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

Melissa D'Ascenzio; Simone Carradori; Daniela Secci; Luisa Mannina; Anatoly P Sobolev; Celeste De Monte; Roberto Cirilli; Matilde Yáñez; Stefano Alcaro; Francesco Ortuso

doi:10.1016/j.bmc.2014.03.042

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. Epub 2014 Apr 5.

Authors

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Drug Design*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure
Monoamine Oxidase / metabolism*
Monoamine Oxidase Inhibitors / chemical synthesis
Monoamine Oxidase Inhibitors / chemistry*
Monoamine Oxidase Inhibitors / pharmacology*
Stereoisomerism
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Isoenzymes
Monoamine Oxidase Inhibitors
Thiazoles
Monoamine Oxidase