(E)-8-(3-Chloro­styr­yl)-1,3,7-trimethylxanthine, a caffeine derivative acting both as antagonist of adenosine A2A receptors and as inhibitor of MAO-B

In the crystal structure of (E)-8-(3-chloro­styr­yl)-1,3,7-trimethylxanthine (CSC) [systematic name: (E)-8-(3-chloro­styr­yl)-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 confirms the pharmacophore elements associated with MAO-B inhibition.

S1. Comment

(E)-8-(3-Chlorostyryl)-1,3,7-trimethylxanthine (CSC) (Fig. 1) is a caffeinyl derivative that acts both as an antagonist of adenosine A2A receptors and as an inhibitor of MAO-B, offering novel therapeutic benefits in patients diagnosed with neurodegenerative disorders such as Parkinson's disease (Castagnoli et al., 2003; Petzer et al., 2003). The crystal structure 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 C—C and/or C—N bonds. Analysis of the torsion angles revealed that the molecule adopts an almost planar conformation; the xanthine ring is coplanar with the lateral styryl moiety, which adopts an all trans conformation (Table 1).

Crystal cohesion of CSC is mainly assumed by stacking interactions involving the five-membered (imidazole-type) ring, C4/C5/N7/C8/N9, and the aryl ring, C17–C22. In particular, there are a pair of five-membered rings stacked across (0, 1,1/2) and a pair of phenyl rings stacked across (0,1/2, 1). The distance between the centroids of the C4/C5/N7/C8/N9 ring in the molecules at (x, y, z) and (−x, 2 − y, 1 − z) is 3.637 (2) Å, with an interplanar spacing of 3.402 (2) Å; the separation between the centroids of the aryl rings of the molecules at (x, y, z) and (−x, 1 − y, 2 − z) is 3.707 (2) Å, with an interplanar spacing of 3.551 (2) Å. Propagation of these stacking interactions by successive inversions then generates a chain along [01–1].

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 identifies 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 carbonyls and atom N9 of the xanthine ring define a unique pharmacophoric pattern similar to that observed among diazoheterocyclic of reversible MAO-B inhibitors (Wouters et al., 1997; Wouters, 1998). This 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.

S2. Experimental

CSC was obtained from 1,3-dimethyl-5,6-diaminouracil and (E)-3-chlorocinnamic acid according to the general procedure reported by Jacobson et al. (1993). M.p. 478 K, literature 478 K (Jacobson et al., 1993). Crystals were grown at room temperature by slow evaporation from a solution of CSC in methanol.

S3. Refinement

H atoms were refined using a riding model. For the methyl groups (C10, C12 and C14), C—H distances were fixed at 0.96 Å, with U_iso(H) = 1.5U_eq(C). All other C—H distances were fixed at 0.93 Å, with U_iso(H) = 1.2U_eq(C).

Computing details

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994); cell refinement: CAD-4 EXPRESS (Enraf–Nonius, 1994); data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2001); software used to prepare material for publication: PLATON (Spek, 2001).

Figures

	Fig. 1. The molecular conformation of CSC, with its atomic numbering scheme and displacement ellipsoids at the 50% probability level.
	Fig. 2. Molecular electostatic potential (MEP) calculated around CSC (ab initio, RHF 6–31G* basis set) using the crystal structure conformation.

(E)-8-(3-chlorostyryl)-1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione

Crystal data

C16H15ClN4O2	Z = 2
Mr = 330.77	F(000) = 344
Triclinic, P1	Dx = 1.423 Mg m^−3
Hall symbol: -P 1	Cu Kα radiation, λ = 1.54175 Å
a = 8.244 (1) Å	Cell parameters from 25 reflections
b = 8.319 (1) Å	θ = 4–45°
c = 12.722 (1) Å	µ = 2.33 mm^−1
α = 77.864 (7)°	T = 298 K
β = 77.502 (6)°	Prism, colourless
γ = 66.214 (5)°	0.32 × 0.30 × 0.10 mm
V = 772.05 (15) Å^3

Data collection

Enraf–Nonius CAD-4 diffractometer	2776 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.016
Graphite monochromator	θmax = 71.8°, θmin = 3.6°
θ/2θ scans	h = −10→0
Absorption correction: analytical (de Meulenaer & Tompa, 1965)	k = −10→9
Tmin = 0.523, Tmax = 0.801	l = −15→15
3240 measured reflections	3 standard reflections every 60 min
3015 independent reflections	intensity decay: 1%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.046	H-atom parameters constrained
wR(F^2) = 0.132	1/[σ^2(Fo^2) + (0.0756P)^2 + 0.2615P] where P = (Fo^2 + 2Fc^2)/3
S = 1.03	(Δ/σ)max = 0.012
3015 reflections	Δρmax = 0.33 e Å^−3
209 parameters	Δρmin = −0.40 e Å^−3
0 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0124 (13)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. Conventional R-factors R are based on F, with F set to zero for negative F².

