6-[(4-Fluoro­phenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol and 6-[(4-meth­oxy­phenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol

The title compounds, C₁₇H₁₃FN₂O₃ and C₁₈H₁₆N₂O₄, are new potent aromatase inhibitors combining the common features of second- and third-generation nonsteroid anti-aromatase compounds. The mol­ecules have a propeller shape, with dihedral angles between adjacent planes in the range 49-86°. A quantum mechanical ab initio Roothaan-Hartree-Fock calculation for the isolated mol­ecules shows values for these angles close to the ideal value of 90°. Docking studies of the mol­ecules in the aromatase substrate show that their strong inhibitor potency can be attributed to mol­ecular flexibility, hydro­phobic inter­actions, heme Fe coordination and hydrogen bonding.

S1. Comment

The title compounds, (I) and (II), respectively, are new potent aromatase inhibitors identified in silico using a fast high-throughput screening methodology based on a pharmacophore model combining the common features of second- and third-generation non-steroid anti-aromatase compounds (Neves et al., 2009). Their inhibition activity was confirmed in vitro using a biochemical assay with aromatase extracted from human term placenta (Neves et al., 2007). Both compounds were able to block the enzyme with strong potency [for compound (I), IC₅₀ = 5.3 nM, and for compound (II), IC₅₀ = 55 nM [Should this be 5.5?]] and a competitive mechanism of inhibition. Letrozole, a third-generation aromatase inhibitor, was tested under the same assay conditions, showing IC₅₀ = 6.1 nM. The unique structure and strong aromatase potency of these new compounds makes them interesting candidates for lead optimization, hence the importance of their accurate structure determination from both X-ray diffraction and molecular quantum mechanical calculations. As compounds (I) and (II) compete with testosterone and androstenedione for the active site of aromatase, docking studies using the X-ray crystal structure of the enzyme (Ghosh et al., 2009) will further contribute to the understanding of the evidenced strong inhibitory potency.

X-ray diffraction studies of (I) and (II) led to the molecular structures depicted in Figs. 1 and 2, respectively. Average bond lengths are within normal ranges (Allen et al., 1987) for both molecules, except for those of the substituted phenyl rings, where the averages of the C—C bonds are shorter than the usual value of 1.395 Å [1.369 Å for (I) and 1.372 Å for (II)]. In addition, the C—C distances differ significantly within these rings. In fact, the C19—C20 and C20—C21 bond lengths are significantly shorter than the remaining fluorophenyl and methoxyphenyl ones (see Tables 1 and 3). Also, for the benzodioxol part, C9—C10 and C11—C12 are significantly shorter than the neighbouring bonds not involved in the attached five-membered ring. One possible explanation could be the effect of thermal motion of the atoms involved in these bonds, which tends to shorten the observed distances, but correcting these distances by applying a rigid-body motion analysis using a TLS model (Schomaker & Trueblood, 1968) [1.372 Å for (I) and 1.375 Å for (II)] is not sufficient to recover the nominal average value for aromatic C—C bonds. Both molecules have propeller structures, as evidenced by the dihedral angles shown on Tables 5 and 6.

The cohesion of the structures of (I) and (II) involves strong hydrogen bonds between the hydroxyl groups, acting as donors, and atoms N4 of the imidazole rings, acting as acceptors. In both compounds the hydrogen-bonding pattern is that of chains, running along the c axis in (I) and the b axis in (II).

In order to gain some insight into how the crystal packing of the molecules might affect their molecular geometry, and to compare the geometry of the free molecules with those adapted to the docking site, we have also performed a quantum chemical calculation on the equilibrium geometry of the isolated molecules. We were also interested in checking whether the observed deviations in the C—C bonds of the aromatic rings could be reproduced. These calculations were performed with the computer program GAMESS (Schmidt et al., 1993). A molecular orbital Roothan–Hartree–Fock method was used with an extended 6–31G(d,p) basis set. Tight conditions for convergence of both the self-consistent field cycles and maximum density and energy gradient variations were imposed (10^-6 atomic units). The program was run on the Milipeia cluster of UC-LCA (using 16 Opteron cores, 2.2 GHz, running Linux).

