The title compound, a new inhibitor of the Hepatitis B virus (HBV), was prepared via alkylation of 3-(chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole in anhydrous dioxane in the presence of triethylamine.
Keywords: crystal structure; 2H-1,2,6-thiadiazine 1,1-dioxide; hepatitis B; HBV; hydrogen bonding; Hirshfeld surface analysis; molecular docking study
Abstract
The title compound, C15H22N4O5S, was prepared via alkylation of 3-(chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole in anhydrous dioxane in the presence of triethylamine. The thiadiazine ring has an envelope conformation with the S atom displaced by 0.4883 (6) Å from the mean plane through the other five atoms. The planar 1,2,4-oxadiazole ring is inclined to the mean plane of the thiadiazine ring by 77.45 (11)°. In the crystal, molecules are linked by C—H⋯N hydrogen bonds, forming chains propagating along the b-axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots have been used to analyse the intermolecular contacts present in the crystal. Molecular docking studies were use to evaluate the title compound as a potential system that interacts effectively with the capsid of the Hepatitis B virus (HBV), supported by an experimental in vitro HBV replication model.
Chemical context
Derivatives of 2H-1,2,6-thiadiazine 1,1-dioxide demonstrate antiviral (Martínez et al., 1999 ▸; Esteban et al., 1997 ▸, 1995 ▸), cannabinoid (Cano et al., 2007 ▸), antidiabetic (Goyal & Bhargava, 1989 ▸; Jain & Malik, 1983 ▸), anti-HIV-1 (Breining et al., 1995 ▸) and antiparasitic (Arán et al., 1986 ▸) activities. In addition, such derivatives are patent protected as pain relievers and antipyretic drugs (Giraldez et al., 1989 ▸). Heterocyclic homologues of 2H-1,2,6-thiadiazine-1,1-dioxides are inhibitors of human cytomegalovirus (Martínez et al., 2003 ▸), Cruzi triposome (Álvarez et al., 2010 ▸) and diuretics (Goya et al., 1992 ▸). In a continuation of our efforts to obtain new HBV inhibitors for the treatment and prevention of human HBV infections (Ivachtchenko et al., 2019 ▸; Ivashchenko et al., 2019 ▸; Kovalenko et al., 2019 ▸), we initiated the design, synthesis, and anti-hepatitis B virus activity testing of the new 2H-1,2,6-thiadiazine 1,1-dioxide derivative, ethyl 5-methyl-1,1-dioxo-2-{[5-(pentan-3-yl)-1,2,4-oxadiazol-3-yl]methyl}-2H-1,2,6-thiadiazine-4-carboxylate (3).
One of the main methods of 2H-1,2,6-thiadiazine 1,1-dioxide synthesis is the intermolecular cyclization of sulfamide with the corresponding 1,3-diketone (Cheone, 2001 ▸; Alberola et al., 1991 ▸), as shown in Fig. 1 ▸. The synthesis of the title compound (3) is illustrated in Fig. 2 ▸. The starting product 1 was converted to compound 3 by alkylation of 3-(chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole (2) in anhydrous dioxane in the presence of triethylamine.
Figure 1.
Synthesis of 2H-1,2,6-thiadiazine 1,1-dioxide via intermolecular cyclization of sulfamide with the corresponding 1,3-diketone.
Figure 2.
Synthesis of the title compound 3.
Single-crystal X-ray diffraction analysis and different spectroscopic techniques confirm the assigned chemical structure of the title compound. Molecular docking simulations were also carried out.
Structural commentary
The molecular structure of compound 3, is illustrated in Fig. 3 ▸. The thiadazine ring (S1/N3/N4/C4–C6) has an envelope conformation [puckering parameters: amplitude Q = 0.3314 (17) Å, θ = 114.2 (3)°, φ = 182.5 (4)°], with atom S1 displaced by 0.4883 (6) Å from the mean plane through the other five atoms. The planar 1,2,4-oxadiazole ring (O1/N1/N2/C1/C2; r.m.s. deviation = 0.008 Å) is inclined to the mean plane of the thiadiazine ring by 77.45 (11)°. The oxadiazole ring is almost normal to the C4—N3 endocyclic bond, with the C4—N3—C3—C2 torsion angle being 92.4 (3)°, and it is twisted with respect to the N3-C3 exocyclic bond, with the N3—C3—C2—N2 torsion angle being 127.1 (2)°. The ester substituent is not completely planar and it is twisted in relation to the C4—C5 endocyclic bond; the C4—C5—C8—O4 torsion angle is 23.7 (4)° as a result of steric repulsion between the hydrogen atom of the thiadiazine-dioxide ring and the oxygen atom of the ester substituent. The iso-pentyl group has an all-trans conformation [the C13—C12—C11—C14 and C12—C11—C14—C15 torsion angles are 173.4 (3) and −175.5 (3)°, respectively] and is oriented in such a way that the N1—C1—C11—H11 torsion angle is −6.7°. The ethyl groups of this substituent have -sc and +sc-conformations in relation to the C1—C11 bond [C1—C11—C12—C13 = −62.4 (3)° and C1—C11—C14—C15 = 61.6 (4)°].
