Published online by Cambridge University Press: 02 December 2014
The general purpose of this study was to deduce the geometry of the bioactive face (pharmacophore) for the hydantoin class of anticonvulsants.
Six hydantoin analogs, selected as probes of hydantoin structure, were synthesized. Nuclear magnetic resonance spectroscopy and molecular modelling calculations were used to determine the geometric relationship between the aromatic group and the amide group in the hydantoin pharmacophore.
In accord with both theoretical and experimental results, the biologically inactive hydantoin analogs containing a benzyl substituent existed in a folded conformation with the benzene flopped over the hydantoin ring. Conversely the biologically active hydantoins had a phenyl ring extended away from the hydantoin ring.
The bioactive face for hydantoins consists of a N(H)-C(=O)-X-phenyl molecular fragment, where X is a carbon or nitrogen atom and where the distance between the centre of the amide bond and the centroid of the phenyl ring is 4.3 Å.
Le but de cette étude était de déduire quelle est la géométrie de la face bioactive (pharmacophore) des anticonvulsivants de la classe de l’hydantoi’ne.
Six analogues de l’hydantoi’ne choisis comme sondes pour examiner la structure de l’hydantoi’ne ont été synthétisés. La spectroscopie par résonance magnétique nucléaire (RMN) et des calculs par modélisation moléculaire ont été utilisés pour déterminer la relation géométrique entre le groupe aromatique et le groupe amide dans le pharmacophore de l’hydantoi’ne.
Les analogues de l’hydantoi’ne qui contiennent un substituant benzyle sont inactifs au point de vue biologique et possèdent une conformation repliée, le benzène étant rabattu sur l’anneau hydantoi’ne, ce qui concorde avec les données théoriques et expérimentales. À l’opposé, les analogues bioactifs de l’hydantoi’ne ont un anneau phényle qui s’écarte de l’anneau hydantoi’ne.
La face bioactive des analogues de l’hydantoi’ne consiste en un fragment moléculaire N(H)–C(=0)–X–phényle où le X est un atome de carbone ou d’azote et où la distance entre le centre du pont amide et le centroide de l’anneau phényle est de 4,3 «.
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