Docking studies using the X-ray crystal structure of aromatase (Ghosh et al., 2009) showed that, when bound to the active site, the studied molecules (I) and (II) adopt a conformation in which the hydrophobic diphenylmethane scaffold partially overlaps with the steroid hydrophobic framework and the N-containing heterocycle points in a similar direction in space to the 19-methyl, coordinating with the heme Fe (Fig. 3). The hydrophobic scaffolds of compounds (I) and (II) are remarkably complemented by apolar residues within the aromatase active site, whereas either the fluorine or methoxy and the dioxol groups interact with hydrogen-bond donors. The backbone amide of methionine 374, involved in a hydrogen bond with the substrate 17-keto O atom in the crystal structure (Ghosh et al., 2009), will likely interact with one of the acceptor groups, aligning the corresponding phenyl moiety with steroid ring C. A new pocket, defined at the helix F, helix I and β-strand 9 interfaces, is occupied by the second phenyl moiety, and a hydrogen bond is established with serine 478.

The results of the ab initio calculations for the free molecules show the high degree of rotational flexibility of the three ring planes of the propeller configuration, which is also important for good docking to the active site of aromatase (Tables 5 and 6). In the free state, the dihedral angles are close to 90°, as expected from the minimization of the steric interaction between adjacent rings. In both the observed crystal conformations and the adapted docking geometries, these angles are substantially smaller, due to packing and intramolecular interactions. Interestingly, the ab initio calculations reproduce the observed short C9—C10 and C11—C12 bond distances compared with the average aromatic values, although the same is not true for the C19—C20 and C20—C21 bonds.

In summary, rotational molecular flexibility, hydrophobic interactions, heme Fe coordination and hydrogen bonding are the main driving forces for strong aromatase binding, explaining the high potency of the studied compounds.

S2. Experimental

Compounds (I) and (II) were obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis of the US National Cancer Institute. The purity of the samples was evaluated by elemental analysis. Compound (I): C 65.38, H 4.20, N 8.97% (calculated); C 65.92, H 4.35, N 8.88% (found). Compound (II): C 66.66, H 4.97, N 8.64% (calculated); C 66.72, H 5.17, N 8.54% (found). GOLD (Version 3.2; Reference?) was used to perform flexible docking of (I) and (II) into the binding pocket of the aromatase X-ray crystal structure (PDB entry 3eqm). The androstenedione substrate was removed and used to define the binding site as a 10 Å sphere above the heme group. An octahedral coordinating geometry was assigned to the heme Fe and the GOLDScore fitness function was used with metal parameters optimized for P450 enzymes, taking account of different hydrogen-bond acceptor types (Kirton et al., 2005). Distance constraints were applied in order to keep the coordination between the imidazole N and the heme Fe within lower and upper limits of 1.9 and 2.5 Å, respectively. A total of 100 independent docking runs were performed with the default genetic algorithm search parameters.

S3. Refinement

Hydroxyl H atoms were located and refined using the AFIX 147 instruction (SHELXL97; Sheldrick, 2008). All other H atoms were placed in calculated idealized positions and refined as riding on their parent atoms, with C—H = 0.93–0.98 Å and U_iso(H) = 1.2U_eq(C), except for methyl groups for which U_iso(H) = 1.5U_eq(C).

Computing details

For both compounds, data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The structure of (I), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. The structure of (II), with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 3. The docking of (I) within the aromatase active site.