Figure 3.
The molecular structure of compound 3, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.
Supramolecular features
In the crystal, molecules are linked by C—H⋯N hydrogen bonds, forming chains propagating along the b-axis direction (Table 1 ▸ and Fig. 4 ▸). There are no other significant intermolecular interactions present in the crystal.
Table 1. Hydrogen-bond geometry (Å, °).
| D—H⋯A | D—H | H⋯A | D⋯A | D—H⋯A |
|---|---|---|---|---|
| C4—H4⋯N2i | 0.93 | 2.54 | 3.431 (3) | 161 |
Symmetry code: (i) 
.
Figure 4.
A partial view along the a axis of the crystal packing of compound 3. Hydrogen bonds (Table 1 ▸) are shown as dashed lines.
Database survey
A search of the Cambridge Structural Database (CSD, Version 5.40, August 2019; Groom et al., 2016 ▸) for the 1,2,6-thiadiazine 1,1-dioxide skeleton yielded 37 hits. Only one structure involves a carboxylate in position 4, viz. methyl 2,3-dimethyl-5-(trichloromethyl)-2H-1,2,6-thiadiazine-4-carboxylate-1,1-dioxide (CSD refcode ZECWAI; Onys’ko et al., 2017 ▸). The thiadiazine ring has the usual envelope conformation with the S atom displaced by 0.679 (1) Å from the mean plane through the other five atoms [cf. 0.488 (1) Å in the title compound]. The acetate group is inclined to this mean plane by 51.3 (2)° compared to 28.98 (18)° in the title compound.
Hirshfeld surface analysis
The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009 ▸) and the associated two-dimensional fingerprint plots (McKinnon et al., 2007 ▸) were performed with CrystalExplorer17 (Turner et al., 2017 ▸). The molecular Hirshfeld surfaces were obtained using a standard (high) surface resolution with the three-dimensional d norm surface (Fig. 5 ▸), mapped over a fixed colour scale of −0.484 (red) to 1.652 (blue). There are four red spots in the d norm surface indicating the regions of donor–acceptor interactions or short contacts. A list of short contacts in the crystal of compound 3 are given in Table 2 ▸.
Figure 5.
The Hirshfeld surface of compound 3, mapped over d norm, with a fixed colour scale of −0.484 to 1.652 a.u.
Table 2. Short contacts (Å) in the crystal of compound 3 .
| Atom1⋯Atom2 | Length | Length – vdW |
|---|---|---|
| S1.·H7B i | 3.090 | 0.090 |
| O2⋯H7B i | 2.813 | 0.093 |
| H7A⋯O4i | 2.687 | −0.033 |
| H12B⋯N2ii | 2.772 | 0.022 |
| O4⋯H14A iii | 2.700 | −0.020 |
| C8⋯H14A iii | 2.913 | 0.013 |
| C6⋯H10B iv | 2.978 | 0.078 |
| O2⋯C3v | 3.275 | 0.055 |
| O2⋯H3A v | 2.634 | −0.086 |
| O3⋯C4v | 3.077 | −0.143 |
| N2⋯H3A v | 2.816 | 0.066 |
| N2⋯HA v | 2.538 | −0.212 |
| H3B⋯O4v | 2.799 | 0.079 |
Symmetry codes: (i) −x + 1, y − 
, −z + ; (ii) x − , −y + , −z + 1; (iii) −x + 1, −y + 1, −z + 1; (iv) −x + , y − , z; (v) −x + 
, y − , z.
