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Acta Crystallographica Section E: Crystallographic Communications logoLink to Acta Crystallographica Section E: Crystallographic Communications
. 2015 Apr 18;71(Pt 5):505–508. doi: 10.1107/S2056989015007367

Crystal structure of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxa­diazol-3-yl)phen­oxy]prop­yl}-N-(11-hy­droxy­undec­yl)isoxazole-3-carboxamide hemihydrate

K Salorinne a, T Lahtinen a,*
PMCID: PMC4420136  PMID: 25995867

The crystal structure and supra­molecular features of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxa­diazol-3-yl)phen­oxy]prop­yl}-N-(11-hy­droxy­undec­yl)isoxazole-3-carboxamide hemihydrate, a derivative of anti­viral ‘WIN compounds’, are reported.

Keywords: crystal structure, anti­viral, WIN derivative, isoxazole, oxa­diazole

Abstract

The title compound, C29H42N4O5·0.5H2O, comprises four structural units. A flexible prop­yloxy unit in a gauche conformation, with a –C(H2)—C(H2)—C(H2)—O– torsion angle of −64.32 (18)°, connects an isoxazole ring and an approximately planar phenyl­oxa­diazole ring system [with a maxixmum devation of 0.061 (2) Å], which are oriented almost parallel to one another with a dihedral angle of 10.75 (7)°. Furthermore, a C11-alkyl chain with a terminal hy­droxy group links to the 3-position of the isoxazole ring via an amide bond. In the crystal, a half-occupancy solvent water mol­ecule connects to a neighbouring mol­ecule via an inter­molecular O—H⋯O(water) hydrogen bond to the C11-alkyl chain hy­droxy group.

Chemical context  

An anti­viral drug family of the so-called ‘WIN compounds’ was developed against various human illnesses caused by enteroviruses including common respiratory infections, rash or mild fever and serious or life-threatening infections, such as meningitis, myocarditis, encephalitis and paralytic poliomyelitis (De Palma et al., 2008 ▸; Diana, 2003 ▸). The WIN compounds were particularly designed to target the early events (attachment, entry and uncoating) of viral replication and they have been shown to bind specifically into the inter­ior hydro­phobic pocket located at the VP1 protein of the enterovirus capsid and replacing the naturally occurring myristic acid (Reisdorph et al., 2003 ▸; Giranda et al., 1995 ▸; Zhang et al., 2004 ▸; Thibaut et al., 2012 ▸). The anti­viral drug candidate development finally led to the WIN 63843 analogue, better known as Pleconaril, which showed a drastic decrease in the metabolic degradation of the mol­ecule and a broad range of anti­viral activity against enteroviruses (Pevear et al., 1999 ▸; Wildenbeest et al., 2012 ▸). The design of the title compound is based on the chemical structure of the WIN 61893 analogue (Diana et al., 1995 ▸), to which an additional C11-alkyl linker arm having a hy­droxy end group was attached at the 3-position of the isoxazole ring via an amide bond.graphic file with name e-71-00505-scheme1.jpg

Structural commentary  

The mol­ecular structure of the title compound is shown in Fig. 1 ▸. The structure contains three essentially planar heterocyclic or aromatic rings, i.e. isoxazole (atoms C19–C21/N22/O23), benzene (C7–C12) and oxa­diazole (C2/O3/N4/C5/N6), of which the latter two are directly connected via atoms C7 and C5. The three heterocyclic rings are approximately coplanar to one another, having dihedral angles between the rings of 11.57 (8) (C19–C21/N22/O23 and C7–C12), 10.68 (9) (C19–C21/N22/O23 and C2/O3/N4/C5/N6) and 4.81 (9)° (C7–C12 and C2/O3/N4/C5/N6), maintaining the WIN framework in a linear conformation. The dihedral angle between the isoxazole ring (C19–C21/N22/O23) and the approximately planar phenyl­oxa­diazole ring system [C7–C12/C2/O3/N4/C5/N6, with a maximum devation of 0.061 (2)Å for atom C12] is 10.75 (7)°. The isoxazole and phenyl­oxa­diazole ring systems are connected by a prop­yloxy unit (O15–C18), which is in a gauche conformation, with a C18—C17—C16—O15 torsion angle of −64.32 (18)°. The amide group (N26–C24) at the 3-position of the isoxazole ring which joins the C11-alkyl chain (C27–O38) and the WIN framework is likewise almost coplanar with the isoxazole ring, with a dihedral angle of 10.92 (9)° between the amide (H26/N26/C24/O25) and isoxazole planes. The amide hydrogen (H26) and the acidic isoxazole hydrogen (H20) are on opposite sides, with a torsion angle (N26—C24—C21—C20) of 172.31 (15)°. The C11-alkyl chain (C27–C37) is in an all-anti conformation, with an average torsion angle of 178.80°. The WIN framework and the C11-linker arm structural units are aligned roughly in a 160° angle and the total length of the title mol­ecule measures up to 3.4 nm.

Figure 1.