(I) 6-[(4-Fluorophenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol

Crystal data

C17H13FN2O3	F(000) = 648
Mr = 312.29	Dx = 1.389 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 7.5621 (2) Å	Cell parameters from 5230 reflections
b = 24.0471 (6) Å	θ = 2.6–25.8°
c = 8.8524 (2) Å	µ = 0.11 mm^−1
β = 111.966 (1)°	T = 293 K
V = 1492.92 (6) Å^3	Prism, colourless
Z = 4	0.42 × 0.22 × 0.20 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	3406 independent reflections
Radiation source: fine-focus sealed tube	2328 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.026
ϕ and ω scans	θmax = 27.5°, θmin = 1.7°
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)	h = −9→9
Tmin = 0.894, Tmax = 0.979	k = −30→31
32248 measured reflections	l = −11→11

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.125	H-atom parameters constrained
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0562P)^2 + 0.3355P] where P = (Fo^2 + 2Fc^2)/3
3406 reflections	(Δ/σ)max < 0.001
209 parameters	Δρmax = 0.17 e Å^−3
0 restraints	Δρmin = −0.24 e Å^−3

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. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
F1	0.6623 (2)	0.30494 (6)	1.0356 (2)	0.1205 (6)
O13	0.02089 (18)	0.12585 (5)	0.42054 (12)	0.0519 (3)
H13	0.0133	0.1201	0.3270	0.078*
O14	0.35440 (18)	−0.05068 (5)	0.53017 (14)	0.0584 (3)
O16	0.4351 (2)	−0.04209 (5)	0.80728 (14)	0.0656 (4)
N2	0.02861 (19)	0.12554 (6)	0.87612 (14)	0.0426 (3)
N4	−0.0025 (2)	0.11365 (7)	1.11106 (16)	0.0584 (4)
C1	0.1054 (2)	0.14161 (7)	0.75046 (17)	0.0431 (4)
H1	0.0008	0.1585	0.6596	0.052*
C3	0.0970 (3)	0.13761 (8)	1.03583 (18)	0.0519 (4)
H3	0.2022	0.1602	1.0869	0.062*
C5	−0.1417 (3)	0.08435 (8)	0.9932 (2)	0.0589 (5)
H5	−0.2342	0.0627	1.0106	0.071*
C6	−0.1249 (3)	0.09159 (8)	0.8485 (2)	0.0542 (4)
H6	−0.2026	0.0764	0.7492	0.065*
C7	0.1683 (2)	0.09006 (6)	0.68609 (16)	0.0403 (4)
C8	0.1232 (2)	0.08447 (7)	0.51906 (17)	0.0392 (4)
C9	0.1804 (2)	0.03744 (7)	0.45566 (17)	0.0434 (4)
H9	0.1491	0.0332	0.3442	0.052*
C10	0.2830 (2)	−0.00160 (7)	0.56296 (18)	0.0422 (4)
C11	0.3295 (2)	0.00352 (7)	0.72798 (18)	0.0446 (4)
C12	0.2722 (2)	0.04825 (7)	0.79189 (18)	0.0483 (4)
H12	0.3013	0.0510	0.9034	0.058*
C15	0.4361 (3)	−0.07853 (8)	0.6824 (2)	0.0594 (5)
