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Crystal structure, Hirshfeld analysis and a mol­ecular docking study of a new inhibitor of the Hepatitis B virus (HBV): 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

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aChemRar Research and Development Institute, 7 Nobel St, Innovation Center, Skolkovo Territory, Moscow, 143026, Russian Federation, bV.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61077, Ukraine, cChemical Diversity Research Institute, 2A Rabochaya St, Khimki, Moscow Region, 141400, Russian Federation, and dUniversity of Vienna, Althanstrasse 14, A-1090, Vienna, Austria
*Correspondence e-mail: mod@chemdiv.com

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 19 November 2019; accepted 27 November 2019; online 1 January 2020)

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.

1. Chemical context

Derivatives of 2H-1,2,6-thia­diazine 1,1-dioxide demonstrate anti­viral (Martínez et al., 1999[Martínez, A., Esteban, A. I., Herrero, A., Ochoa, C., Andrei, G., Snoeck, R., Balzarini, J. & Clercq, E. D. (1999). Bioorg. Med. Chem. 7, 1617-1623.]; Esteban et al., 1997[Esteban, A. I., De Clercq, E. & Martínez, A. (1997). Nucleosides Nucleotides, 16, 265-276.], 1995[Esteban, A. I., Juanes, O., Conde, S., Goya, P., De Clercq, E. & Martínez, A. (1995). Bioorg. Med. Chem. 3, 1527-1535.]), cannabinoid (Cano et al., 2007[Cano, C., Goya, P., Paez, J. A., Girón, R., Sánchez, E. & Martín, M. I. (2007). Bioorg. Med. Chem. 15, 7480-7493.]), anti­diabetic (Goyal & Bhargava, 1989[Goyal, R. N. & Bhargava, S. (1989). Curr. Sci. 58, 287-290.]; Jain & Malik, 1983[Jain, R. & Malik, W. (1983). Indian J. Chem. Sec. A, 22, 331-332.]), anti-HIV-1 (Breining et al., 1995[Breining, T., Cimpoia, A. R., Mansour, T. S., Cammack, N., Hopewell, P. & Ashman, C. (1995). Heterocycles, 41, 87-94.]) and anti­parasitic (Arán et al., 1986[Arán, V. J., Bielsa, A. G., Goya, P., Ochoa, C., Paez, J. A., Stud, M., Contreras, M., Escario, J. A., Jimenez Duran, M. I. & Farmaco, E. A. (1986). Edizione Scientifica, 41, 862-872.]) activities. In addition, such derivatives are patent protected as pain relievers and anti­pyretic drugs (Giraldez et al., 1989[Giraldez, A., Nieves, R., Ochoa, C., Vara de Rey, C., Cenarruzabeitia, E. & Lasheras, B. (1989). Eur. J. Med. Chem. 24, 497-502.]). Heterocyclic homologues of 2H-1,2,6-thia­diazine-1,1-dioxides are inhibitors of human cytomegalovirus (Martínez et al., 2003[Martínez, A., Gil, C., Castro, A., Bruno, A. M., Pérez, C., Prieto, C. & Otero, J. (2003). Antivir. Chem. Chemother. 14, 107-114.]), Cruzi triposome (Álvarez et al., 2010[Álvarez, G., Aguirre-López, B., Varela, J., Cabrera, M., Merlino, A., López, G. V., Lavaggi, M. L., Porcal, W., Di Maio, R., González, M., Cerecetto, H., Cabrera, N., Pérez-Montfort, R., de Gómez-Puyou, M. T. & Gómez-Puyou, A. (2010). Eur. J. Med. Chem. 45, 5767-5772.]) and diuretics (Goya et al., 1992[Goya, P., Paez, J. A., Alkorta, I., Carrasco, E., Grau, M., Anton, F., Julia, S. & Martínez-Ripoll, M. (1992). J. Med. Chem. 35, 3977-3983.]). In a continuation of our efforts to obtain new HBV inhibitors for the treatment and prevention of human HBV infections (Ivachtchenko et al., 2019[Ivachtchenko, A. V., Mitkin, O. D., Kravchenko, D. V., Kovalenko, S. M., Shishkina, S. V., Bunyatyan, N. D., Konovalova, I. S., Dmitrieva, I. G., Ivanov, V. V. T. & Langer (2019). Heliyon, 5, e02738.]; Ivashchenko et al., 2019[Ivashchenko, A. V., Mitkin, O. D., Kravchenko, D. V., Kuznetsova, I. V., Kovalenko, S. M., Bunyatyan, N. D. & Langer, T. (2019). Crystals, 9, 379-385.]; Kovalenko et al., 2019[Kovalenko, S. M., Drushlyak, O. G., Konovalova, I. S., Mariutsa, I. O., Kravchenko, D. V., Ivachtchenko, A. V. & Mitkin, O. D. (2019). Molbank, M1085. doi: 10.3390/M1085.]), 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[Cheone, S. H. (2001). EROS Encyclopedia of Reagents for Organic Synthesis, Sulfamide, 1-4. Chichester: Wiley.]; Alberola et al., 1991[Alberola, A., Andrés, J. M., González, A., Pedrosa, R. & Vicente, M. (1991). Synthesis, 1991, 355-356.]), as shown in Fig. 1[link]. The synthesis of the title compound (3) is illustrated in Fig. 2[link]. 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]
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]
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.