Figure 1

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The mol­ecular structure of the title compound with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Supra­molecular features  

The title compound packs in the crystal lattice in layers, in which the mol­ecules are held together by solvent-mediated O—H⋯O and C—H⋯O hydrogen bonds (motif 1), as well as C—H⋯N and C—H⋯O inter­molecular inter­actions between the heterocyclic isoxazole and phenyl­oxa­diazole units of neighbouring mol­ecules (motif 2) (Table 1 ▸). In the solvent-mediated assembly, an inter­molecular hydrogen-bonded network of the type Inline graphic(9) is formed between the C11-alkyl chain hy­droxy [O—H⋯O = 1.90 (1) Å], solvent water [O—H⋯O = 1.87 (1) Å], amide carbonyl and isoxazole hydrogen (C—H⋯O = 2.56 Å) groups of two parallel neighbouring mol­ecules (Fig. 2 ▸). In a similar manner, two pairs of C—H⋯N and C—H⋯O hydrogen bonds connect three opposite-facing neighbouring mol­ecules via R 2 2(8) and Inline graphic(16) loops between the isoxazole (C—H⋯O = 2.51 Å) and phenyl­oxa­diazole (C—H⋯O = 2.64 Å and C—H⋯N = 2.65 Å) groups (Fig. 2 ▸).

Table 1. Hydrogen-bond geometry (, ).

DHA DH HA D A DHA
C28H28AO3i 0.99 2.64 3.2567(19) 120
C20H20O38ii 0.95 2.56 3.505(2) 175
C13H13BO23i 0.98 2.51 3.416(2) 154
C1H1BN6 0.98 2.65 3.622(2) 174
O100H10BO25iii 0.84(1) 1.87(1) 2.710(3) 180(6)
O38H38O100 0.82(1) 1.90(1) 2.695(4) 164(2)
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Symmetry codes: (i) Inline graphic; (ii) Inline graphic; (iii) Inline graphic.

Figure 2.

Figure 2

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A view along the c axis of the crystal packing of the title compound. Inter­molecular inter­actions formed between neighbouring mol­ecules highlighting the solvent water mediated hydrogen bonding network (motif 1, orange box) and the two coordination loops between the heterocyclic isoxazole and phenyl- oxa­diazole units (motif 2, blue box).

Database survey  

A search of the Cambridge Structural Database (CSD; Version 5.36, November 2014; Groom & Allen, 2014 ▸) revealed the presence of nine structures (CSD refcode VOGDAY contains two independent mol­ecules; Salorinne et al., 2014 ▸) with the substructure 3-{3,5-dimethyl-4-[3-(3-methyl­isoxazol-5-yl)prop­oxy]phen­yl}-5-methyl-1,2,4-oxa­diazole. These nine structures belong to three similar compounds of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxa­diazol-3-yl)phen­oxy]prop­yl}iso­xazole-3-carb­oxy­lic acid (Salorinne et al., 2014 ▸), ethyl 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxa­diazol-3-yl)phen­oxy]prop­yl}iso­xazole-3-carboxyl­ate (Salorinne et al., 2014 ▸) and 3-{3,5-di­methyl-4-[3-(3-methyl­isoxazol-5-yl)prop­oxy]phen­yl}-5-tri­fluoro­methyl-1,2,4-oxa­diazole (Coste et al., 2004 ▸). In six of the nine structures (CSD refcodes VOGCOL01, VOGDAY, HAJYUN, HAJYUN01, HAJYUN02 and HAJYUN03; Salorinne et al., 2014 ▸; Coste et al., 2004 ▸), the isoxazole and phenyl­oxa­diazole heterocyclic rings of the WIN framework are almost coplanar, similar to the title compound. However, in two of the structures (CSD refcodes VOGCOL and VOGDEL; Salorinne et al., 2014 ▸), the heterocyclic ring systems are tilted slightly with angles of 34–38° between the ring planes, whereas in one of the structures (CSD refcode VOGCOL; Salorinne et al., 2014 ▸), the heterocyclic ring systems are closer to a perpendicular orientation, with an angle of ca 60.8°. In all of the structures, the prop­yloxy unit is in a gauche conformation, with torsion angles in the range 62.4–69.2°.

Synthesis and crystallization  

An amide coupling reaction of 5-{3-[2,6-dimethyl-4-(5-methyl-1,2,4-oxa­diazol-3-yl)phen­oxy]prop­yl}isoxazole-3-carb­oxy­lic acid (0.17 mmol, Salorinne et al., 2014 ▸) with 11-amino-1-undeca­nol (0.18 mmol) in di­chloro­methane (20 ml) in the presence of N-[3-(di­methyl­amino)­prop­yl]-N-ethyl­carbodi­imide (0.19 mmol) and a catalytic amount of 1-hy­droxy­benzotriazole at 273 K gave the title compound in 68% yield after subsequent chromatographic purification in silica with a di­chloro­methane–methanol mixture (95:5 v/v). Needle-like crystals of the title compound were obtained from an ethanol solution by vapor diffusion with water.

Refinement  

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. All H atoms were positioned geometrically and allowed to ride on their parent atoms, with C—H = 0.95–0.99 Å, and with U iso(H) = 1.5U eq(C) for methyl and 1.2U eq(C) for other H atoms, and N—H = 0.88 Å and U iso(H) = 1.2U eq(N). The positions of the O-bound H atoms were located in a difference Fourier map and refined as riding atoms with U iso(H) = 1.5U eq(O). The O—H distance of the half-occupied water molecule was restrained to 0.84 (1) Å.

Table 2. Experimental details.