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Cl23	−0.16218 (9)	0.22491 (8)	0.97197 (5)	0.0806 (2)
O13	0.27332 (19)	1.36092 (17)	0.41146 (13)	0.0615 (4)
O11	0.6358 (2)	0.8922 (2)	0.23024 (11)	0.0656 (4)
N1	0.45156 (19)	1.12513 (19)	0.32115 (11)	0.0426 (3)
N3	0.4474 (2)	0.83708 (18)	0.37860 (11)	0.0448 (3)
N7	0.13513 (17)	1.09412 (18)	0.57147 (11)	0.0404 (3)
N9	0.24140 (18)	0.81028 (18)	0.54338 (11)	0.0412 (3)
C15	0.0150 (2)	0.8930 (2)	0.70531 (14)	0.0447 (4)
H15	−0.0588	0.9849	0.7451	0.054*
C8	0.1285 (2)	0.9311 (2)	0.60731 (13)	0.0395 (4)
C4	0.3208 (2)	0.9026 (2)	0.46501 (12)	0.0373 (3)
C5	0.2602 (2)	1.0771 (2)	0.47867 (13)	0.0379 (4)
C17	−0.0964 (2)	0.6782 (2)	0.83802 (14)	0.0426 (4)
C18	−0.2158 (2)	0.7940 (3)	0.90952 (15)	0.0507 (4)
H18	−0.2283	0.9124	0.8968	0.061*
C22	−0.0796 (2)	0.5016 (2)	0.85981 (15)	0.0483 (4)
H22	0.0015	0.4209	0.8144	0.058*
C16	0.0120 (2)	0.7324 (2)	0.74058 (14)	0.0451 (4)
H16	0.0875	0.6439	0.6987	0.054*
C10	0.5132 (3)	0.6491 (3)	0.36641 (19)	0.0662 (6)
H10A	0.6091	0.5827	0.4084	0.099*
H10B	0.5561	0.6350	0.2912	0.099*
H10C	0.4174	0.6063	0.3917	0.099*
C2	0.5190 (2)	0.9470 (2)	0.30541 (13)	0.0450 (4)
C20	−0.3014 (3)	0.5604 (3)	1.01882 (15)	0.0577 (5)
H20	−0.3706	0.5212	1.0784	0.069*
C14	0.0255 (3)	1.2595 (3)	0.61581 (18)	0.0597 (5)
H14A	−0.0891	1.3084	0.5911	0.090*
H14B	0.0844	1.3424	0.5917	0.090*
H14C	0.0091	1.2366	0.6938	0.090*
C12	0.5243 (3)	1.2425 (3)	0.24032 (15)	0.0539 (5)
H12A	0.4314	1.3278	0.2008	0.081*
H12B	0.6201	1.1734	0.1908	0.081*
H12C	0.5690	1.3030	0.2765	0.081*
C6	0.3219 (2)	1.2032 (2)	0.40571 (14)	0.0414 (4)
C21	−0.1834 (3)	0.4460 (3)	0.94899 (15)	0.0515 (4)
C19	−0.3158 (3)	0.7346 (3)	0.99910 (16)	0.0600 (5)
H19	−0.3937	0.8131	1.0467	0.072*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl23	0.1005 (5)	0.0608 (4)	0.0858 (4)	−0.0481 (3)	0.0027 (3)	−0.0012 (3)
O13	0.0651 (8)	0.0348 (7)	0.0789 (10)	−0.0207 (6)	0.0017 (7)	−0.0049 (6)
O11	0.0755 (9)	0.0672 (9)	0.0512 (8)	−0.0323 (8)	0.0176 (7)	−0.0182 (7)
N1	0.0464 (7)	0.0427 (7)	0.0398 (7)	−0.0210 (6)	−0.0069 (6)	0.0014 (6)
N3	0.0529 (8)	0.0373 (7)	0.0425 (7)	−0.0176 (6)	0.0022 (6)	−0.0096 (6)
N7	0.0400 (7)	0.0343 (7)	0.0442 (7)	−0.0115 (5)	−0.0039 (6)	−0.0075 (5)
N9	0.0451 (7)	0.0351 (7)	0.0424 (7)	−0.0162 (6)	−0.0028 (6)	−0.0044 (5)
C15	0.0417 (8)	0.0460 (9)	0.0436 (9)	−0.0152 (7)	−0.0007 (7)	−0.0086 (7)
C8	0.0389 (8)	0.0377 (8)	0.0410 (8)	−0.0140 (6)	−0.0057 (6)	−0.0044 (6)
C4	0.0395 (8)	0.0347 (8)	0.0376 (8)	−0.0134 (6)	−0.0055 (6)	−0.0057 (6)
C5	0.0388 (8)	0.0343 (8)	0.0398 (8)	−0.0126 (6)	−0.0066 (6)	−0.0049 (6)
C17	0.0402 (8)	0.0482 (9)	0.0412 (8)	−0.0192 (7)	−0.0048 (6)	−0.0061 (7)
C18	0.0533 (10)	0.0486 (10)	0.0496 (10)	−0.0205 (8)	−0.0007 (8)	−0.0093 (8)
C22	0.0506 (9)	0.0505 (10)	0.0468 (9)	−0.0231 (8)	−0.0012 (7)	−0.0106 (8)
C16	0.0422 (8)	0.0479 (9)	0.0444 (9)	−0.0180 (7)	0.0006 (7)	−0.0098 (7)
C10	0.0797 (14)	0.0442 (10)	0.0678 (13)	−0.0237 (10)	0.0192 (10)	−0.0236 (9)
C2	0.0506 (9)	0.0479 (9)	0.0381 (8)	−0.0212 (8)	−0.0034 (7)	−0.0069 (7)
C20	0.0608 (11)	0.0689 (13)	0.0423 (9)	−0.0319 (10)	0.0024 (8)	−0.0001 (8)
C14	0.0585 (11)	0.0422 (10)	0.0716 (13)	−0.0148 (8)	0.0103 (9)	−0.0222 (9)
C12	0.0578 (11)	0.0585 (11)	0.0492 (10)	−0.0332 (9)	−0.0082 (8)	0.0085 (8)
C6	0.0415 (8)	0.0345 (8)	0.0478 (9)	−0.0140 (6)	−0.0104 (7)	−0.0015 (6)
C21	0.0580 (10)	0.0520 (10)	0.0490 (10)	−0.0287 (9)	−0.0087 (8)	0.0008 (8)
C19	0.0609 (11)	0.0670 (13)	0.0461 (10)	−0.0219 (10)	0.0069 (8)	−0.0148 (9)