[Scheme 1]

2. Structural commentary

The mol­ecular structure of compound 3, is illustrated in Fig. 3[link]. 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]
Figure 3
The mol­ecular structure of compound 3, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

3. Supra­molecular features

In the crystal, mol­ecules are linked by C—H⋯N hydrogen bonds, forming chains propagating along the b-axis direction (Table 1[link] and Fig. 4[link]). There are no other significant inter­molecular inter­actions present in the crystal.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
C4—H4⋯N2i 0.93 2.54 3.431 (3) 161
Symmetry code: (i) [-x+{\script{3\over 2}}, y+{\script{1\over 2}}, z].
[Figure 4]
Figure 4
A partial view along the a axis of the crystal packing of compound 3. Hydrogen bonds (Table 1[link]) are shown as dashed lines.

4. Database survey

A search of the Cambridge Structural Database (CSD, Version 5.40, August 2019; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) 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[Onys'ko, P. P., Zamulko, K. A., Kyselyova, O. I., Shalimov, O. O. & Rusanov, E. B. (2017). Tetrahedron, 73, 3513-3520.]). 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.

5. Hirshfeld surface analysis

The Hirshfeld surface analysis (Spackman & Jayatilaka, 2009[Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm, 11, 19-32.]) and the associated two-dimensional fingerprint plots (McKinnon et al., 2007[McKinnon, J. J., Jayatilaka, D. & Spackman, M. A. (2007). Chem. Commun. pp. 3814.]) were performed with CrystalExplorer17 (Turner et al., 2017[Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. University of Western Australia. https://hirshfeldsurface.net.]). The mol­ecular Hirshfeld surfaces were obtained using a standard (high) surface resolution with the three-dimensional dnorm surface (Fig. 5[link]), mapped over a fixed colour scale of −0.484 (red) to 1.652 (blue). There are four red spots in the dnorm 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[link].

Table 2
Short contacts (Å) in the crystal of compound 3

Atom1⋯Atom2 Length Length – vdW
S1.·H7Bi 3.090 0.090
O2⋯H7Bi 2.813 0.093
H7A⋯O4i 2.687 −0.033
H12B⋯N2ii 2.772 0.022
O4⋯H14Aiii 2.700 −0.020
C8⋯H14Aiii 2.913 0.013
C6⋯H10Biv 2.978 0.078
O2⋯C3v 3.275 0.055
O2⋯H3Av 2.634 −0.086
O3⋯C4v 3.077 −0.143
N2⋯H3Av 2.816 0.066
N2⋯HAv 2.538 −0.212
H3B⋯O4v 2.799 0.079
Symmetry codes: (i) −x + 1, y − [{1\over 2}], −z + [{1\over 2}]; (ii) x − [{1\over 2}], −y + [{1\over 2}], −z + 1; (iii) −x + 1, −y + 1, −z + 1; (iv) −x + [{1\over 2}], y − [{1\over 2}], z; (v) −x + [{3\over 2}], y − [{1\over 2}], z.
[Figure 5]
Figure 5
The Hirshfeld surface of compound 3, mapped over dnorm, with a fixed colour scale of −0.484 to 1.652 a.u.