Crystal data
Chemical formula 2C29H42N4O5H2O
M r 1071.34
Crystal system, space group Triclinic, P Inline graphic
Temperature (K) 170
a, b, c () 6.7137(3), 14.0263(5), 16.6757(8)
, , () 113.889(4), 94.515(4), 90.976(4)
V (3) 1429.29(12)
Z 1
Radiation type Mo K
(mm1) 0.09
Crystal size (mm) 0.42 0.15 0.09
 
Data collection
Diffractometer Agilent SuperNova, Single source at offset, Eos
Absorption correction Analytical [CrysAlis PRO (Agilent, 2013 ▸), based on expressions derived by Clark Reid (1995 ▸)]
T min, T max 0.990, 0.998
No. of measured, independent and observed [I > 2(I)] reflections 13976, 7670, 5463
R int 0.016
(sin /)max (1) 0.716
 
Refinement
R[F 2 > 2(F 2)], wR(F 2), S 0.053, 0.148, 1.05
No. of reflections 7670
No. of parameters 364
No. of restraints 3
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
max, min (e 3) 0.36, 0.26
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Computer programs: CrysAlis PRO (Agilent, 2013 ▸), SHELXS97 (Sheldrick, 2008 ▸), SHELXL2013 (Sheldrick, 2015 ▸) and OLEX2 (Dolomanov et al., 2009 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989015007367/lh5758sup1.cif

e-71-00505-sup1.cif (487.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989015007367/lh5758Isup2.hkl

e-71-00505-Isup2.hkl (420.1KB, hkl)
Click here for additional data file. (11.6KB, cml)

Supporting information file. DOI: 10.1107/S2056989015007367/lh5758Isup3.cml

CCDC reference: 1059505

Additional supporting information: crystallographic information; 3D view; checkCIF report

Enhanced figure: interactive version of Fig. 3

supplementary crystallographic information

Crystal data

2C29H42N4O5·H2O Z = 1
Mr = 1071.34 F(000) = 578
Triclinic, P1 Dx = 1.245 Mg m−3
a = 6.7137 (3) Å Mo Kα radiation, λ = 0.71073 Å
b = 14.0263 (5) Å Cell parameters from 5261 reflections
c = 16.6757 (8) Å θ = 2.5–30.3°
α = 113.889 (4)° µ = 0.09 mm−1
β = 94.515 (4)° T = 170 K
γ = 90.976 (4)° Needle, clear colourless
V = 1429.29 (12) Å3 0.42 × 0.15 × 0.09 mm
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Data collection

Agilent SuperNova, Single source at offset, Eos diffractometer 7670 independent reflections
Radiation source: SuperNova (Mo) X-ray Source 5463 reflections with I > 2σ(I)
Mirror monochromator Rint = 0.016
Detector resolution: 16.0107 pixels mm-1 θmax = 30.6°, θmin = 2.5°
ω scans h = −8→9
Absorption correction: analytical [CrysAlis PRO (Agilent, 2013), based on expressions derived by Clark & Reid (1995)] k = −19→20
Tmin = 0.990, Tmax = 0.998 l = −23→23
13976 measured reflections
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Refinement

Refinement on F2 Primary atom site location: structure-invariant direct methods
Least-squares matrix: full Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.053 H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.148 w = 1/[σ2(Fo2) + (0.0537P)2 + 0.3588P] where P = (Fo2 + 2Fc2)/3
S = 1.05 (Δ/σ)max = 0.001
7670 reflections Δρmax = 0.36 e Å−3
364 parameters Δρmin = −0.26 e Å−3
3 restraints
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Special details