H15A	0.3630	−0.1117	0.6824	0.071*
H15B	0.5658	−0.0896	0.7007	0.071*
C17	0.2580 (2)	0.18574 (7)	0.81971 (19)	0.0462 (4)
C18	0.2077 (3)	0.23938 (8)	0.8468 (2)	0.0601 (5)
H18	0.0794	0.2485	0.8155	0.072*
C19	0.3435 (3)	0.27926 (8)	0.9188 (3)	0.0718 (6)
H19	0.3081	0.3149	0.9371	0.086*
C20	0.5284 (3)	0.26567 (9)	0.9621 (3)	0.0770 (6)
C21	0.5845 (3)	0.21460 (10)	0.9346 (4)	0.0974 (9)
H21	0.7133	0.2065	0.9635	0.117*
C22	0.4480 (3)	0.17449 (9)	0.8629 (3)	0.0744 (6)
H22	0.4859	0.1393	0.8437	0.089*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.1039 (11)	0.0742 (9)	0.1676 (16)	−0.0321 (8)	0.0326 (11)	−0.0211 (9)
O13	0.0651 (7)	0.0642 (7)	0.0272 (5)	0.0092 (6)	0.0184 (5)	0.0070 (5)
O14	0.0666 (8)	0.0635 (8)	0.0443 (7)	0.0117 (6)	0.0197 (6)	−0.0082 (6)
O16	0.0820 (9)	0.0646 (8)	0.0414 (7)	0.0231 (7)	0.0132 (6)	−0.0001 (6)
N2	0.0469 (7)	0.0555 (8)	0.0261 (6)	0.0038 (6)	0.0146 (5)	−0.0004 (6)
N4	0.0732 (10)	0.0730 (10)	0.0326 (7)	0.0068 (8)	0.0238 (7)	0.0057 (7)
C1	0.0490 (9)	0.0553 (9)	0.0258 (7)	0.0083 (8)	0.0149 (6)	0.0043 (7)
C3	0.0585 (11)	0.0677 (11)	0.0265 (7)	0.0014 (9)	0.0124 (7)	0.0007 (7)
C5	0.0660 (12)	0.0662 (12)	0.0523 (10)	0.0012 (10)	0.0311 (9)	0.0034 (9)
C6	0.0578 (10)	0.0670 (11)	0.0395 (9)	−0.0044 (9)	0.0202 (8)	−0.0080 (8)
C7	0.0423 (8)	0.0513 (9)	0.0268 (7)	−0.0007 (7)	0.0125 (6)	−0.0013 (6)
C8	0.0381 (8)	0.0531 (9)	0.0273 (7)	−0.0045 (7)	0.0131 (6)	0.0020 (7)
C9	0.0456 (9)	0.0604 (10)	0.0265 (7)	−0.0046 (8)	0.0160 (7)	−0.0037 (7)
C10	0.0389 (8)	0.0525 (9)	0.0369 (8)	−0.0024 (7)	0.0161 (7)	−0.0079 (7)
C11	0.0445 (9)	0.0529 (9)	0.0322 (8)	0.0043 (8)	0.0097 (7)	0.0018 (7)
C12	0.0560 (10)	0.0603 (10)	0.0253 (7)	0.0057 (8)	0.0116 (7)	−0.0017 (7)
C15	0.0618 (11)	0.0623 (11)	0.0526 (10)	0.0106 (9)	0.0197 (9)	−0.0047 (9)
C17	0.0547 (10)	0.0482 (9)	0.0388 (8)	0.0067 (8)	0.0208 (7)	0.0045 (7)
C18	0.0631 (11)	0.0555 (11)	0.0648 (12)	0.0134 (9)	0.0275 (10)	0.0089 (9)
C19	0.0905 (16)	0.0439 (10)	0.0847 (15)	0.0015 (10)	0.0371 (13)	−0.0008 (10)
C20	0.0741 (15)	0.0549 (12)	0.0975 (17)	−0.0132 (11)	0.0269 (13)	−0.0053 (11)
C21	0.0572 (13)	0.0702 (15)	0.153 (3)	−0.0013 (12)	0.0262 (14)	−0.0161 (16)
C22	0.0561 (12)	0.0550 (11)	0.1079 (18)	0.0035 (10)	0.0256 (11)	−0.0125 (11)

Geometric parameters (Å, º)

