X-ray crystallographic and theoretical studies of an anticonvulsant enaminone: methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate.
OBJECTIVE
The aims of this study were to establish the structure of the potent anticonvulsant enaminone methyl 4-(4'-bromophenyl)amino-6-methyl-2-oxocyclohex-3-en-1-oate (E139), and to determine the energetically preferred conformation of the molecule, which is responsible for the biological activity.


METHODS
The structure of the molecule was determined by X-ray crystallography. Theoretical ab initio calculations with different basis sets were used to compare the energies of the different enantiomers and to other structurally related compounds.


RESULTS
The X-ray crystal structure revealed two independent molecules of E139, both with absolute configuration C11(S), C12(R), and their inverse. Ab initio calculations with the 6-31G, 3-21G and STO-3G basis sets confirmed that the C11(S), C12(R) enantiomer with both substituents equatorial had the lowest energy. Compared to relevant crystal structures, the geometry of the theoretical structures shows a longer C-N and shorter C=O distance with more cyclohexene ring puckering in the isolated molecule.


CONCLUSIONS
Based on a pharmacophoric model it is suggested that the enaminone system HN-C=C-C=O and the 4-bromophenyl group in E139 are necessary to confer anticonvulsant property that could lead to the design of new and improved anticonvulsant agents.
Edafiogho
I O
IO
Faculty of Pharmacy, Kuwait University, Safat, Kuwait. ivanoe@hsc.kuniv.edu.kw
Denny
B J
BJ
Schwalbe
C H
CH
Lowe
P R
PR
D000927:Anticonvulsants / Q000737:chemistry*; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000737:chemistry*; D015394:Molecular Structure; D013237:Stereoisomerism
D000927:Anticonvulsants; D003510:Cyclohexanes; C482385:E139 compound