2. Academic Validation
  3. Identification of the stereochemical requirements in the 4-aryl-2-cycloalkylidenhydrazinylthiazole scaffold for the design of selective human monoamine oxidase B inhibitors

Identification of the stereochemical requirements in the 4-aryl-2-cycloalkylidenhydrazinylthiazole scaffold for the design of selective human monoamine oxidase B inhibitors

  • Bioorg Med Chem. 2014 May 15;22(10):2887-95. doi: 10.1016/j.bmc.2014.03.042.
Melissa D'Ascenzio 1,  Simone Carradori 2,  Daniela Secci 1,  Luisa Mannina 3,  Anatoly P Sobolev 4,  Celeste De Monte 1,  Roberto Cirilli 5,  Matilde Yáñez 6,  Stefano Alcaro 7,  Francesco Ortuso 7
Affiliations

Affiliations

  • 1 Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 2 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.
  • 3 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.
  • 4 Istituto di Metodologie Chimiche, Laboratorio di Risonanza Magnetica 'Annalaura Segre', CNR, via Salaria km 29.300, 00015 Monterotondo, Rome, Italy.
  • 5 Istituto Superiore di Sanità, Dipartimento del Farmaco, V.le Regina Elena 299, 00161 Rome, Italy.
  • 6 Departamento de Farmacología, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur, E-15782 Santiago de Compostela (La Coruña), Spain.
  • 7 Dipartimento di Scienze della Salute, 'Magna Graecia' University of Catanzaro, Campus Universitario 'S. Venuta', Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy.
PMID: 24746464 DOI: 10.1016/j.bmc.2014.03.042
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.

Keywords

Diastereoseparation; Methylcyclopentane; Molecular modeling; Monoamine oxidase inhibitors; Thiazole.

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