F1—C20	1.359 (2)	C7—C12	1.398 (2)
O13—C8	1.3582 (18)	C8—C9	1.401 (2)
O13—H13	0.8200	C9—C10	1.354 (2)
O14—C10	1.3733 (19)	C9—H9	0.9300
O14—C15	1.423 (2)	C10—C11	1.374 (2)
O16—C11	1.3836 (19)	C11—C12	1.360 (2)
O16—C15	1.412 (2)	C12—H12	0.9300
N2—C3	1.3430 (19)	C15—H15A	0.9700
N2—C6	1.364 (2)	C15—H15B	0.9700
N2—C1	1.4856 (19)	C17—C22	1.369 (3)
N4—C3	1.310 (2)	C17—C18	1.391 (2)
N4—C5	1.368 (2)	C18—C19	1.375 (3)
C1—C7	1.514 (2)	C18—H18	0.9300
C1—C17	1.518 (2)	C19—C20	1.345 (3)
C1—H1	0.9800	C19—H19	0.9300
C3—H3	0.9300	C20—C21	1.351 (3)
C5—C6	1.345 (2)	C21—C22	1.381 (3)
C5—H5	0.9300	C21—H21	0.9300
C6—H6	0.9300	C22—H22	0.9300
C7—C8	1.3939 (19)
C8—O13—H13	109.5	C9—C10—C11	122.35 (15)
C10—O14—C15	105.66 (12)	O14—C10—C11	109.71 (14)
C11—O16—C15	105.41 (13)	C12—C11—C10	121.24 (15)
C3—N2—C6	106.53 (14)	C12—C11—O16	129.01 (14)
C3—N2—C1	128.89 (14)	C10—C11—O16	109.75 (14)
C6—N2—C1	124.48 (13)	C11—C12—C7	118.47 (14)
C3—N4—C5	105.28 (14)	C11—C12—H12	120.8
N2—C1—C7	109.57 (13)	C7—C12—H12	120.8
N2—C1—C17	109.29 (12)	O16—C15—O14	108.78 (14)
C7—C1—C17	115.21 (13)	O16—C15—H15A	109.9
N2—C1—H1	107.5	O14—C15—H15A	109.9
C7—C1—H1	107.5	O16—C15—H15B	109.9
C17—C1—H1	107.5	O14—C15—H15B	109.9
N4—C3—N2	111.85 (16)	H15A—C15—H15B	108.3
N4—C3—H3	124.1	C22—C17—C18	117.46 (17)
N2—C3—H3	124.1	C22—C17—C1	122.33 (15)
C6—C5—N4	109.83 (17)	C18—C17—C1	120.17 (16)
C6—C5—H5	125.1	C19—C18—C17	121.48 (19)
N4—C5—H5	125.1	C19—C18—H18	119.3
C5—C6—N2	106.50 (16)	C17—C18—H18	119.3
C5—C6—H6	126.7	C20—C19—C18	118.64 (19)
N2—C6—H6	126.7	C20—C19—H19	120.7
C8—C7—C12	119.65 (14)	C18—C19—H19	120.7
C8—C7—C1	119.44 (13)	C19—C20—C21	122.2 (2)
C12—C7—C1	120.91 (13)	C19—C20—F1	118.5 (2)
O13—C8—C7	117.73 (14)	C21—C20—F1	119.4 (2)
O13—C8—C9	121.41 (13)	C20—C21—C22	119.1 (2)
C7—C8—C9	120.86 (14)	C20—C21—H21	120.4
C10—C9—C8	117.41 (13)	C22—C21—H21	120.4
C10—C9—H9	121.3	C17—C22—C21	121.09 (19)
C8—C9—H9	121.3	C17—C22—H22	119.5
C9—C10—O14	127.95 (14)	C21—C22—H22	119.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O13—H13···N4^i	0.82	1.88	2.6947 (17)	175

Symmetry code: (i) x, y, z−1.

(II) 6-[(4-methoxyphenyl)(1H-imidazol-1-yl)methyl]-1,3-benzodioxol-5-ol

Crystal data

C18H16N2O4	Z = 2
Mr = 324.33	F(000) = 340
Triclinic, P1	Dx = 1.323 Mg m^−3
a = 7.6404 (2) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.8734 (2) Å	Cell parameters from 4810 reflections
c = 13.0368 (3) Å	θ = 2.5–23.4°
α = 100.627 (1)°	µ = 0.10 mm^−1
β = 91.113 (1)°	T = 293 K
γ = 109.804 (1)°	Prism, colourless
V = 814.10 (3) Å^3	0.25 × 0.18 × 0.14 mm