Experimental. Absorption correction: [CrysAlisPro (Agilent, 2013). Analytical numeric absorption correction using a multifaceted crystal model based on expressions derived by Clark & Reid (1995)
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.
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Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq Occ. (<1)
N26 0.4579 (2) 0.58797 (10) 0.29818 (9) 0.0368 (3)
H26 0.5168 0.5282 0.2794 0.044*
O15 1.50948 (17) 0.80964 (8) 0.69521 (7) 0.0345 (3)
O23 0.98187 (18) 0.57258 (8) 0.43787 (8) 0.0419 (3)
C33 −0.5511 (2) 0.30398 (12) −0.11261 (10) 0.0345 (4)
H33A −0.6504 0.3164 −0.0691 0.041*
H33B −0.5519 0.3632 −0.1305 0.041*
C28 0.1978 (2) 0.49429 (12) 0.17862 (10) 0.0333 (3)
H28A 0.2024 0.4347 0.1960 0.040*
H28B 0.2944 0.4832 0.1342 0.040*
C27 0.2593 (2) 0.59363 (13) 0.25821 (10) 0.0367 (4)
H27A 0.2598 0.6531 0.2406 0.044*
H27B 0.1607 0.6061 0.3021 0.044*
C35 −0.8237 (3) 0.20232 (12) −0.23541 (10) 0.0364 (4)
H35A −0.8320 0.2614 −0.2534 0.044*
H35B −0.9211 0.2122 −0.1915 0.044*
O25 0.4853 (2) 0.75915 (9) 0.38872 (8) 0.0472 (3)
C31 −0.2796 (2) 0.40101 (12) 0.01197 (10) 0.0333 (3)
H31A −0.3782 0.4129 0.0558 0.040*
H31B −0.2810 0.4607 −0.0053 0.040*
C7 2.0845 (2) 0.78185 (12) 0.79254 (10) 0.0327 (3)
C30 −0.0726 (2) 0.39840 (12) 0.05502 (10) 0.0337 (3)
H30A 0.0267 0.3889 0.0119 0.040*
H30B −0.0698 0.3374 0.0707 0.040*
O3 2.54720 (19) 0.71434 (9) 0.87183 (8) 0.0418 (3)
C32 −0.3442 (2) 0.30171 (12) −0.06881 (10) 0.0348 (4)
H32A −0.3433 0.2421 −0.0514 0.042*
H32B −0.2450 0.2897 −0.1124 0.042*
C12 2.0006 (3) 0.87875 (12) 0.82186 (10) 0.0365 (4)
H12 2.0747 0.9378 0.8653 0.044*
N6 2.3818 (2) 0.85718 (11) 0.90254 (9) 0.0388 (3)
N4 2.3705 (2) 0.68521 (11) 0.81288 (9) 0.0389 (3)
C29 −0.0119 (2) 0.49672 (12) 0.13743 (10) 0.0339 (3)
H29A −0.1090 0.5053 0.1813 0.041*
H29B −0.0178 0.5580 0.1222 0.041*
C10 1.7059 (2) 0.80337 (12) 0.72431 (10) 0.0311 (3)
C34 −0.6142 (2) 0.20383 (12) −0.19294 (10) 0.0357 (4)
H34A −0.5177 0.1933 −0.2374 0.043*
H34B −0.6067 0.1444 −0.1754 0.043*
C8 1.9776 (2) 0.69561 (12) 0.72722 (10) 0.0323 (3)
H8 2.0353 0.6295 0.7065 0.039*
N22 0.7992 (2) 0.55954 (11) 0.38631 (9) 0.0413 (4)
C9 1.7885 (2) 0.70490 (12) 0.69204 (10) 0.0314 (3)
C24 0.5515 (2) 0.67201 (12) 0.36269 (10) 0.0331 (3)
C36 −0.8799 (3) 0.10077 (13) −0.31550 (11) 0.0409 (4)
H36A −0.7808 0.0904 −0.3588 0.049*
H36B −0.8732 0.0420 −0.2971 0.049*
C18 1.2226 (2) 0.70293 (12) 0.53997 (10) 0.0337 (3)
H18A 1.3308 0.6702 0.5025 0.040*
H18B 1.2189 0.6737 0.5849 0.040*
C20 0.8824 (2) 0.73138 (12) 0.46614 (10) 0.0313 (3)
H20 0.8742 0.8051 0.4895 0.038*
C5 2.2806 (2) 0.77262 (12) 0.83423 (10) 0.0329 (3)
C21 0.7448 (2) 0.65460 (12) 0.40427 (10) 0.0309 (3)
C11 1.8104 (3) 0.89102 (12) 0.78886 (10) 0.0354 (4)
C37 −1.0859 (3) 0.09851 (13) −0.35931 (10) 0.0387 (4)
H37A −1.1872 0.1026 −0.3181 0.046*
H37B −1.0970 0.1597 −0.3744 0.046*
C17 1.2696 (3) 0.82027 (12) 0.58603 (11) 0.0380 (4)
H17A 1.2454 0.8517 0.5428 0.046*
H17B 1.1780 0.8511 0.6326 0.046*
C19 1.0283 (2) 0.67627 (12) 0.48446 (10) 0.0314 (3)
C16 1.4831 (3) 0.84709 (13) 0.62690 (11) 0.0380 (4)
H16A 1.5766 0.8139 0.5817 0.046*
H16B 1.5111 0.9236 0.6519 0.046*
C2 2.5404 (3) 0.81666 (13) 0.92158 (11) 0.0374 (4)
C13 1.6694 (3) 0.61197 (12) 0.62341 (11) 0.0401 (4)
H13A 1.5376 0.6064 0.6431 0.060*
H13B 1.7401 0.5484 0.6146 0.060*
H13C 1.6528 0.6205 0.5678 0.060*
C1 2.7090 (3) 0.86781 (15) 0.98960 (12) 0.0469 (4)
H1A 2.7096 0.8402 1.0350 0.070*