The inter­molecular inter­actions in the crystal of the title compound are shown on the two-dimensional fingerprint plots presented in Fig. 6[link]. 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[link]c). The fingerprint plots indicate that the principal contributions are from H⋯H (48.7%; Fig. 6[link]b), O⋯H/H⋯O (27.5%; Fig. 6[link]c), N⋯H/H⋯N (14.9%; Fig. 6[link]d) and C⋯H/H⋯C (5.2%; Fig. 6[link]e) contacts.

[Figure 6]
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.

6. 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[Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. & Bourne, P. E. (2000). Nucleic Acids Res. 28, 235-242.]; accessed on 24 July 2019). The pharmacophore model was generated by using the Ligandscout 4.3 program (Wolber & Langer, 2005[Wolber, G. & Langer, T. (2005). J. Chem. Inf. Model. 45, 160-169.]; 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[link].

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[link], 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[link], left) and poses in proteins (Fig. 7[link], right). The red lines designate hydrogen-bond acceptors, while yellow lines designated hydro­phobic inter­actions.

[Figure 7]
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[link]. The calculated structure of the title compound is illustrated in Fig. 8[link]. 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]
Figure 8
Calculated structure of the title compound.

The obtained data demonstrate significant geometrical relaxation associated with immersion of the mol­ecule in a protein.

7. 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[Sun, Y., Qi, Y., Peng, B. & Li, W. (2016). NTCP-Reconstituted In Vitro HBV Infection System. Hepatitis B Virus, 1-14.]) was developed in our laboratories for identification of viral entry inhibitors able to prevent development of resistant HBV forms (Ivachtchenko et al., 2019b[Ivachtchenko, A. V., Mitkin, O. D., Kravchenko, D. V., Kovalenko, S. M., Shishkina, S. V., Bunyatyan, N. D., Konovalova, I. S., Dmitrieva, I. G., Ivanov, V. V. T. & Langer (2019). Heliyon, 5, e02738.]). 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[Donkers, J. M., Zehnder, B., van Westen, G. J. P., Kwakkenbos, M. J., IJzerman, A. P., Oude Elferink, R. P. J., Beuers, U., Urban, S. & van de Graaf, F. J. (2017). Sci. Rep. 7, 15307.]).

8. Synthesis and crystallization

The synthesis of the title compound is illustrated in Fig. 2[link]. 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.

9. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 5[link]. H atoms were included in calculated positions and treated as riding on their parent C atom: C—H = 0.93–0.98 Å with Uiso(H) = 1.5Ueq(C-meth­yl) and 1.2Ueq(C) for other H atoms.

Table 5
Experimental details

Crystal data
Chemical formula C15H22N4O5S
Mr 370.42
Crystal system, space group Orthorhombic, Pbca
Temperature (K) 293
a, b, c (Å) 12.4962 (5), 9.9237 (4), 29.5925 (15)
V3) 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[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.])
Tmin, Tmax 0.466, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections 26547, 3211, 2510
Rint 0.070
(sin θ/λ)max−1) 0.595
 
Refinement
R[F2 > 2σ(F2)], wR(F2), 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
Computer programs: CrysAlis PRO (Rigaku OD, 2018[Rigaku OD (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Yarnton, England.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]), Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]), PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information


Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009) and Mercury (Macrae et al., 2008); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009), SHELXL (Sheldrick, 2015b), PLATON (Spek, 2009) and publCIF (Westrip, 2010).

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 top
Crystal data top
C15H22N4O5SDx = 1.341 Mg m3
Mr = 370.42Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, PbcaCell parameters from 3271 reflections
a = 12.4962 (5) Åθ = 3.6–23.3°
b = 9.9237 (4) ŵ = 0.21 mm1
c = 29.5925 (15) ÅT = 293 K
V = 3669.7 (3) Å3Block, colourless
Z = 80.4 × 0.2 × 0.1 mm
F(000) = 1568
Data collection top
Rigaku Oxford Diffraction Xcalibur, Sapphire3
diffractometer
3211 independent reflections
Radiation source: fine-focus sealed X-ray tube, Enhance (Mo) X-ray Source2510 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.070
Detector resolution: 16.1827 pixels mm-1θmax = 25.0°, θmin = 3.0°
ω scansh = 1414
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku OD, 2018)
k = 1111
Tmin = 0.466, Tmax = 1.000l = 2535
26547 measured reflections
Refinement top
Refinement on F2Primary atom site location: dual
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.050Hydrogen site location: difference Fourier map
wR(F2) = 0.127H-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 parametersΔρmax = 0.24 e Å3
0 restraintsΔρmin = 0.32 e Å3
Special details top