The intermolecular interactions in the crystal of the title compound are shown on the two-dimensional fingerprint plots presented in Fig. 6 ▸. The contribution of the O⋯H/H⋯O contacts, corresponding to the C—H⋯O interactions, is represented by a pair of sharp spikes. The interactions appear in the middle of the scattered points in the two-dimensional fingerprint plot with a contribution to the overall Hirshfeld surface of 27.5% (Fig. 6 ▸ c). The fingerprint plots indicate that the principal contributions are from H⋯H (48.7%; Fig. 6 ▸ b), O⋯H/H⋯O (27.5%; Fig. 6 ▸ c), N⋯H/H⋯N (14.9%; Fig. 6 ▸ d) and C⋯H/H⋯C (5.2%; Fig. 6 ▸ e) contacts.
Figure 6.
(a) The two-dimensional fingerprint plot for compound 3, and delineated into (b) H⋯H (48.7%), (c) O⋯H/H⋯O (27.5%), (d) N⋯H/H⋯N (14.9%) and (e) C⋯H/H⋯C (5.2%) contacts.
Molecular docking evaluation
The title molecule (3) was investigated as a potential system that can interact effectively with the capsid of the Hepatitis B virus (HBV). We performed molecular modelling of the interaction of title molecule with core HBV proteins including 5E0I, 5GMZ, 5WRE and 5T2P. The crystal structures of these proteins were obtained at high resolution (1.5–2 Å), all necessary information about the crystal structures being downloaded from the Protein Data bank (Berman et al., 2000 ▸; accessed on 24 July 2019). The pharmacophore model was generated by using the Ligandscout 4.3 program (Wolber & Langer, 2005 ▸; accessed on 24 July 2019). All of the above-mentioned protein structures contain six chains (designated as A, B, C, D, E, F). The docking poses of ligands (reference molecules) were extracted from the obtained crystallographic data. For the correct choice of appropriate chain and poses for molecular modelling (docking), all the reference ligands were re-docked. According to our calculations, the minimal values of the residual mean-square deviations (r.m.s.d.) for the geometry were obtained for poses in the D chains (r.m.s.d. < 1 Å). Hence, the active-site selection and corresponding pharmacophore analyses were performed for the D chains of the above-mentioned proteins. The most significant information is collected in Table 3 ▸.
Table 3. Binding affinity parameters of title molecule with HBV core proteins.
| PDB refcode | Est. binding energy (kcal mol−1) | Binding affinity score |
|---|---|---|
| 5E0I | −14.54 | −25.2 |
| 5GMZ | −14.30 | −14.99 |
| 5WRE | −16.03 | −8.28 |
| 5T2P | −17.05 | −22.34 |
As can be seen from Table 3 ▸, our system demonstrated rather large values of binding affinity for all the proteins. The corresponding graphical representation describes the pharmacophore environment of the ligands (Fig. 7 ▸, left) and poses in proteins (Fig. 7 ▸, right). The red lines designate hydrogen-bond acceptors, while yellow lines designated hydrophobic interactions.
Figure 7.
Calculated docking poses for the complex ‘title molecule–protein’.
It should be noted that the geometrical configuration of the title molecule (as ligand immersed to protein) essentially depends on the pharmacophore surroundings. The most significant geometrical parameters (torsion angles) obtained from the docking procedure are compared with results of the non-empirical calculations and X-ray data in Table 4 ▸. The calculated structure of the title compound is illustrated in Fig. 8 ▸. The ab initio calculations were performed by using density functional theory with M062x functional and cc-pVDZ basis set.
Table 4. Torsion angles (°) comparison for X-ray, ab initio and docking data.
| Torsion angle | X-ray | M062x/cc-pVDZ | 5E0I | 5GMZ | 5WRE | 5T2P |
|---|---|---|---|---|---|---|
| O2—S1—N4—C6 | 83.5 (2) | 78.7 | 93.13 | 93.2 | 93.1 | 137.4 |
| C5—C8—O5—C9 | 178.4 (2) | 178.9 | −112.9 | −79.3 | −110.4 | −163.1 |
| S1—N3—C3—C2 | −71.7 (2) | −71.5 | −148.5 | −126.7 | −172.5 | −80 |
| O1—C1—C11—C14 | 57.8 (3) | 49.9 | 50.1 | −112.9 | 9.8 | 52.8 |
Figure 8.
Calculated structure of the title compound.