Geometric parameters (Å, º)

Cl23—C21	1.743 (2)	C17—C22	1.391 (2)
O11—C2	1.217 (2)	C18—C19	1.381 (3)
O13—C6	1.221 (2)	C19—C20	1.378 (3)
N1—C2	1.399 (2)	C20—C21	1.370 (3)
N1—C6	1.399 (2)	C21—C22	1.383 (3)
N1—C12	1.468 (3)	C10—H10A	0.9603
N3—C2	1.375 (2)	C10—H10B	0.9602
N3—C4	1.375 (2)	C10—H10C	0.9606
N3—C10	1.465 (3)	C12—H12A	0.9598
N7—C5	1.380 (2)	C12—H12B	0.9602
N7—C8	1.356 (2)	C12—H12C	0.9600
N7—C14	1.460 (3)	C14—H14A	0.9600
N9—C4	1.347 (2)	C14—H14B	0.9604
N9—C8	1.342 (2)	C14—H14C	0.9605
C4—C5	1.368 (2)	C15—H15	0.9302
C5—C6	1.428 (2)	C16—H16	0.9302
C8—C15	1.449 (2)	C18—H18	0.9303
C15—C16	1.326 (2)	C19—H19	0.9303
C16—C17	1.466 (2)	C20—H20	0.9303
C17—C18	1.393 (3)	C22—H22	0.9303
C2—N1—C6	126.87 (14)	Cl23—C21—C22	118.69 (16)
C2—N1—C12	116.55 (15)	C20—C21—C22	121.5 (2)
C6—N1—C12	116.59 (15)	C17—C22—C21	120.01 (17)
C2—N3—C4	119.84 (14)	N3—C10—H10A	109.48
C2—N3—C10	119.46 (16)	N3—C10—H10B	109.49
C4—N3—C10	120.64 (16)	N3—C10—H10C	109.47
C5—N7—C8	106.29 (13)	H10A—C10—H10B	109.51
C5—N7—C14	125.54 (15)	H10A—C10—H10C	109.44
C8—N7—C14	128.05 (16)	H10B—C10—H10C	109.44
C4—N9—C8	103.92 (13)	N1—C12—H12A	109.47
O11—C2—N1	121.33 (16)	N1—C12—H12B	109.47
O11—C2—N3	121.64 (15)	N1—C12—H12C	109.46
N1—C2—N3	117.03 (14)	H12A—C12—H12B	109.47
N3—C4—N9	126.28 (14)	H12A—C12—H12C	109.49
N3—C4—C5	121.41 (15)	H12B—C12—H12C	109.48
N9—C4—C5	112.32 (14)	N7—C14—H14A	109.47
N7—C5—C4	105.14 (14)	N7—C14—H14B	109.48
N7—C5—C6	131.68 (14)	N7—C14—H14C	109.51
C4—C5—C6	123.18 (15)	H14A—C14—H14B	109.45
O13—C6—N1	121.20 (16)	H14A—C14—H14C	109.49
O13—C6—C5	127.17 (17)	H14B—C14—H14C	109.44
N1—C6—C5	111.63 (14)	C8—C15—H15	118.71
N7—C8—N9	112.34 (15)	C16—C15—H15	118.64