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) top
xyzUiso*/Ueq
S10.66349 (5)0.40561 (6)0.31677 (2)0.0462 (2)
O10.74895 (14)0.29562 (18)0.46836 (6)0.0577 (5)
O20.60666 (16)0.31342 (17)0.34444 (7)0.0646 (6)
O30.76374 (15)0.3626 (2)0.30037 (8)0.0726 (6)
O40.47430 (16)0.86020 (18)0.34934 (7)0.0668 (6)
O50.35185 (14)0.7296 (2)0.31536 (7)0.0654 (6)
N10.65072 (15)0.4628 (2)0.44365 (7)0.0472 (5)
N20.80748 (16)0.3561 (2)0.43291 (8)0.0514 (5)
N30.68614 (14)0.54419 (19)0.34784 (7)0.0415 (5)
N40.58953 (16)0.4585 (2)0.27686 (7)0.0495 (5)
C10.65689 (19)0.3647 (2)0.47179 (9)0.0463 (6)
C20.74512 (17)0.4525 (2)0.42013 (8)0.0402 (5)
C30.77420 (18)0.5405 (2)0.38103 (9)0.0467 (6)
H3A0.7889160.6310170.3917040.056*
H3B0.8384610.5061420.3666930.056*
C40.61014 (18)0.6400 (2)0.34937 (8)0.0427 (6)
H40.6155840.7058750.3715920.051*
C50.52574 (18)0.6464 (2)0.32039 (8)0.0412 (6)
C60.52217 (19)0.5588 (2)0.28224 (9)0.0457 (6)
C70.4479 (2)0.5814 (3)0.24327 (10)0.0660 (8)
H7A0.4711610.5286460.2179090.099*
H7B0.4482040.6751010.2352380.099*
H7C0.3767810.5548460.2516850.099*
C80.4500 (2)0.7587 (3)0.32946 (9)0.0497 (6)
C90.2702 (2)0.8316 (4)0.32370 (14)0.0881 (11)
H9A0.2759330.8647840.3544320.106*
H9B0.2797510.9069020.3031920.106*
C100.1671 (3)0.7707 (5)0.31670 (19)0.1275 (19)
H10A0.1639500.7327180.2868910.191*
H10B0.1122820.8378790.3198560.191*
H10C0.1560920.7009000.3386740.191*
C110.5779 (2)0.3135 (3)0.50547 (10)0.0601 (7)
H110.5171530.3759270.5060230.072*
C120.5362 (3)0.1749 (3)0.49009 (12)0.0756 (9)
H12A0.5965270.1138040.4875780.091*
H12B0.4890290.1396890.5132840.091*
C130.4770 (3)0.1756 (4)0.44585 (14)0.0939 (12)
H13A0.5224060.2118010.4226620.141*
H13B0.4139820.2303440.4485750.141*
H13C0.4568360.0852110.4380770.141*
C140.6254 (3)0.3084 (3)0.55267 (11)0.0799 (10)
H14A0.5727750.2699130.5730350.096*
H14B0.6868160.2487100.5523280.096*
C150.6597 (3)0.4429 (4)0.57096 (13)0.1016 (13)
H15A0.7144390.4800740.5518910.152*
H15B0.6873170.4316900.6010030.152*
H15C0.5994540.5027980.5716570.152*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0472 (4)0.0396 (4)0.0518 (4)0.0034 (3)0.0079 (3)0.0008 (3)
O10.0566 (11)0.0612 (11)0.0553 (12)0.0133 (9)0.0089 (9)0.0161 (9)
O20.0825 (14)0.0438 (10)0.0674 (13)0.0180 (10)0.0177 (11)0.0143 (9)
O30.0531 (11)0.0764 (13)0.0881 (16)0.0224 (10)0.0045 (11)0.0190 (12)
O40.0760 (13)0.0518 (11)0.0725 (15)0.0144 (10)0.0007 (11)0.0081 (10)
O50.0439 (10)0.0727 (13)0.0796 (15)0.0152 (9)0.0022 (9)0.0008 (10)
