Deducing the bioactive face of hydantoin anticonvulsant drugs using NMR spectroscopy.
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 A.
Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, Canada.
Kathryn E
KE
Tiedje
Donald F
DF
Weaver
D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000139:chemically induced / Q000175:diagnosis / Q000188:drug therapy*; D006827:Hydantoins / Q000737:chemistry / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008956:Models, Chemical; D008968:Molecular Conformation; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley
D000927:Anticonvulsants; D006827:Hydantoins; D010862:Pilocarpine