H1B 2.6934 0.9433 1.0165 0.070*
H1C 2.8354 0.8537 0.9623 0.070*
C14 1.7185 (3) 0.99591 (13) 0.82549 (12) 0.0475 (5)
H14A 1.7798 1.0371 0.8854 0.071*
H14B 1.5742 0.9857 0.8268 0.071*
H14C 1.7419 1.0330 0.7880 0.071*
O100 −1.4973 (6) −0.0308 (2) −0.5193 (2) 0.0642 (9) 0.5
H10A −1.586 (8) 0.012 (4) −0.504 (4) 0.096* 0.5
H10B −1.503 (9) −0.0960 (10) −0.548 (3) 0.096* 0.5
O38 −1.1236 (2) 0.00445 (10) −0.43770 (9) 0.0517 (4)
H38 −1.238 (2) 0.006 (2) −0.4585 (15) 0.077*
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Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
N26 0.0317 (8) 0.0351 (7) 0.0377 (7) 0.0030 (6) −0.0097 (6) 0.0109 (6)
O15 0.0290 (6) 0.0373 (6) 0.0372 (6) 0.0034 (5) −0.0018 (5) 0.0159 (5)
O23 0.0362 (7) 0.0310 (6) 0.0464 (7) 0.0040 (5) −0.0147 (5) 0.0066 (5)
C33 0.0279 (8) 0.0327 (8) 0.0349 (8) 0.0021 (6) −0.0032 (6) 0.0067 (6)
C28 0.0285 (8) 0.0344 (8) 0.0335 (8) 0.0024 (6) −0.0040 (6) 0.0114 (6)
C27 0.0296 (9) 0.0393 (9) 0.0353 (8) 0.0039 (7) −0.0063 (7) 0.0109 (7)
C35 0.0291 (8) 0.0341 (8) 0.0362 (8) 0.0043 (7) −0.0038 (7) 0.0055 (6)
O25 0.0417 (7) 0.0386 (6) 0.0514 (7) 0.0096 (6) −0.0092 (6) 0.0104 (5)
C31 0.0280 (8) 0.0327 (8) 0.0331 (8) 0.0018 (6) −0.0032 (6) 0.0084 (6)
C7 0.0304 (8) 0.0343 (8) 0.0336 (8) 0.0039 (6) 0.0003 (6) 0.0145 (6)
C30 0.0291 (8) 0.0341 (8) 0.0335 (8) 0.0019 (6) −0.0024 (6) 0.0102 (6)
O3 0.0372 (7) 0.0394 (6) 0.0455 (7) 0.0085 (5) −0.0034 (5) 0.0150 (5)
C32 0.0298 (9) 0.0353 (8) 0.0314 (8) 0.0017 (7) −0.0030 (6) 0.0064 (6)
C12 0.0367 (9) 0.0308 (8) 0.0366 (8) 0.0010 (7) −0.0048 (7) 0.0098 (6)
N6 0.0373 (8) 0.0369 (7) 0.0375 (7) 0.0054 (6) −0.0039 (6) 0.0114 (6)
N4 0.0345 (8) 0.0379 (7) 0.0417 (7) 0.0047 (6) −0.0034 (6) 0.0147 (6)
C29 0.0281 (8) 0.0343 (8) 0.0329 (8) 0.0011 (6) −0.0047 (6) 0.0086 (6)
C10 0.0285 (8) 0.0327 (8) 0.0316 (7) 0.0034 (6) −0.0004 (6) 0.0133 (6)
C34 0.0293 (8) 0.0344 (8) 0.0328 (8) 0.0055 (7) −0.0035 (6) 0.0038 (6)
C8 0.0329 (9) 0.0300 (7) 0.0334 (8) 0.0051 (6) 0.0029 (6) 0.0120 (6)
N22 0.0348 (8) 0.0352 (7) 0.0421 (8) 0.0040 (6) −0.0131 (6) 0.0067 (6)
C9 0.0326 (9) 0.0304 (7) 0.0302 (7) 0.0017 (6) 0.0009 (6) 0.0116 (6)
C24 0.0301 (8) 0.0370 (8) 0.0314 (7) 0.0006 (7) −0.0029 (6) 0.0141 (6)
C36 0.0328 (9) 0.0357 (8) 0.0389 (9) 0.0042 (7) −0.0078 (7) 0.0013 (7)
C18 0.0278 (8) 0.0345 (8) 0.0339 (8) 0.0029 (6) −0.0032 (6) 0.0099 (6)
C20 0.0287 (8) 0.0297 (7) 0.0320 (7) 0.0015 (6) −0.0006 (6) 0.0095 (6)
C5 0.0321 (9) 0.0341 (8) 0.0334 (8) 0.0039 (7) 0.0025 (6) 0.0147 (6)
C21 0.0277 (8) 0.0329 (8) 0.0294 (7) 0.0026 (6) −0.0012 (6) 0.0106 (6)
C11 0.0355 (9) 0.0298 (7) 0.0373 (8) 0.0041 (7) −0.0022 (7) 0.0110 (6)
C37 0.0308 (9) 0.0386 (9) 0.0355 (8) 0.0003 (7) −0.0039 (7) 0.0049 (7)
C17 0.0330 (9) 0.0354 (8) 0.0414 (9) 0.0001 (7) −0.0076 (7) 0.0134 (7)
C19 0.0292 (8) 0.0302 (7) 0.0302 (7) 0.0025 (6) −0.0008 (6) 0.0082 (6)
C16 0.0351 (9) 0.0383 (8) 0.0413 (9) −0.0027 (7) −0.0082 (7) 0.0192 (7)
C2 0.0366 (9) 0.0378 (8) 0.0367 (8) 0.0060 (7) 0.0005 (7) 0.0143 (7)
C13 0.0367 (10) 0.0320 (8) 0.0429 (9) 0.0028 (7) −0.0029 (7) 0.0076 (7)
C1 0.0397 (10) 0.0508 (10) 0.0451 (10) 0.0044 (8) −0.0072 (8) 0.0164 (8)
C14 0.0488 (12) 0.0321 (8) 0.0512 (10) 0.0087 (8) −0.0088 (9) 0.0085 (7)
O100 0.0418 (18) 0.0401 (18) 0.085 (3) −0.0014 (17) −0.0171 (18) 0.0032 (16)
O38 0.0355 (7) 0.0480 (7) 0.0479 (7) −0.0014 (6) −0.0147 (6) −0.0013 (6)
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Geometric parameters (Å, º)