N10.0432 (11)0.0428 (11)0.0555 (14)0.0035 (9)0.0051 (10)0.0075 (10)
N20.0458 (11)0.0587 (13)0.0497 (14)0.0063 (10)0.0053 (10)0.0090 (10)
N30.0394 (10)0.0387 (11)0.0463 (12)0.0029 (9)0.0046 (9)0.0043 (9)
N40.0549 (12)0.0466 (12)0.0470 (13)0.0060 (10)0.0082 (10)0.0014 (9)
C10.0476 (14)0.0438 (14)0.0474 (16)0.0064 (11)0.0042 (11)0.0003 (11)
C20.0353 (12)0.0417 (12)0.0435 (14)0.0036 (10)0.0049 (10)0.0006 (10)
C30.0374 (12)0.0491 (14)0.0536 (16)0.0082 (11)0.0061 (11)0.0061 (12)
C40.0438 (13)0.0377 (12)0.0466 (15)0.0035 (11)0.0052 (11)0.0043 (10)
C50.0372 (12)0.0410 (13)0.0453 (15)0.0003 (10)0.0036 (10)0.0056 (10)
C60.0454 (13)0.0421 (13)0.0496 (16)0.0006 (11)0.0025 (11)0.0073 (11)
C70.0763 (19)0.0634 (17)0.0583 (19)0.0160 (15)0.0215 (15)0.0017 (14)
C80.0493 (15)0.0527 (15)0.0471 (16)0.0037 (13)0.0046 (12)0.0088 (12)
C90.061 (2)0.103 (3)0.100 (3)0.0384 (19)0.0100 (18)0.008 (2)
C100.0468 (19)0.139 (4)0.196 (6)0.024 (2)0.007 (2)0.025 (4)
C110.0652 (17)0.0544 (16)0.0607 (19)0.0094 (13)0.0206 (14)0.0102 (13)
C120.074 (2)0.0620 (19)0.091 (3)0.0053 (16)0.0256 (19)0.0133 (17)
C130.083 (2)0.088 (2)0.110 (3)0.023 (2)0.007 (2)0.003 (2)
C140.102 (2)0.081 (2)0.056 (2)0.008 (2)0.0207 (18)0.0155 (17)
C150.135 (4)0.099 (3)0.071 (3)0.005 (2)0.001 (2)0.009 (2)
Geometric parameters (Å, º) top
S1—O21.4183 (19)C12—C131.504 (5)
S1—O31.4097 (19)C14—C151.503 (5)
S1—N31.678 (2)C3—H3A0.9700
S1—N41.589 (2)C3—H3B0.9700
O1—N21.413 (3)C4—H40.9300
O1—C11.343 (3)C7—H7A0.9600
O4—C81.205 (3)C7—H7B0.9600
O5—C81.327 (3)C7—H7C0.9600
O5—C91.458 (3)C9—H9A0.9700
N1—C11.283 (3)C9—H9B0.9700
N1—C21.373 (3)C10—H10A0.9600
N2—C21.291 (3)C10—H10B0.9600
N3—C31.476 (3)C10—H10C0.9600
N3—C41.344 (3)C11—H110.9800
N4—C61.313 (3)C12—H12A0.9700
C1—C111.492 (4)C12—H12B0.9700
C2—C31.494 (3)C13—H13A0.9600
C4—C51.361 (3)C13—H13B0.9600
C5—C61.425 (3)C13—H13C0.9600
C5—C81.487 (3)C14—H14A0.9700
C6—C71.497 (3)C14—H14B0.9700
C9—C101.439 (5)C15—H15A0.9600
C11—C121.539 (4)C15—H15B0.9600
C11—C141.518 (4)C15—H15C0.9600
O2—S1—N3107.26 (11)N2—C2—C3120.9 (2)
O2—S1—N4110.56 (11)N3—C3—C2110.41 (18)
O3—S1—O2116.64 (13)N3—C4—C5124.0 (2)
O3—S1—N3106.67 (11)C4—C5—C6119.7 (2)
O3—S1—N4111.17 (13)C4—C5—C8114.5 (2)
N4—S1—N3103.55 (10)C6—C5—C8125.5 (2)
C1—O1—N2106.41 (17)N4—C6—C5122.6 (2)
C8—O5—C9116.2 (2)N4—C6—C7114.7 (2)
C1—N1—C2102.8 (2)C5—C6—C7122.6 (2)
C2—N2—O1102.71 (18)O4—C8—O5124.6 (2)
C3—N3—S1118.03 (15)O4—C8—C5123.6 (2)
C4—N3—S1118.60 (16)O5—C8—C5111.6 (2)
C4—N3—C3121.5 (2)C10—C9—O5108.1 (3)
C6—N4—S1122.23 (18)C1—C11—C12109.3 (2)