The obtained data demonstrate significant geometrical relaxation associated with immersion of the molecule in a protein.
in vitro HBV replication model
The biological activity of the title compound 3 was studied using an experimental in vitro hepatitis B virus infection model maintaining a full virus replication cycle. This model based on the human hepatoma line HepG2 stably transfected with the NTCP gene (Sun et al., 2016 ▸) was developed in our laboratories for identification of viral entry inhibitors able to prevent development of resistant HBV forms (Ivachtchenko et al., 2019b ▸). Compound 3 demonstrated 80% inhibition of HBV replication (in 10 µM concentration) in this model and could be considered to be a promising candidate for the development of a potent anti-HBV medicine capable of preventing the development of resistant HBV forms (Donkers et al., 2017 ▸).
Synthesis and crystallization
The synthesis of the title compound is illustrated in Fig. 2 ▸. 3-(Chloromethyl)-5-(pentan-3-yl)-1,2,4-oxadiazole (2) (1.1 mmol, 208 mg) was added to a solution of ethyl 5-methyl-2H-1,2,6-thiadiazine-4-carboxylate 1,1-dioxide (1) (1.0 mmol, 218 mg) and NEt3 (1.1 mmol) in 1 ml of DXN (2,6-dimethyl-1,3-dioxan-4-yl acetate) and the resulting mixture was heated at 353 K for 12 h. After cooling to room temperature, the solution was diluted with water (50 ml) and extracted with CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo. The product, compound 3, was purified by crystallization from acetonitrile giving a white crystalline powder (yield 308 mg, 83%; m.p. 338–339 K). Further crystallization by slow evaporation of an acetonitrile solution yielded colourless irregularly shaped crystals.
Refinement
Crystal data, data collection and structure refinement details are summarized in Table 5 ▸. H atoms were included in calculated positions and treated as riding on their parent C atom: C—H = 0.93–0.98 Å with U iso(H) = 1.5U eq(C-methyl) and 1.2U eq(C) for other H atoms.
Table 5. Experimental details.
| Crystal data | |
| Chemical formula | C15H22N4O5S |
| M r | 370.42 |
| Crystal system, space group | Orthorhombic, P b c a |
| Temperature (K) | 293 |
| a, b, c (Å) | 12.4962 (5), 9.9237 (4), 29.5925 (15) |
| V (Å3) | 3669.7 (3) |
| Z | 8 |
| Radiation type | Mo Kα |
| μ (mm−1) | 0.21 |
| Crystal size (mm) | 0.4 × 0.2 × 0.1 |
| Data collection | |
| Diffractometer | Rigaku Oxford Diffraction Xcalibur, Sapphire3 |
| Absorption correction | Multi-scan (CrysAlis PRO; Rigaku OD, 2018 ▸) |
| T min, T max | 0.466, 1.000 |
| No. of measured, independent and observed [I > 2σ(I)] reflections | 26547, 3211, 2510 |
| R int | 0.070 |
| (sin θ/λ)max (Å−1) | 0.595 |
| Refinement | |
| R[F 2 > 2σ(F 2)], wR(F 2), S | 0.050, 0.127, 1.06 |
| No. of reflections | 3211 |
| No. of parameters | 230 |
| H-atom treatment | H-atom parameters constrained |
| Δρmax, Δρmin (e Å−3) | 0.24, −0.32 |
Supplementary Material
Crystal structure: contains datablock(s) Global, I. DOI: 10.1107/S2056989019015986/su5529sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989019015986/su5529Isup2.hkl
Supporting information file. DOI: 10.1107/S2056989019015986/su5529Isup3.cml
CCDC reference: 1968398
Additional supporting information: crystallographic information; 3D view; checkCIF report
Acknowledgments
We are grateful to the Ministry of Science and Higher Education of the Russian Federation in the framework of an agreement on reimbursement of costs associated with the development of a platform for biologically active compound libraries design for actual biotargets, including the platform testing on the example of invention and preparation of candidate libraries for HBV treatment designed as inhibitors of viral penetration and assembly of viral core particles.