N26—H26 0.8800 C10—C9 1.406 (2)
N26—C27 1.4614 (19) C10—C11 1.394 (2)
N26—C24 1.3352 (19) C34—H34A 0.9900
O15—C10 1.3854 (18) C34—H34B 0.9900
O15—C16 1.4356 (19) C8—H8 0.9500
O23—N22 1.4056 (17) C8—C9 1.387 (2)
O23—C19 1.3591 (18) N22—C21 1.308 (2)
C33—H33A 0.9900 C9—C13 1.504 (2)
C33—H33B 0.9900 C24—C21 1.494 (2)
C33—C32 1.525 (2) C36—H36A 0.9900
C33—C34 1.521 (2) C36—H36B 0.9900
C28—H28A 0.9900 C36—C37 1.506 (2)
C28—H28B 0.9900 C18—H18A 0.9900
C28—C27 1.507 (2) C18—H18B 0.9900
C28—C29 1.524 (2) C18—C17 1.523 (2)
C27—H27A 0.9900 C18—C19 1.487 (2)
C27—H27B 0.9900 C20—H20 0.9500
C35—H35A 0.9900 C20—C21 1.412 (2)
C35—H35B 0.9900 C20—C19 1.349 (2)
C35—C34 1.520 (2) C11—C14 1.510 (2)
C35—C36 1.522 (2) C37—H37A 0.9900
O25—C24 1.2242 (19) C37—H37B 0.9900
C31—H31A 0.9900 C37—O38 1.4329 (19)
C31—H31B 0.9900 C17—H17A 0.9900
C31—C30 1.521 (2) C17—H17B 0.9900
C31—C32 1.520 (2) C17—C16 1.510 (2)
C7—C12 1.391 (2) C16—H16A 0.9900
C7—C8 1.394 (2) C16—H16B 0.9900
C7—C5 1.473 (2) C2—C1 1.481 (2)
C30—H30A 0.9900 C13—H13A 0.9800
C30—H30B 0.9900 C13—H13B 0.9800
C30—C29 1.521 (2) C13—H13C 0.9800
O3—N4 1.4194 (18) C1—H1A 0.9800
O3—C2 1.339 (2) C1—H1B 0.9800
C32—H32A 0.9900 C1—H1C 0.9800
C32—H32B 0.9900 C14—H14A 0.9800
C12—H12 0.9500 C14—H14B 0.9800
C12—C11 1.392 (2) C14—H14C 0.9800
N6—C5 1.387 (2) O100—O100i 0.847 (5)
N6—C2 1.293 (2) O100—H10A 0.834 (10)
N4—C5 1.304 (2) O100—H10B 0.841 (10)
C29—H29A 0.9900 O38—H38 0.819 (10)
C29—H29B 0.9900
C27—N26—H26 119.5 C8—C9—C10 118.41 (14)
C24—N26—H26 119.5 C8—C9—C13 121.52 (14)
C24—N26—C27 121.03 (13) N26—C24—C21 116.22 (14)
C10—O15—C16 115.72 (13) O25—C24—N26 123.45 (15)
C19—O23—N22 109.09 (11) O25—C24—C21 120.32 (14)
H33A—C33—H33B 107.7 C35—C36—H36A 108.9
C32—C33—H33A 108.9 C35—C36—H36B 108.9
C32—C33—H33B 108.9 H36A—C36—H36B 107.7
C34—C33—H33A 108.9 C37—C36—C35 113.23 (14)
C34—C33—H33B 108.9 C37—C36—H36A 108.9
C34—C33—C32 113.38 (13) C37—C36—H36B 108.9
H28A—C28—H28B 107.9 H18A—C18—H18B 107.8
C27—C28—H28A 109.1 C17—C18—H18A 109.1
C27—C28—H28B 109.1 C17—C18—H18B 109.1
C27—C28—C29 112.36 (13) C19—C18—H18A 109.1
C29—C28—H28A 109.1 C19—C18—H18B 109.1
C29—C28—H28B 109.1 C19—C18—C17 112.46 (13)
N26—C27—C28 111.29 (13) C21—C20—H20 127.9
N26—C27—H27A 109.4 C19—C20—H20 127.9
N26—C27—H27B 109.4 C19—C20—C21 104.27 (13)
C28—C27—H27A 109.4 N6—C5—C7 121.88 (14)
C28—C27—H27B 109.4 N4—C5—C7 123.71 (14)
H27A—C27—H27B 108.0 N4—C5—N6 114.37 (14)
H35A—C35—H35B 107.8 N22—C21—C24 120.05 (14)
C34—C35—H35A 109.1 N22—C21—C20 112.71 (14)
C34—C35—H35B 109.1 C20—C21—C24 127.21 (14)
C34—C35—C36 112.48 (13) C12—C11—C10 118.13 (14)
C36—C35—H35A 109.1 C12—C11—C14 120.24 (15)
C36—C35—H35B 109.1 C10—C11—C14 121.58 (15)
H31A—C31—H31B 107.7 C36—C37—H37A 109.6
C30—C31—H31A 108.8 C36—C37—H37B 109.6
C30—C31—H31B 108.8 H37A—C37—H37B 108.1
C32—C31—H31A 108.8 O38—C37—C36 110.40 (13)
C32—C31—H31B 108.8 O38—C37—H37A 109.6
C32—C31—C30 113.69 (13) O38—C37—H37B 109.6
C12—C7—C8 119.31 (15) C18—C17—H17A 109.1
C12—C7—C5 118.79 (14) C18—C17—H17B 109.1
C8—C7—C5 121.86 (14) H17A—C17—H17B 107.8
C31—C30—H30A 108.9 C16—C17—C18 112.46 (14)
C31—C30—H30B 108.9 C16—C17—H17A 109.1
