title: Identification of the stereochemical requirements in the 4-aryl-2-cycloalkylidenhydrazinylthiazole scaffold for the design of selective human monoamine oxidase B inhibitors.
abstract: Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted CN bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies.
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Melissa
authors.initials: M
authors.lastname: D'Ascenzio
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: simone.carradori@uniroma1.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Carradori
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Secci
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Istituto di Metodologie Chimiche, Laboratorio di Risonanza Magnetica 'Annalaura Segre', CNR, via Salaria km 29.300, 00015 Monterotondo, Rome, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mannina
authors.affiliation: Istituto di Metodologie Chimiche, Laboratorio di Risonanza Magnetica 'Annalaura Segre', CNR, via Salaria km 29.300, 00015 Monterotondo, Rome, Italy.
authors.forename: Anatoly P
authors.initials: AP
authors.lastname: Sobolev
authors.affiliation: Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Celeste
authors.initials: C
authors.lastname: De Monte
authors.affiliation: Istituto Superiore di Sanità, Dipartimento del Farmaco, V.le Regina Elena 299, 00161 Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cirilli
authors.affiliation: Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur, E-15782 Santiago de Compostela (La Coruña), Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Yáñez
authors.affiliation: Dipartimento di Scienze della Salute, 'Magna Graecia' University of Catanzaro, Campus Universitario 'S. Venuta', Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Dipartimento di Scienze della Salute, 'Magna Graecia' University of Catanzaro, Campus Universitario 'S. Venuta', Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D013844:Thiazoles; D008995:Monoamine Oxidase
keywords: Diastereoseparation; Methylcyclopentane; Molecular modeling; Monoamine oxidase inhibitors; Thiazole