supplementary crystallographic information
Crystal data
| C15H22N4O5S | Dx = 1.341 Mg m−3 |
| Mr = 370.42 | Mo Kα radiation, λ = 0.71073 Å |
| Orthorhombic, Pbca | Cell parameters from 3271 reflections |
| a = 12.4962 (5) Å | θ = 3.6–23.3° |
| b = 9.9237 (4) Å | µ = 0.21 mm−1 |
| c = 29.5925 (15) Å | T = 293 K |
| V = 3669.7 (3) Å3 | Block, colourless |
| Z = 8 | 0.4 × 0.2 × 0.1 mm |
| F(000) = 1568 |
Data collection
| Rigaku Oxford Diffraction Xcalibur, Sapphire3 diffractometer | 3211 independent reflections |
| Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source | 2510 reflections with I > 2σ(I) |
| Graphite monochromator | Rint = 0.070 |
| Detector resolution: 16.1827 pixels mm-1 | θmax = 25.0°, θmin = 3.0° |
| ω scans | h = −14→14 |
| Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018) | k = −11→11 |
| Tmin = 0.466, Tmax = 1.000 | l = −25→35 |
| 26547 measured reflections |
Refinement
| Refinement on F2 | Primary atom site location: dual |
| Least-squares matrix: full | Secondary atom site location: difference Fourier map |
| R[F2 > 2σ(F2)] = 0.050 | Hydrogen site location: difference Fourier map |
| wR(F2) = 0.127 | H-atom parameters constrained |
| S = 1.06 | w = 1/[σ2(Fo2) + (0.053P)2 + 1.1666P] where P = (Fo2 + 2Fc2)/3 |
| 3211 reflections | (Δ/σ)max < 0.001 |
| 230 parameters | Δρmax = 0.24 e Å−3 |
| 0 restraints | Δρmin = −0.32 e Å−3 |
Special details
| Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. |
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
| x | y | z | Uiso*/Ueq | ||
| S1 | 0.66349 (5) | 0.40561 (6) | 0.31677 (2) | 0.0462 (2) | |
| O1 | 0.74895 (14) | 0.29562 (18) | 0.46836 (6) | 0.0577 (5) | |
| O2 | 0.60666 (16) | 0.31342 (17) | 0.34444 (7) | 0.0646 (6) | |
| O3 | 0.76374 (15) | 0.3626 (2) | 0.30037 (8) | 0.0726 (6) | |
| O4 | 0.47430 (16) | 0.86020 (18) | 0.34934 (7) | 0.0668 (6) | |
| O5 | 0.35185 (14) | 0.7296 (2) | 0.31536 (7) | 0.0654 (6) | |
| N1 | 0.65072 (15) | 0.4628 (2) | 0.44365 (7) | 0.0472 (5) | |
| N2 | 0.80748 (16) | 0.3561 (2) | 0.43291 (8) | 0.0514 (5) | |
| N3 | 0.68614 (14) | 0.54419 (19) | 0.34784 (7) | 0.0415 (5) | |
| N4 | 0.58953 (16) | 0.4585 (2) | 0.27686 (7) | 0.0495 (5) | |
| C1 | 0.65689 (19) | 0.3647 (2) | 0.47179 (9) | 0.0463 (6) | |
| C2 | 0.74512 (17) | 0.4525 (2) | 0.42013 (8) | 0.0402 (5) | |
| C3 | 0.77420 (18) | 0.5405 (2) | 0.38103 (9) | 0.0467 (6) | |
| H3A | 0.788916 | 0.631017 | 0.391704 | 0.056* | |
| H3B | 0.838461 | 0.506142 | 0.366693 | 0.056* | |
| C4 | 0.61014 (18) | 0.6400 (2) | 0.34937 (8) | 0.0427 (6) | |
| H4 | 0.615584 | 0.705875 | 0.371592 | 0.051* | |
| C5 | 0.52574 (18) | 0.6464 (2) | 0.32039 (8) | 0.0412 (6) | |