Data collection

Bruker APEXII CCD area-detector diffractometer	3738 independent reflections
Radiation source: fine-focus sealed tube	2069 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.024
ϕ and ω scans	θmax = 27.9°, θmin = 1.6°
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)	h = −9→10
Tmin = 0.914, Tmax = 0.987	k = −11→11
15530 measured reflections	l = −17→17

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.046	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.130	H-atom parameters constrained
S = 1.00	w = 1/[σ^2(Fo^2) + (0.0556P)^2 + 0.1205P] where P = (Fo^2 + 2Fc^2)/3
3738 reflections	(Δ/σ)max < 0.001
219 parameters	Δρmax = 0.15 e Å^−3
0 restraints	Δρmin = −0.19 e Å^−3

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. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
O13	0.49733 (18)	1.15049 (13)	0.22814 (10)	0.0577 (4)
H13	0.4974	1.2395	0.2191	0.087*
O14	0.13395 (17)	0.94471 (15)	−0.10950 (10)	0.0622 (4)
O16	0.05646 (19)	0.67605 (15)	−0.09199 (10)	0.0682 (4)
O23	−0.0574 (3)	0.7416 (3)	0.58414 (13)	0.1065 (6)
N2	0.4919 (2)	0.69716 (15)	0.23070 (11)	0.0472 (4)
N4	0.5113 (2)	0.45188 (18)	0.20989 (14)	0.0669 (5)
C1	0.4238 (2)	0.83622 (19)	0.25755 (14)	0.0476 (4)
H1	0.5323	0.9331	0.2875	0.057*
C3	0.4171 (3)	0.5454 (2)	0.24840 (16)	0.0621 (5)
H3	0.3110	0.5103	0.2838	0.075*
C5	0.6532 (3)	0.5489 (2)	0.16444 (16)	0.0651 (5)
H5	0.7437	0.5161	0.1300	0.078*
C6	0.6430 (3)	0.7001 (2)	0.17692 (15)	0.0592 (5)
H6	0.7238	0.7889	0.1533	0.071*
C7	0.3479 (2)	0.86956 (19)	0.15922 (13)	0.0435 (4)
C8	0.3884 (2)	1.03001 (19)	0.14862 (13)	0.0429 (4)
C9	0.3228 (2)	1.0678 (2)	0.05937 (13)	0.0474 (4)
H9	0.3519	1.1753	0.0514	0.057*
C10	0.2141 (2)	0.9394 (2)	−0.01539 (13)	0.0449 (4)
C11	0.1697 (2)	0.7798 (2)	−0.00520 (13)	0.0476 (4)
C12	0.2360 (2)	0.7413 (2)	0.08036 (13)	0.0510 (5)
H12	0.2077	0.6329	0.0862	0.061*
C15	0.0440 (3)	0.7790 (2)	−0.16043 (16)	0.0662 (6)
H15A	−0.0861	0.7594	−0.1802	0.079*
H15B	0.1032	0.7554	−0.2236	0.079*
C17	0.2891 (3)	0.8083 (2)	0.34184 (14)	0.0501 (5)
C18	0.1052 (3)	0.7880 (3)	0.32508 (17)	0.0879 (8)
H18	0.0592	0.7903	0.2590	0.105*
C19	−0.0156 (3)	0.7643 (4)	0.40342 (19)	0.1056 (10)
H19	−0.1406	0.7502	0.3896	0.127*
