Low Temperature X-Ray Crystallographic Structure of the Antiplasmodial Compound 5-N-Hydroxyethanequindoline Hydrochloride 0.5CH₃OH

Authors: Hampson, Hannah¹; Ho, Chung¹; Palmer, Rex²; Potter, Brian³; Helliwell, Madeleine⁴; Wright, Colin¹

Source: Journal of Chemical Crystallography, Volume 41, Number 11, November 2011 , pp. 1757-1762(6)

Publisher: Springer

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Abstract:

The structure of 5-N-hydroxyethanequindoline hydrochloride methanolate, C₁₇H₁₅ON₂ Cl·½CH₃OH, M _r = 314.78, has been determined from X-ray diffraction data. The crystals are monoclinic, space group C2/c, with Z = 8 molecules per unit cell and a = 18.179(11), b = 7.317(5), c = 24.125(15) Å, β = 110.155(10)°, V _c = 3012(3) Å³, crystal density D _c = 1.388 Mg m⁻³. The structure was solved by direct methods, and the asymmetric unit comprises the 5-N-hydroxyethanequindoline hydrochloride and ½CH₃OH moiety. The methanol is unusually disordered over a twofold axis with the C atom slightly removed from the twofold axis. Restraints were applied to the bond lengths of the two components of the disordered CH₃OH, and to the anisotropic thermal displacement parameters of the disordered CH₃OH carbon atom. The heterocyclic quindoline ring system and the first C atom of the hydroxyethane side chain are planar within 0.02 Å, with the terminal C-OH atoms of the side chain significantly out of the plane. The crystal structure is maintained via three hydrogen bonds all involving the chlorine atom an oxygen in the hydroxyethane side chain, a nitrogen in the quindoline moiety and the methanol oxygen.

The novel cryptolepine analogue, 5-N-hydroxyethanequindoline was synthesised as part of an ongoing exploration of cryptolepine analogues as lead compounds towards antimalarial and anticancer agents. In previous work it has been shown that halogen ring substituents enhance the antimalarial properties of cryptolepine and improve its selectivity but the effects of modification of the 5-N substituent on antiplasmodial activity has not so far been investigated. Although, the antiplasmodial activity of this analogue was found to be less than that of cryptolepine, the X-ray structure of this compound will help to determine whether or not 5-N-hydroxyethanequindoline is able to intercalate into DNA and facilitate the design of new cryptolepine analogues with DNA binding properties appropriate for antimalarial (with no DNA intercalation) or anticancer (sequence-specific binding) applications.<Figure Category="Standard" Float="No" ID="Figa"> <MediaObject ID="MO1"> </MediaObject> </Figure>

Keywords: Antiplasmodial; Crystal structure; Cryptolepine; NMR; DNA intercalation

Document Type: Research article

DOI: http://dx.doi.org/10.1007/s10870-011-0169-5

Affiliations: 1: The School of Pharmacy, University of Bradford, West Yorkshire, BD7 4ER, UK 2: School of Crystallography, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK, Email: rex.palmer@btinternet.com 3: School of Crystallography, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK 4: School of Chemistry, University of Manchester, Brunswick Street, Manchester, M13 9PL, UK

Publication date: 2011-11-01