| C6 | 0.52217 (19) | 0.5588 (2) | 0.28224 (9) | 0.0457 (6) | |
| C7 | 0.4479 (2) | 0.5814 (3) | 0.24327 (10) | 0.0660 (8) | |
| H7A | 0.471161 | 0.528646 | 0.217909 | 0.099* | |
| H7B | 0.448204 | 0.675101 | 0.235238 | 0.099* | |
| H7C | 0.376781 | 0.554846 | 0.251685 | 0.099* | |
| C8 | 0.4500 (2) | 0.7587 (3) | 0.32946 (9) | 0.0497 (6) | |
| C9 | 0.2702 (2) | 0.8316 (4) | 0.32370 (14) | 0.0881 (11) | |
| H9A | 0.275933 | 0.864784 | 0.354432 | 0.106* | |
| H9B | 0.279751 | 0.906902 | 0.303192 | 0.106* | |
| C10 | 0.1671 (3) | 0.7707 (5) | 0.31670 (19) | 0.1275 (19) | |
| H10A | 0.163950 | 0.732718 | 0.286891 | 0.191* | |
| H10B | 0.112282 | 0.837879 | 0.319856 | 0.191* | |
| H10C | 0.156092 | 0.700900 | 0.338674 | 0.191* | |
| C11 | 0.5779 (2) | 0.3135 (3) | 0.50547 (10) | 0.0601 (7) | |
| H11 | 0.517153 | 0.375927 | 0.506023 | 0.072* | |
| C12 | 0.5362 (3) | 0.1749 (3) | 0.49009 (12) | 0.0756 (9) | |
| H12A | 0.596527 | 0.113804 | 0.487578 | 0.091* | |
| H12B | 0.489029 | 0.139689 | 0.513284 | 0.091* | |
| C13 | 0.4770 (3) | 0.1756 (4) | 0.44585 (14) | 0.0939 (12) | |
| H13A | 0.522406 | 0.211801 | 0.422662 | 0.141* | |
| H13B | 0.413982 | 0.230344 | 0.448575 | 0.141* | |
| H13C | 0.456836 | 0.085211 | 0.438077 | 0.141* | |
| C14 | 0.6254 (3) | 0.3084 (3) | 0.55267 (11) | 0.0799 (10) | |
| H14A | 0.572775 | 0.269913 | 0.573035 | 0.096* | |
| H14B | 0.686816 | 0.248710 | 0.552328 | 0.096* | |
| C15 | 0.6597 (3) | 0.4429 (4) | 0.57096 (13) | 0.1016 (13) | |
| H15A | 0.714439 | 0.480074 | 0.551891 | 0.152* | |
| H15B | 0.687317 | 0.431690 | 0.601003 | 0.152* | |
| H15C | 0.599454 | 0.502798 | 0.571657 | 0.152* |
Atomic displacement parameters (Å2)
| U11 | U22 | U33 | U12 | U13 | U23 | |
| S1 | 0.0472 (4) | 0.0396 (4) | 0.0518 (4) | 0.0034 (3) | −0.0079 (3) | 0.0008 (3) |
| O1 | 0.0566 (11) | 0.0612 (11) | 0.0553 (12) | 0.0133 (9) | 0.0089 (9) | 0.0161 (9) |
| O2 | 0.0825 (14) | 0.0438 (10) | 0.0674 (13) | −0.0180 (10) | −0.0177 (11) | 0.0143 (9) |
| O3 | 0.0531 (11) | 0.0764 (13) | 0.0881 (16) | 0.0224 (10) | −0.0045 (11) | −0.0190 (12) |
| O4 | 0.0760 (13) | 0.0518 (11) | 0.0725 (15) | 0.0144 (10) | 0.0007 (11) | −0.0081 (10) |
| O5 | 0.0439 (10) | 0.0727 (13) | 0.0796 (15) | 0.0152 (9) | 0.0022 (9) | −0.0008 (10) |
| N1 | 0.0432 (11) | 0.0428 (11) | 0.0555 (14) | 0.0035 (9) | 0.0051 (10) | 0.0075 (10) |
| N2 | 0.0458 (11) | 0.0587 (13) | 0.0497 (14) | 0.0063 (10) | 0.0053 (10) | 0.0090 (10) |
| N3 | 0.0394 (10) | 0.0387 (11) | 0.0463 (12) | −0.0029 (9) | −0.0046 (9) | 0.0043 (9) |
| N4 | 0.0549 (12) | 0.0466 (12) | 0.0470 (13) | 0.0060 (10) | −0.0082 (10) | −0.0014 (9) |
