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. Materials and 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. Conclusion: 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. Copyright © 2003 S. Karger AG, Basel.

Publication DOI: https://doi.org/10.1159/000072290
Divisions: College of Health & Life Sciences > Aston Pharmacy School
Additional Information: This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only.
Uncontrolled Keywords: ab initio quantum mechanics,anticonvulsant enaminone,x-ray structure,Medicine(all)
Publication ISSN: 1423-0151
Full Text Link: http://www.karg ... /FullText/72290
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2003-12-17
Authors: Edafiogho, I.O.
Denny, B.J.
Schwalbe, C.H.
Lowe, P.R.



Version: Published Version

License: Creative Commons Attribution Non-commercial

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