organic compounds
Acta Crystallographica Section C
Crystal Structure
xanthine ring is coplanar with the lateral styryl moiety, which
adopts an all trans conformation (Table 1).
Communications
ISSN 0108-2701
(E)-8-(3-Chlorostyryl)-1,3,7-trimethyl-
xanthine, a caffeine derivative acting
both as antagonist of adenosine A2A
receptors and as inhibitor of MAO-B
Crystal cohesion of CSC is mainly assumed by stacking
interactions involving the ®ve-membered (imidazole-type)
ring, C4/C5/N7/C8/N9, and the benzene ring, C17±C22. In
particular, there are a pair of ®ve-membered rings stacked
across (0, 1, 12 ) and a pair of benzene rings stacked across (0, 12,
1). The distance between the centroids of the C4/C5/N7/C8/N9
a
a
b
 Â
Raphael Frederick, Frederic Ooms, ³ Neal Castagnoli Jr,
È
Jacques P. Petzer,c Jiang-Fan Feng,d Michael A.
Schwarzschild,d Cornelis J. Van der Schyfc,e and Johan
Woutersa*
ring in the molecules at (x, y, z) and ( x, 2
Ê
y, 1
z) is
Ê
3.637 (2) A, with an interplanar spacing of 3.402 (2) A; the
separation between the centroids of the benzene rings of the
Ê
molecules at (x, y, z) and ( x, 1 y, 2 z) is 3.707 (2) A, with
Ê
an interplanar spacing of 3.551 (2) A. Propagation of these
stacking interactions by successive inversions then generates a
chain along [011].
aUniversity of Namur, 61 Rue de Bruxelles, B-5000 Namur, Belgium, bDepartment of
Chemistry, Virginia Tech, Blacksburg, VA 24061, USA, cSchool of Pharmacy, North-
West University, Potchefstroom 2520, South Africa, dDepartment of Neurology, Mass
General Institute for Neurodegenerative Disease, Harvard Medical School, Boston,
MA 02129, USA, and eTexas Tech University Health Sciences Centre, School of
Pharmacy, Amarillo, Texas 79106, USA
The coplanar conformation adopted by CSC is in agreement
with our previously determined MAO-B pharmacophore
(Wouters et al., 1997; Wouters, 1998; Ooms et al., 2003). The
molecular electostatic potential (MEP) around the molecule
(Fig. 2) was calculated (ab initio, RHF 6-31G* basis set) using
the crystal structure conformation. The features of the MEP
map conform with stereoelectronic elements already found
among other families of reversible MAO-B inhibitors. In
particular, the MEP map identi®es three attractive potential
wells that show a high degree of similarity compared with
other MAO-B inhibitors. These attractive potential wells
generated by the two carbonyl groups and atom N9 of the
xanthine ring de®ne a unique pharmacophoric pattern similar
to that observed among diazaheterocyclic groups of reversible
MAO-B inhibitors (Wouters et al., 1997; Wouters, 1998). This
fact suggests that the heteroatoms of the xanthine ring can
stabilize this new family of reversible MAO-B inhibitors with
appropriate hydrogen-donor residues found within the MAO-
B active site.
Correspondence e-mail: johan.wouters@fundp.ac.be
Received 5 July 2005
Accepted 19 July 2005
Online 10 August 2005
In the crystal structure of (E)-8-(3-chlorostyryl)-1,3,7-
trimethylxanthine (CSC) [systematic name: (E)-8-(3-chloro-
styryl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione],
C16H15ClN4O2, the xanthine ring and the lateral styryl chain
are coplanar. The crystal packing involves mainly parallel
stacking of these planar molecules. The electrostatic potential
calculated on the crystal structure conformation con®rms the
pharmacophore elements associated with MAO-B inhibition.
Comment
(E)-8-(3-Chlorostyryl)-1,3,7-trimethylxanthine (CSC) (Fig. 1)
is a caffeine derivative that acts both as an antagonist of
adenosine A2A receptors and as an inhibitor of MAO-B,
offering novel therapeutic bene®ts in patients diagnosed with
neurodegenerative disorders, such as Parkinson's disease
(Castagnoli et al., 2003; Petzer et al., 2003). The crystal struc-
ture reported here will be the starting point for three-
dimensional quantitative structure±activity relationship and
docking studies, which may aid in the future design of potent
A2A receptor antagonists that also possess monoamine
oxidase B (MAO-B) inhibitory activity.
The bond lengths (Table 1) within the xanthine ring are
systematically intermediate between single and double CÐC
and/or CÐN bonds. Analysis of the torsion angles revealed
that the molecule adopts an almost planar conformation; the
Figure 1
The molecular conformation of CSC, showing the atomic numbering
scheme and displacement ellipsoids at the 50% probability level.
³ Present address: Euroscreen SA, 47 rue Adrienne Boland, B-6041 Gosselies,
Belgium.
Acta Cryst. (2005). C61, o531±o532
DOI: 10.1107/S0108270105023140
# 2005 International Union of Crystallography o531
Frederick, Raphael
