase
keywords: 3D-QSAR; 4-Substituted-7-(halo)benzyloxy-2H-chromene-2-ones; Molecular docking; Monoamine oxidase inhibitors; Parkinson's disease; Selective MAO-B inhibitors