| C1 | 0.0476 (14) | 0.0438 (14) | 0.0474 (16) | 0.0064 (11) | 0.0042 (11) | 0.0003 (11) |
| C2 | 0.0353 (12) | 0.0417 (12) | 0.0435 (14) | −0.0036 (10) | −0.0049 (10) | −0.0006 (10) |
| C3 | 0.0374 (12) | 0.0491 (14) | 0.0536 (16) | −0.0082 (11) | −0.0061 (11) | 0.0061 (12) |
| C4 | 0.0438 (13) | 0.0377 (12) | 0.0466 (15) | −0.0035 (11) | 0.0052 (11) | 0.0043 (10) |
| C5 | 0.0372 (12) | 0.0410 (13) | 0.0453 (15) | 0.0003 (10) | 0.0036 (10) | 0.0056 (10) |
| C6 | 0.0454 (13) | 0.0421 (13) | 0.0496 (16) | −0.0006 (11) | −0.0025 (11) | 0.0073 (11) |
| C7 | 0.0763 (19) | 0.0634 (17) | 0.0583 (19) | 0.0160 (15) | −0.0215 (15) | −0.0017 (14) |
| C8 | 0.0493 (15) | 0.0527 (15) | 0.0471 (16) | 0.0037 (13) | 0.0046 (12) | 0.0088 (12) |
| C9 | 0.061 (2) | 0.103 (3) | 0.100 (3) | 0.0384 (19) | 0.0100 (18) | 0.008 (2) |
| C10 | 0.0468 (19) | 0.139 (4) | 0.196 (6) | 0.024 (2) | 0.007 (2) | 0.025 (4) |
| C11 | 0.0652 (17) | 0.0544 (16) | 0.0607 (19) | 0.0094 (13) | 0.0206 (14) | 0.0102 (13) |
| C12 | 0.074 (2) | 0.0620 (19) | 0.091 (3) | −0.0053 (16) | 0.0256 (19) | 0.0133 (17) |
| C13 | 0.083 (2) | 0.088 (2) | 0.110 (3) | −0.023 (2) | 0.007 (2) | −0.003 (2) |
| C14 | 0.102 (2) | 0.081 (2) | 0.056 (2) | 0.008 (2) | 0.0207 (18) | 0.0155 (17) |
| C15 | 0.135 (4) | 0.099 (3) | 0.071 (3) | 0.005 (2) | 0.001 (2) | −0.009 (2) |
Geometric parameters (Å, º)
| S1—O2 | 1.4183 (19) | C12—C13 | 1.504 (5) |
| S1—O3 | 1.4097 (19) | C14—C15 | 1.503 (5) |
| S1—N3 | 1.678 (2) | C3—H3A | 0.9700 |
| S1—N4 | 1.589 (2) | C3—H3B | 0.9700 |
| O1—N2 | 1.413 (3) | C4—H4 | 0.9300 |
| O1—C1 | 1.343 (3) | C7—H7A | 0.9600 |
| O4—C8 | 1.205 (3) | C7—H7B | 0.9600 |
| O5—C8 | 1.327 (3) | C7—H7C | 0.9600 |
| O5—C9 | 1.458 (3) | C9—H9A | 0.9700 |
| N1—C1 | 1.283 (3) | C9—H9B | 0.9700 |
| N1—C2 | 1.373 (3) | C10—H10A | 0.9600 |
| N2—C2 | 1.291 (3) | C10—H10B | 0.9600 |
| N3—C3 | 1.476 (3) | C10—H10C | 0.9600 |
| N3—C4 | 1.344 (3) | C11—H11 | 0.9800 |
| N4—C6 | 1.313 (3) | C12—H12A | 0.9700 |
| C1—C11 | 1.492 (4) | C12—H12B | 0.9700 |
| C2—C3 | 1.494 (3) | C13—H13A | 0.9600 |
| C4—C5 | 1.361 (3) | C13—H13B | 0.9600 |
| C5—C6 | 1.425 (3) | C13—H13C | 0.9600 |
| C5—C8 | 1.487 (3) | C14—H14A | 0.9700 |
| C6—C7 | 1.497 (3) | C14—H14B | 0.9700 |
| C9—C10 | 1.439 (5) | C15—H15A | 0.9600 |
| C11—C12 | 1.539 (4) | C15—H15B | 0.9600 |
| C11—C14 | 1.518 (4) | C15—H15C | 0.9600 |
| O2—S1—N3 | 107.26 (11) | N2—C2—C3 | 120.9 (2) |
| O2—S1—N4 | 110.56 (11) | N3—C3—C2 | 110.41 (18) |
| O3—S1—O2 | 116.64 (13) | N3—C4—C5 | 124.0 (2) |
| O3—S1—N3 | 106.67 (11) | C4—C5—C6 | 119.7 (2) |
| O3—S1—N4 | 111.17 (13) | C4—C5—C8 | 114.5 (2) |
| N4—S1—N3 | 103.55 (10) | C6—C5—C8 | 125.5 (2) |
