Hostname: page-component-5cf477f64f-zrtmk Total loading time: 0 Render date: 2025-04-04T02:26:14.475Z Has data issue: false hasContentIssue false
  • English
  • Français

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.
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
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

References

1. Merritt, HH. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. Arch Neurol Psychiat. 1938; 39: 1003–8.Google Scholar
2. Dichter, MA. Mechanisms of action of new antiepileptic drugs. Adv Neurol. 1998; 76: 1–9.Google Scholar
3. Codding, PW, Lee, TA, Richardson, JF. Cyheptamide and 3-hydroxy- 3-phenacyloxindole: structural similarity to diphenylhydantoin as the basis for anticonvulsant activity. J Med Chem. 1984; 27: 649–52.CrossRefGoogle ScholarPubMed
4. Weaver, DF. Applications of molecular physics biotechnology to the rational design of an improved phenytoin analogue. Seizure. 1993; 1: 223–46.Google Scholar
5. Boyd, WJ. Isolation of amino acids in the form of the corresponding carbamido acids and hydantoins. I. The derivatives of the monoaminomonocarboxylic acids. Biochem J. 1933; 26: 1838–48.CrossRefGoogle Scholar
6. Frerichs, G, Hollmann, M, Beckurts, H. Beiträge zur Kenntnis der Arylhydantoine. Arch Pharm. 1905; 243: 684–710.Google Scholar
7. Finkbeiner, HL, Stiles, M. Chelation as a driving force in organic reactions. IV. Synthesis of a-nitro acids by control of the carboxylation-decarboxylation equilibrium. J Am Chem Soc. 1963; 85: 616–72.Google Scholar
8. Finkbeiner, HL. The carboxylation of hydantoins. J Org Chem. 1965; 30: 3414–19.Google Scholar
9. Aschan, O. Ueber die Einwirkung von Phenylsenföl auf Amidofettsaüren. Chem Ber. 1883; 16: 1544–5.Google Scholar
10. Fischer, E. Spaltung racemischer Aminosäuren in die optisch activen Componenten. III. Chem Ber. 1900; 33: 2370–82.Google Scholar
11. Dunnavant, WR, James, FL. Molecular rearrangements. I. The base-catalyzed condensation of benzil with urea. J Am Chem Soc. 1956; 78: 2740–3.Google Scholar
12. Lyon, AP, Wainman, D, Marone, S, Weaver, DF. Implementing a bioassay to screen molecules for antiepileptogenic activity: chronic pilocarpine versus subdudral haematoma models. Seizure. 2004; 13: 82–6.Google Scholar
13. Lyon, AP, Wainman, D, Marone, S, Weaver, DF. A spontaneous recurrent seizure bioassay for anti-epileptogenic molecules. Can J Neurol Sci. 2005; 32: 97–102.CrossRefGoogle ScholarPubMed
14. Turski, L, Ikonomidou, C, Turski, WA, Bortolotto, ZA, Cavalheiro, EA. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: a novel experimental model of intractable epilepsy. Synapse. 1989; 3: 154–71.Google Scholar
15. Close, WJ, Doub, L, Spielman, MA. Anticonvulsant drugs. J Med Chem. 1961; 5: 1–78.Google Scholar
16. Chem 3D Ultra. 2004. Version 8.0.Google Scholar
17. Fujiwara, H, Bose, AK, Manhas, MS, van der Veen, JM. Non-bonded aromatic-amide attraction in 5-benzyl-3-arylhydantoins. J Chem Soc Perkin Trans. II. 1979; 653–8.Google Scholar
18. Fujiwara, H, van der Veen, JM. An x-ray study of the aromatic ringdipole interaction in hydantoin crystals. J Chem Soc Perkin Trans. II. 1979; 659–63.Google Scholar
19. Robinson, R, Jencks, WP. The effect of concentrated salt solutions on the activity coefficient of acetyltetraglycine ethyl ester. J Am Chem Soc. 1965; 87: 2470–2.Google Scholar