C31—C30—C29 113.32 (13) C16—C17—H17B 109.1
H30A—C30—H30B 107.7 O23—C19—C18 115.49 (13)
C29—C30—H30A 108.9 C20—C19—O23 109.31 (13)
C29—C30—H30B 108.9 C20—C19—C18 135.17 (14)
C2—O3—N4 106.40 (12) O15—C16—C17 108.21 (14)
C33—C32—H32A 108.8 O15—C16—H16A 110.1
C33—C32—H32B 108.8 O15—C16—H16B 110.1
C31—C32—C33 113.98 (13) C17—C16—H16A 110.1
C31—C32—H32A 108.8 C17—C16—H16B 110.1
C31—C32—H32B 108.8 H16A—C16—H16B 108.4
H32A—C32—H32B 107.7 O3—C2—C1 117.70 (15)
C7—C12—H12 119.3 N6—C2—O3 113.45 (15)
C7—C12—C11 121.41 (15) N6—C2—C1 128.85 (16)
C11—C12—H12 119.3 C9—C13—H13A 109.5
C2—N6—C5 102.68 (13) C9—C13—H13B 109.5
C5—N4—O3 103.10 (12) C9—C13—H13C 109.5
C28—C29—H29A 109.0 H13A—C13—H13B 109.5
C28—C29—H29B 109.0 H13A—C13—H13C 109.5
C30—C29—C28 112.80 (13) H13B—C13—H13C 109.5
C30—C29—H29A 109.0 C2—C1—H1A 109.5
C30—C29—H29B 109.0 C2—C1—H1B 109.5
H29A—C29—H29B 107.8 C2—C1—H1C 109.5
O15—C10—C9 117.88 (13) H1A—C1—H1B 109.5
O15—C10—C11 120.18 (14) H1A—C1—H1C 109.5
C11—C10—C9 121.74 (14) H1B—C1—H1C 109.5
C33—C34—H34A 108.7 C11—C14—H14A 109.5
C33—C34—H34B 108.7 C11—C14—H14B 109.5
C35—C34—C33 114.39 (13) C11—C14—H14C 109.5
C35—C34—H34A 108.7 H14A—C14—H14B 109.5
C35—C34—H34B 108.7 H14A—C14—H14C 109.5
H34A—C34—H34B 107.6 H14B—C14—H14C 109.5
C7—C8—H8 119.5 O100i—O100—H10A 45 (5)
C9—C8—C7 120.98 (14) O100i—O100—H10B 166 (4)
C9—C8—H8 119.5 H10A—O100—H10B 132 (6)
C21—N22—O23 104.61 (12) C37—O38—H38 107.1 (18)
C10—C9—C13 120.03 (14)
N26—C24—C21—N22 −9.9 (2) C34—C33—C32—C31 −179.60 (14)
N26—C24—C21—C20 172.31 (15) C34—C35—C36—C37 −179.10 (15)
O15—C10—C9—C8 −173.62 (14) C8—C7—C12—C11 1.5 (3)
O15—C10—C9—C13 4.2 (2) C8—C7—C5—N6 −176.35 (15)
O15—C10—C11—C12 174.16 (14) C8—C7—C5—N4 1.3 (3)
O15—C10—C11—C14 −3.2 (3) N22—O23—C19—C18 −177.78 (14)
O23—N22—C21—C24 −178.41 (14) N22—O23—C19—C20 0.63 (18)
O23—N22—C21—C20 −0.32 (19) C9—C10—C11—C12 −0.6 (2)
C27—N26—C24—O25 −4.6 (3) C9—C10—C11—C14 −177.98 (16)
C27—N26—C24—C21 174.35 (14) C24—N26—C27—C28 171.58 (14)
C27—C28—C29—C30 177.88 (14) C36—C35—C34—C33 179.91 (15)
C35—C36—C37—O38 175.68 (15) C18—C17—C16—O15 −64.32 (18)
O25—C24—C21—N22 169.10 (16) C5—C7—C12—C11 −175.97 (15)
O25—C24—C21—C20 −8.7 (3) C5—C7—C8—C9 176.58 (15)
C31—C30—C29—C28 −178.56 (14) C5—N6—C2—O3 −0.4 (2)
C7—C12—C11—C10 −0.8 (3) C5—N6—C2—C1 179.90 (18)
C7—C12—C11—C14 176.62 (17) C21—C20—C19—O23 −0.78 (18)
C7—C8—C9—C10 −0.5 (2) C21—C20—C19—C18 177.18 (18)
C7—C8—C9—C13 −178.27 (15) C11—C10—C9—C8 1.2 (2)
C30—C31—C32—C33 −179.69 (14) C11—C10—C9—C13 179.01 (15)
O3—N4—C5—C7 −178.08 (14) C17—C18—C19—O23 176.76 (14)
O3—N4—C5—N6 −0.30 (19) C17—C18—C19—C20 −1.1 (3)
C32—C33—C34—C35 177.44 (14) C19—O23—N22—C21 −0.18 (18)
C32—C31—C30—C29 −178.21 (14) C19—C18—C17—C16 −168.20 (14)
C12—C7—C8—C9 −0.8 (2) C19—C20—C21—N22 0.69 (19)
C12—C7—C5—N6 1.1 (2) C19—C20—C21—C24 178.63 (16)
C12—C7—C5—N4 178.67 (16) C16—O15—C10—C9 −100.42 (16)
N4—O3—C2—N6 0.2 (2) C16—O15—C10—C11 84.64 (18)
N4—O3—C2—C1 179.98 (15) C2—O3—N4—C5 0.04 (17)
C29—C28—C27—N26 178.10 (14) C2—N6—C5—C7 178.26 (15)
C10—O15—C16—C17 164.12 (13) C2—N6—C5—N4 0.4 (2)
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Symmetry code: (i) −x−3, −y, −z−1.