C20	0.0499 (3)	0.7615 (3)	0.50094 (16)	0.0764 (7)
C21	0.2334 (3)	0.7827 (3)	0.52024 (16)	0.0750 (6)
H21	0.2791	0.7813	0.5866	0.090*
C22	0.3509 (3)	0.8060 (3)	0.44160 (16)	0.0680 (6)
H22	0.4760	0.8209	0.4560	0.082*
C24	−0.2414 (4)	0.7415 (5)	0.5700 (2)	0.1374 (14)
H24A	−0.3141	0.6462	0.5193	0.206*
H24B	−0.2382	0.8380	0.5456	0.206*
H24C	−0.2967	0.7402	0.6354	0.206*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O13	0.0753 (8)	0.0326 (6)	0.0608 (8)	0.0162 (6)	−0.0052 (7)	0.0046 (6)
O14	0.0695 (8)	0.0573 (8)	0.0582 (8)	0.0166 (7)	−0.0053 (7)	0.0194 (6)
O16	0.0866 (10)	0.0500 (8)	0.0558 (8)	0.0106 (7)	−0.0155 (7)	0.0087 (6)
O23	0.1219 (14)	0.1824 (19)	0.0632 (11)	0.0957 (14)	0.0344 (10)	0.0575 (11)
N2	0.0555 (9)	0.0337 (7)	0.0533 (9)	0.0165 (7)	0.0004 (7)	0.0097 (6)
N4	0.0819 (12)	0.0374 (8)	0.0810 (12)	0.0230 (9)	0.0014 (10)	0.0070 (8)
C1	0.0554 (10)	0.0318 (8)	0.0537 (11)	0.0154 (8)	−0.0035 (9)	0.0042 (7)
C3	0.0682 (13)	0.0357 (10)	0.0791 (15)	0.0130 (9)	0.0090 (11)	0.0130 (9)
C5	0.0777 (14)	0.0584 (12)	0.0674 (14)	0.0356 (11)	0.0085 (11)	0.0099 (10)
C6	0.0643 (12)	0.0524 (11)	0.0682 (13)	0.0251 (10)	0.0124 (10)	0.0208 (9)
C7	0.0500 (10)	0.0352 (9)	0.0465 (10)	0.0164 (8)	0.0057 (8)	0.0086 (7)
C8	0.0471 (9)	0.0353 (9)	0.0466 (10)	0.0158 (8)	0.0091 (8)	0.0059 (7)
C9	0.0519 (10)	0.0360 (9)	0.0574 (11)	0.0166 (8)	0.0082 (9)	0.0143 (8)
C10	0.0459 (10)	0.0494 (10)	0.0462 (10)	0.0210 (8)	0.0095 (8)	0.0174 (8)
C11	0.0513 (10)	0.0404 (9)	0.0473 (11)	0.0126 (8)	0.0024 (8)	0.0061 (8)
C12	0.0641 (11)	0.0335 (9)	0.0544 (11)	0.0147 (8)	0.0019 (9)	0.0109 (8)
C15	0.0700 (13)	0.0640 (13)	0.0593 (13)	0.0168 (11)	−0.0059 (10)	0.0132 (10)
C17	0.0592 (11)	0.0492 (10)	0.0443 (11)	0.0237 (9)	−0.0035 (9)	0.0068 (8)
C18	0.0722 (15)	0.153 (2)	0.0502 (13)	0.0455 (15)	0.0035 (11)	0.0371 (14)
C19	0.0767 (15)	0.204 (3)	0.0614 (16)	0.0657 (19)	0.0150 (13)	0.0564 (18)
C20	0.0909 (16)	0.1143 (19)	0.0475 (13)	0.0579 (15)	0.0150 (12)	0.0300 (12)
C21	0.0926 (16)	0.1025 (18)	0.0432 (12)	0.0490 (14)	−0.0028 (12)	0.0192 (11)
C22	0.0697 (13)	0.0863 (15)	0.0556 (13)	0.0367 (12)	−0.0073 (11)	0.0159 (11)
C24	0.126 (2)	0.236 (4)	0.119 (3)	0.115 (3)	0.065 (2)	0.102 (3)

Geometric parameters (Å, º)