N7—C8—C15	123.19 (14)	C15—C16—H16	116.22
N9—C8—C15	124.46 (14)	C17—C16—H16	116.29
C8—C15—C16	122.65 (15)	C17—C18—H18	119.69
C15—C16—C17	127.49 (15)	C19—C18—H18	119.72
C16—C17—C18	123.58 (15)	C18—C19—H19	119.61
C16—C17—C22	118.11 (15)	C20—C19—H19	119.62
C18—C17—C22	118.31 (17)	C19—C20—H20	120.64
C17—C18—C19	120.6 (2)	C21—C20—H20	120.59
C18—C19—C20	120.8 (2)	C17—C22—H22	120.01
C19—C20—C21	118.8 (2)	C21—C22—H22	119.99
Cl23—C21—C20	119.78 (17)
N7—C8—C15—C16	−178.8 (2)	C14—N7—C8—C15	−5.3 (3)
C8—C15—C16—C17	179.9 (2)	C8—N9—C4—N3	−179.30 (17)
C15—C16—C17—C18	0.0 (3)	C8—N9—C4—C5	0.0 (2)
C6—N1—C2—O11	−177.97 (18)	C4—N9—C8—N7	0.0 (2)
C6—N1—C2—N3	2.0 (3)	C4—N9—C8—C15	−178.45 (17)
C12—N1—C2—O11	2.1 (3)	N9—C4—C5—N7	0.0 (2)
C12—N1—C2—N3	−177.86 (17)	N9—C4—C5—C6	−179.23 (16)
C2—N1—C6—O13	179.78 (18)	N3—C4—C5—N7	179.33 (16)
C2—N1—C6—C5	−0.3 (3)	N3—C4—C5—C6	0.1 (3)
C12—N1—C6—O13	−0.3 (3)	C4—C5—C6—O13	179.11 (19)
C12—N1—C6—C5	179.58 (17)	N7—C5—C6—O13	0.1 (3)
C4—N3—C2—O11	177.34 (18)	N7—C5—C6—N1	−179.78 (18)
C4—N3—C2—N1	−2.7 (2)	C4—C5—C6—N1	−0.8 (2)
C10—N3—C2—O11	0.2 (3)	N9—C8—C15—C16	−0.5 (3)
C10—N3—C2—N1	−179.80 (18)	C15—C16—C17—C22	179.60 (19)
C2—N3—C4—N9	−179.03 (17)	C16—C17—C18—C19	179.07 (19)
C2—N3—C4—C5	1.7 (3)	C22—C17—C18—C19	−0.6 (3)
C10—N3—C4—N9	−1.9 (3)	C16—C17—C22—C21	−178.00 (19)
C10—N3—C4—C5	178.84 (19)	C18—C17—C22—C21	1.7 (3)
C8—N7—C5—C4	0.03 (19)	C17—C18—C19—C20	−0.9 (3)
C8—N7—C5—C6	179.14 (19)	C18—C19—C20—C21	1.2 (4)
C14—N7—C5—C4	−176.31 (18)	C19—C20—C21—Cl23	179.93 (19)
C14—N7—C5—C6	2.8 (3)	C19—C20—C21—C22	−0.1 (4)
C5—N7—C8—N9	0.0 (2)	Cl23—C21—C22—C17	178.61 (16)
C5—N7—C8—C15	178.47 (16)	C20—C21—C22—C17	−1.4 (3)
C14—N7—C8—N9	176.19 (18)