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A
C28—H28A···O3ii 0.99 2.64 3.2567 (19) 120
C20—H20···O38iii 0.95 2.56 3.505 (2) 175
C13—H13B···O23ii 0.98 2.51 3.416 (2) 154
C1—H1B···N6 0.98 2.65 3.622 (2) 174
O100—H10B···O25iv 0.84 (1) 1.87 (1) 2.710 (3) 180 (6)
O38—H38···O100 0.82 (1) 1.90 (1) 2.695 (4) 164 (2)
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Symmetry codes: (ii) −x+3, −y+1, −z+1; (iii) x+2, y+1, z+1; (iv) x−2, y−1, z−1.

References

  1. Agilent (2013). CrysAlis PRO. Agilent Technologies Ltd, Yarnton, Oxfordshire, England.
  2. Clark, R. C. & Reid, J. S. (1995). Acta Cryst. A51, 887–897.
  3. Coste, S., Schneider, J. M., Petit, M. N. & Coquerel, G. (2004). Cryst. Growth Des. 4, 1237–1244.
  4. De Palma, A. M., Vliegen, I., Clercq, E. D. & Neyts, I. (2008). Med. Res. Rev. 28, 823–884. [DOI] [PubMed]
  5. Diana, G. D. (2003). Curr. Med. Chem. 2, 1–12.
  6. Diana, G. D., Rudewicz, P., Pevear, D. C., Nitz, T. J., Aldous, S. C., Aldous, D. J., Robinson, D. T., Draper, T., Dutko, F. J., Aldi, C., Gendron, G., Oglesby, R. C., Volkots, D. L., Reuman, M., Bailey, T. R., Czerniak, R., Block, T., Roland, R. & Opperman, J. (1995). J. Med. Chem. 38, 1355–1371. [DOI] [PubMed]
  7. Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341.
  8. Giranda, V. L., Russo, G. R., Felock, P. J., Bailey, T. R., Draper, T., Aldous, D. J., Guiles, J., Dutko, F. J., Diana, G. D., Pevear, D. C. & McMillan, M. (1995). Acta Cryst. D51, 496–503. [DOI] [PubMed]
  9. Groom, C. R. & Allen, F. H. (2014). Angew. Chem. Int. Ed. 53, 662–671. [DOI] [PubMed]
  10. Pevear, D. C., Tull, T. M., Seipel, M. E. & Groarke, J. M. (1999). Antimicrob. Agents Chemother. 43, 2109–2115. [DOI] [PMC free article] [PubMed]
  11. Reisdorph, N., Thomas, J. J., Katpally, U., Chase, E., Harris, K., Siuzdak, G. & Smith, T. J. (2003). Virology, 314, 34–44. [DOI] [PubMed]
  12. Salorinne, K., Lahtinen, T., Marjomäki, V. & Häkkinen, H. (2014). CrystEngComm, 16, 9001–9009.
  13. Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [DOI] [PubMed]
  14. Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8.
  15. Thibaut, H. J., De Palma, A. M. & Neyts, J. (2012). Biochem. Pharmacol. 83, 185–192. [DOI] [PubMed]
  16. Wildenbeest, J. G., van den Broek, P. J., Benschop, K. S. M., Koen, G., Wierenga, P. C., Vossen, A. C. T. M., Kuijpers, T. W. & Wolthers, K. C. (2012). Antiviral Ther. 17, 459–466. [DOI] [PubMed]
  17. Zhang, Y., Simpson, A. A., Ledford, R. M., Bator, C. M., Chakravarty, S., Skochko, G. A., Demenczuk, T. M., Watanyar, A., Pevear, D. C. & Rossmann, M. G. (2004). J. Virol. 78, 11061–11069. [DOI] [PMC free article] [PubMed]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989015007367/lh5758sup1.cif

e-71-00505-sup1.cif (487.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989015007367/lh5758Isup2.hkl

e-71-00505-Isup2.hkl (420.1KB, hkl)
Click here for additional data file. (11.6KB, cml)

Supporting information file. DOI: 10.1107/S2056989015007367/lh5758Isup3.cml

CCDC reference: 1059505

Additional supporting information: crystallographic information; 3D view; checkCIF report

Enhanced figure: interactive version of Fig. 3

Articles from Acta Crystallographica Section E: Crystallographic Communications are provided here courtesy of International Union of Crystallography

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