research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 77| Part 10| October 2021| Pages 999-1002
https://doi.org/10.1107/S2056989021009245

Crystal structure of nafamostat dimesylate

crossmark logo
Isao Fujiia*

aSTEM Education Center, Tokai University, 4-1-1 Kitakaname, Hiratuka, Kanagawa 259-1292, Japan
*Correspondence e-mail: fujii@wing.ncc.u-tokai.ac.jp

Edited by B. Therrien, University of Neuchâtel, Switzerland (Received 2 September 2021; accepted 6 September 2021; online 10 September 2021)

Nafamostat dimesylate {systematic name: [amino({6-[(4-{[amino(iminiumyl)methyl]amino}phenyl)carbonyloxy]naphthalen-2-yl})methylidene]azanium bis(methanesulfonate)}, C19H19N5O22+·2CH3O3S−, is a broad-spectrum serine protease inhibitor and has been applied clinically as an anti­coagulant agent during hemodialysis and for treatment of severe acute pancreatitis (SAP). Since nafamostat contains flexible moieties, it is necessary to determine the conformation to understand the structure–activity relationships. The divalent cation has a screw-like motif. The guanidinium group is approximately perpendicular to the naphthyl ring system, subtending a dihedral angle of 84.30 (14)°. In the crystal, the nafamostat mol­ecules form columnar structures surrounded by a hydro­philic region.

CCDC reference: 2107852

Similar articles

1. Chemical context

Nafamostat mesylate (I)[link] is the bis­methane­sulfonic salt of 6-amidino-2-naphthyl-4-guanidinobenzoate. It shows broad-spectrum serine protease inhibition effect, and is also a reversible competitive inhibitor as camostat mesylate (II) (Tamura et al., 1977[Tamura, Y., Hirado, M., Okamura, K., Minato, Y. & Fujii, S. (1977). Biochim. Biophys. Acta Enzymology, 484, 417-422.]; Fujii & Hitomi, 1981[Fujii, S. & Hitomi, Y. (1981). Biochim. Biophys. Acta Enzymology, 661, 342-345.]; Matsumoto et al., 1989[Matsumoto, O., Taga, T. & Machida, K. (1989). Acta Cryst. C45, 913-915.]). Although nafamostat mesylate has been applied clinically with success as an effective anti­coagulant and anti-inflammatory agent during hemodialysis and for treatment of severe acute pancreatitis (Takeda et al., 1989[Takeda, K., Kakugawa, Y., Kobari, M. & Matsuno, S. (1989). Gastroenterol. Jpn. 24, 340.]), the crystal structure has not previously been reported.

[Scheme 1]

In addition, nafamostat has attracted attention as an inhibitor for the activity of transmembrane protease serine 2 (TMPRSS2), a host cell serine protease that mediates viral cell incursion for influenza virus and coronavirus, thereby inhibiting viral infection and replication (Yamamoto et al., 2016[Yamamoto, M., Matsuyama, S., Li, X., Takeda, M., Kawaguchi, Y., Inoue, J. & Matsuda, Z. (2016). Antimicrob. Agents Chemother. 60, 6532-6539.], 2020[Yamamoto, M., Kiso, M., Sakai-Tagawa, Y., Iwatsuki-Horimoto, K., Imai, M., Takeda, M., Kinoshita, N., Ohmagari, N., Gohda, J., Semba, K., Matsuda, Z., Kawaguchi, Y., Kawaoka, Y. & Inoue, J. (2020). Viruses, 12, 629-638.]; Hoffmann et al., 2020[Hoffmann, M., Schroeder, S., Kleine-Weber, H., Müller, M. A., Drosten, C. & Pöhlmann, S. (2020). Antimicrob. Agents Chemother. 64, e00754-20.]). Since nafamostat contains flexible moieties, it is necessary to determine the conformation to understand the structure–activity relationships. The crystal structure of nafamostat mesylate (I)[link] is reported herein. From the crystallographic study, the phenyl­guanidine groups in nafamostat and camostat are essentially similar except for the direction of residual groups.

2. Structural commentary

The nafamostat moiety in the title compound (Fig. 1[link]) shows a divalent cation with a screw-like motif, which consists of four planar parts: the amidino group, the naphthyl group (rings A and B), phenyl ring C and the guanidinium group (shown in Fig.1). The dihedral angles between the amidino and naphthyl groups, the naphthyl group and ring C, and ring C and guanidinium group are 11.35 (13), 44.66 (10) and 51.11 (15)°, respectively. The guanidinium group is approximately perpendicular to the naphthyl group, subtending a dihedral angle of 84.30 (14)°.