| C1—O1—N2 | 106.41 (17) | N4—C6—C5 | 122.6 (2) |
| C8—O5—C9 | 116.2 (2) | N4—C6—C7 | 114.7 (2) |
| C1—N1—C2 | 102.8 (2) | C5—C6—C7 | 122.6 (2) |
| C2—N2—O1 | 102.71 (18) | O4—C8—O5 | 124.6 (2) |
| C3—N3—S1 | 118.03 (15) | O4—C8—C5 | 123.6 (2) |
| C4—N3—S1 | 118.60 (16) | O5—C8—C5 | 111.6 (2) |
| C4—N3—C3 | 121.5 (2) | C10—C9—O5 | 108.1 (3) |
| C6—N4—S1 | 122.23 (18) | C1—C11—C12 | 109.3 (2) |
| O1—C1—C11 | 116.3 (2) | C1—C11—C14 | 111.5 (2) |
| N1—C1—O1 | 112.9 (2) | C14—C11—C12 | 112.0 (3) |
| N1—C1—C11 | 130.7 (2) | C13—C12—C11 | 114.8 (3) |
| N1—C2—C3 | 123.9 (2) | C15—C14—C11 | 114.4 (3) |
| N2—C2—N1 | 115.1 (2) | ||
| S1—N3—C3—C2 | −71.7 (2) | N4—S1—N3—C4 | 31.0 (2) |
| S1—N3—C4—C5 | −14.3 (3) | C1—O1—N2—C2 | 0.6 (3) |
| S1—N4—C6—C5 | 13.9 (3) | C1—N1—C2—N2 | −0.9 (3) |
| S1—N4—C6—C7 | −171.32 (19) | C1—N1—C2—C3 | 176.3 (2) |
| O1—N2—C2—N1 | 0.2 (3) | C1—C11—C12—C13 | −62.4 (3) |
| O1—N2—C2—C3 | −177.1 (2) | C1—C11—C14—C15 | 61.6 (4) |
| O1—C1—C11—C12 | −66.6 (3) | C2—N1—C1—O1 | 1.4 (3) |
| O1—C1—C11—C14 | 57.8 (3) | C2—N1—C1—C11 | −175.8 (3) |
| O2—S1—N3—C3 | 78.61 (19) | C3—N3—C4—C5 | −178.3 (2) |
| O2—S1—N3—C4 | −85.95 (19) | C4—N3—C3—C2 | 92.4 (3) |
| O2—S1—N4—C6 | 83.5 (2) | C4—C5—C6—N4 | 9.6 (4) |
| O3—S1—N3—C3 | −47.1 (2) | C4—C5—C6—C7 | −164.7 (2) |
| O3—S1—N3—C4 | 148.37 (19) | C4—C5—C8—O4 | 23.7 (4) |
| O3—S1—N4—C6 | −145.3 (2) | C4—C5—C8—O5 | −152.6 (2) |
| N1—C1—C11—C12 | 110.4 (3) | C6—C5—C8—O4 | −149.2 (3) |
| N1—C1—C11—C14 | −125.2 (3) | C6—C5—C8—O5 | 34.4 (3) |
| N1—C2—C3—N3 | −50.0 (3) | C8—O5—C9—C10 | −166.0 (3) |
| N2—O1—C1—N1 | −1.3 (3) | C8—C5—C6—N4 | −177.8 (2) |
| N2—O1—C1—C11 | 176.3 (2) | C8—C5—C6—C7 | 7.9 (4) |
| N2—C2—C3—N3 | 127.1 (2) | C9—O5—C8—O4 | 2.1 (4) |
| N3—S1—N4—C6 | −31.1 (2) | C9—O5—C8—C5 | 178.4 (2) |
| N3—C4—C5—C6 | −8.5 (4) | C12—C11—C14—C15 | −175.5 (3) |
| N3—C4—C5—C8 | 178.1 (2) | C14—C11—C12—C13 | 173.4 (3) |
| N4—S1—N3—C3 | −164.45 (17) |
Hydrogen-bond geometry (Å, º)
| D—H···A | D—H | H···A | D···A | D—H···A |
| C4—H4···N2i | 0.93 | 2.54 | 3.431 (3) | 161 |
Symmetry code: (i) −x+3/2, y+1/2, z.
Funding Statement
This work was funded by Ministry of Science and Higher Education of the Russian Federation grant RFMEFI57917X0154.
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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) Global, I. DOI: 10.1107/S2056989019015986/su5529sup1.cif
Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989019015986/su5529Isup2.hkl
Supporting information file. DOI: 10.1107/S2056989019015986/su5529Isup3.cml
CCDC reference: 1968398
Additional supporting information: crystallographic information; 3D view; checkCIF report