O13—C8	1.3657 (19)	C8—C9	1.397 (2)
O13—H13	0.8200	C9—C10	1.362 (2)
O14—C10	1.376 (2)	C9—H9	0.9300
O14—C15	1.419 (2)	C10—C11	1.372 (2)
O16—C11	1.383 (2)	C11—C12	1.361 (2)
O16—C15	1.413 (2)	C12—H12	0.9300
O23—C20	1.373 (2)	C15—H15A	0.9700
O23—C24	1.414 (3)	C15—H15B	0.9700
N2—C3	1.339 (2)	C17—C18	1.363 (3)
N2—C6	1.358 (2)	C17—C22	1.381 (2)
N2—C1	1.483 (2)	C18—C19	1.387 (3)
N4—C3	1.312 (2)	C18—H18	0.9300
N4—C5	1.360 (3)	C19—C20	1.364 (3)
C1—C7	1.515 (2)	C19—H19	0.9300
C1—C17	1.516 (2)	C20—C21	1.362 (3)
C1—H1	0.9800	C21—C22	1.374 (3)
C3—H3	0.9300	C21—H21	0.9300
C5—C6	1.350 (3)	C22—H22	0.9300
C5—H5	0.9300	C24—H24A	0.9600
C6—H6	0.9300	C24—H24B	0.9600
C7—C8	1.385 (2)	C24—H24C	0.9600
C7—C12	1.399 (2)
C8—O13—H13	109.5	C12—C11—O16	128.81 (15)
C10—O14—C15	105.45 (13)	C10—C11—O16	109.95 (15)
C11—O16—C15	105.17 (13)	C11—C12—C7	118.08 (15)
C20—O23—C24	117.20 (19)	C11—C12—H12	121.0
C3—N2—C6	106.36 (15)	C7—C12—H12	121.0
C3—N2—C1	128.74 (16)	O16—C15—O14	109.33 (15)
C6—N2—C1	124.82 (14)	O16—C15—H15A	109.8
C3—N4—C5	105.14 (16)	O14—C15—H15A	109.8
N2—C1—C7	110.22 (13)	O16—C15—H15B	109.8
N2—C1—C17	110.41 (13)	O14—C15—H15B	109.8
C7—C1—C17	114.79 (14)	H15A—C15—H15B	108.3
N2—C1—H1	107.0	C18—C17—C22	116.68 (19)
C7—C1—H1	107.0	C18—C17—C1	122.86 (17)
C17—C1—H1	107.0	C22—C17—C1	120.44 (17)
N4—C3—N2	112.08 (17)	C17—C18—C19	122.1 (2)
N4—C3—H3	124.0	C17—C18—H18	119.0
N2—C3—H3	124.0	C19—C18—H18	119.0
C6—C5—N4	109.75 (18)	C20—C19—C18	119.7 (2)
C6—C5—H5	125.1	C20—C19—H19	120.1
N4—C5—H5	125.1	C18—C19—H19	120.1
C5—C6—N2	106.66 (17)	C21—C20—C19	119.5 (2)
C5—C6—H6	126.7	C21—C20—O23	116.27 (19)
N2—C6—H6	126.7	C19—C20—O23	124.2 (2)
C8—C7—C12	119.92 (15)	C20—C21—C22	119.91 (19)
C8—C7—C1	119.03 (14)	C20—C21—H21	120.0
C12—C7—C1	121.05 (14)	C22—C21—H21	120.0
O13—C8—C7	117.53 (15)	C21—C22—C17	122.09 (19)
O13—C8—C9	121.03 (14)	C21—C22—H22	119.0
C7—C8—C9	121.44 (15)	C17—C22—H22	119.0
C10—C9—C8	116.74 (15)	O23—C24—H24A	109.5
C10—C9—H9	121.6	O23—C24—H24B	109.5
C8—C9—H9	121.6	H24A—C24—H24B	109.5
C9—C10—C11	122.55 (16)	O23—C24—H24C	109.5
C9—C10—O14	127.69 (15)	H24A—C24—H24C	109.5
C11—C10—O14	109.76 (15)	H24B—C24—H24C	109.5
C12—C11—C10	121.24 (16)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O13—H13···N4^i	0.82	1.88	2.6949 (19)	175

Symmetry code: (i) x, y+1, z.