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Deducing the Bioactive Face of Hydantoin Anticonvulsant Drugs Using NMR Spectroscopy

Published online by Cambridge University Press:  02 December 2014

Kathryn E Tiedje  and
Donald F Weaver
Kathryn E Tiedje
Affiliation:
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada
Donald F Weaver*
Affiliation:
Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada
*
Departments of Medicine and Chemistry, Chemistry Building, Dalhousie University, Halifax, Nova Scotia, B3H 4J3, Canada.
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Abstract

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Background:

The general purpose of this study was to deduce the geometry of the bioactive face (pharmacophore) for the hydantoin class of anticonvulsants.

Methods:

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.

Results:

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.

Conclusions:

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.

résumé:

<span class='bold'>RÉSUMÉ:</span> <span class='bold'> <span class='italic'>Contexte:</span></span>

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.

<span class='bold'> <span class='italic'>Méthodes:</span></span>

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.

<span class='bold'> <span class='italic'>Résultats:</span></span>

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.

<span class='bold'> <span class='italic'>Conclusion:</span></span>

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 «.

Type
Original Articles
Information
Canadian Journal of Neurological Sciences , Volume 35 , Issue 2 , May 2008 , pp. 232 - 236
Copyright
Copyright © The Canadian Journal of Neurological 2008

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