CNR ExploRA

Articolo in rivista, 2014, ENG, 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

M. D'Ascenzio, S. Carradori, D. Secci, L. Mannina, A.P. Sobolev, C. De Monte, R. Cirilli, M. Yanez, S. Alcaro, F. Ortuso

Dipartimento di Chimica e Tecnologie Del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Istituto Superiore di Sanità, Dipartimento Del Farmaco, V.le Regina Elena 299, 00161 Rome, Italy; Departamento de Farmacología, Universidad de Santiago de Compostela, Campus Universitario sur, E-15782 Santiago de Compostela (La Coruña), Spain; Dipartimento di Scienze della Salute, 'Magna Graecia' University of Catanzaro, Campus Universitario 'S. Venuta', Viale Europa Loc. Germaneto, 88100 Catanzaro, Italy; Istituto di Metodologie Chimiche, Laboratorio di Risonanza Magnetica 'Annalaura Segre', CNR, via Salaria km 29.300, 00015 Monterotondo, Rome, Italy

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.

Bioorganic & medicinal chemistry (Print) 22 (10), pp. 2887–2895