O1—C1—C11116.3 (2)C1—C11—C14111.5 (2)
N1—C1—O1112.9 (2)C14—C11—C12112.0 (3)
N1—C1—C11130.7 (2)C13—C12—C11114.8 (3)
N1—C2—C3123.9 (2)C15—C14—C11114.4 (3)
N2—C2—N1115.1 (2)
S1—N3—C3—C271.7 (2)N4—S1—N3—C431.0 (2)
S1—N3—C4—C514.3 (3)C1—O1—N2—C20.6 (3)
S1—N4—C6—C513.9 (3)C1—N1—C2—N20.9 (3)
S1—N4—C6—C7171.32 (19)C1—N1—C2—C3176.3 (2)
O1—N2—C2—N10.2 (3)C1—C11—C12—C1362.4 (3)
O1—N2—C2—C3177.1 (2)C1—C11—C14—C1561.6 (4)
O1—C1—C11—C1266.6 (3)C2—N1—C1—O11.4 (3)
O1—C1—C11—C1457.8 (3)C2—N1—C1—C11175.8 (3)
O2—S1—N3—C378.61 (19)C3—N3—C4—C5178.3 (2)
O2—S1—N3—C485.95 (19)C4—N3—C3—C292.4 (3)
O2—S1—N4—C683.5 (2)C4—C5—C6—N49.6 (4)
O3—S1—N3—C347.1 (2)C4—C5—C6—C7164.7 (2)
O3—S1—N3—C4148.37 (19)C4—C5—C8—O423.7 (4)
O3—S1—N4—C6145.3 (2)C4—C5—C8—O5152.6 (2)
N1—C1—C11—C12110.4 (3)C6—C5—C8—O4149.2 (3)
N1—C1—C11—C14125.2 (3)C6—C5—C8—O534.4 (3)
N1—C2—C3—N350.0 (3)C8—O5—C9—C10166.0 (3)
N2—O1—C1—N11.3 (3)C8—C5—C6—N4177.8 (2)
N2—O1—C1—C11176.3 (2)C8—C5—C6—C77.9 (4)
N2—C2—C3—N3127.1 (2)C9—O5—C8—O42.1 (4)
N3—S1—N4—C631.1 (2)C9—O5—C8—C5178.4 (2)
N3—C4—C5—C68.5 (4)C12—C11—C14—C15175.5 (3)
N3—C4—C5—C8178.1 (2)C14—C11—C12—C13173.4 (3)
N4—S1—N3—C3164.45 (17)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C4—H4···N2i0.932.543.431 (3)161
Symmetry code: (i) x+3/2, y+1/2, z.
Short contacts (Å) in the crystal of compound 3 top
Atom1···Atom2LengthLength - vdW
S1..H7Bi3.0900.090
O2···H7Bi2.8130.093
H7A···O4i2.687-0.033
H12B···N2ii2.7720.022
O4···H14Aiii2.700-0.020
C8···H14Aiii2.9130.013
C6···H10Biv2.9780.078
O2···C3v3.2750.055
O2···H3Av2.634-0.086
O3···C4v3.077-0.143
N2···H3Av2.8160.066
N2···HAv2.538-0.212
H3B···O4v2.7990.079
Symmetry codes: (i) -x + 1, y - 1/2, -z + 1/2; (ii) x - 1/2, -y + 1/2, -z + 1; (iii) -x + 1, -y + 1, -z + 1; (iv) -x + 1/2, y - 1/2, z; (v) -x + 3/2, y - 1/2, z.
Binding affinity parameters of title molecule with HBV core proteins top
PDB refcodeEst. 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
Torsion angles (°) comparison for X-ray, ab initio and docking data top
Torsion angleX-rayM062x/cc-pVDZ5E0I5GMZ5WRE5T2P
O2—S1—N4—C683.5 (2)78.793.1393.293.1137.4
C5—C8—O5—C9178.4 (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—C1457.8 (3)49.950.1-112.99.852.8
 

Acknowledgements

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.

Funding information

Funding for this research was provided by: Ministry of Science and Higher Education of the Russian Federation (grant No. RFMEFI57917X0154).

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