[Figure 1]
Figure 1
The title compound nafamostat mesylate (I)[link] showing the atom and ring labelling. Displacement ellipsoids are drawn at the 50% probability level.

The C14—N15 and C14—N22 bond distances [1.319 (3) and 1.311 (3) Å, respectively] indicate a resonance structure in the protonated amidinium group (Table 1[link]). On the other hand, the bond distances C24—N23 = 1.357 (3), C24—N25 = 1.302 (4) and C24—N26 = 1.325 (3) Å indicate a localized electron on the C24—N25 bond in the protonated guanidinium group.

Table 1
Selected bond lengths (Å)

C1—O11 1.391 (3) C30—S27 1.764 (3)
C12—O13 1.204 (3) C35—S32 1.762 (3)
C12—O11 1.377 (3) O28—S27 1.4515 (19)
C14—N22 1.311 (3) O29—S27 1.4570 (19)
C14—N15 1.319 (3) O31—S27 1.4700 (18)
C19—N23 1.417 (3) O33—S32 1.4545 (18)
C24—N26 1.325 (3) O34—S32 1.4553 (19)
C24—N25 1.302 (4) O36—S32 1.448 (2)
C24—N23 1.357 (3)    

The overlay of nafamostat (green) and camostat (red) is presented in Fig. 2[link], in which the r.m.s. deviation is 0.027 Å for phenyl­guanidinium groups. The partial structures are essentially similar, except for the direction of residual groups. Very recently, the crystal structure of human TMPRSS2 in a covalent complex with nafamostat has been solved (Fraser et al., 2021[Fraser, B., Beldar, S., Hutchinson, A., Li, Y., Seitova, A., Edwards, A. M., Benard, F., Arrowsmith, C. H. & Halabelian, L. (2021). doi: 10.2210/pdb7MEQ/pdb.]). The nafamostat in the complex is hydrolysed, and results in phenyl­guanidino acyl­ation of Ser441 (yellow) in the active site. It was considered that the nafamostat moiety may be easily nucleophilic-attacked, approaching from the O13 atom side without steric hindrance.

[Figure 2]
Figure 2
Overlay of the crystal structures of nafamostat moiety (green), camostat moiety (red) and covalently binding partial structure (yellow) of mature nafamostat with Ser441 in the active site from pdb7MEQ (Fraser et al., 2021[Fraser, B., Beldar, S., Hutchinson, A., Li, Y., Seitova, A., Edwards, A. M., Benard, F., Arrowsmith, C. H. & Halabelian, L. (2021). doi: 10.2210/pdb7MEQ/pdb.]), using Mercury (Macrae et al., 2020[Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226-235.]).

3. Supra­molecular features

In the crystal, the naphthyl groups of nafamostat form hydro­phobic columnar structures, shown in Fig. 3[link]. The naphthyl groups correlated with the inversion center (yellow) are stacking along the b-axis direction, in which the perpendicular distances of the centroid of the naphthyl ring system and those at (−x, 1 − y, 1 − z) and (−x, 2 − y, 1 − z) are 3.4208 (8) and 3.5134 (8) Å, respectively.

[Figure 3]
Figure 3
Part of the crystal structure of nafamostat mesylate (I)[link]. The naphthyl groups related by the inversion center (yellow) and equivalent (grey) are stacking along the b-axis direction, forming a columnar structure. The methane­sulfonate groups containing the S27 and S32 atoms are represented in blue and red, respectively. H atoms have been omitted for clarity.

The columnar structures are surrounded by a hydro­philic region consisting of the methane­sulfonate ions and the guanidinium, imidamidium and ester groups. The two independent methane­sulfonate ions play different roles. The columnar structure inter­calates the methane­sulfonate group (blue) containing the S27 atom, and is linked to three neighbouring guanidinium groups and one di­amine group. Hydrogen bonds [N25—H25A⋯O28 = 2.827 (3) and N26—H26B⋯O29vii = 2.925 (3) Å; Table 2[link]] link the mol­ecules, forming an infinite C22(8) chain, with other hydrogen bonds [N25—H25B⋯O29vi = 2.931 (3) and N26—H26A⋯O31vi = 2.916 (3) Å] forming an R22(8) ring.

Table 2
Hydrogen-bond geometry (Å, °)

Cg(C) is the center of gravity of phenyl ring C.
D—H⋯A D—H H⋯A D⋯A D—H⋯A
C18—H18⋯O13i 0.95 2.64 3.419 (3) 140
C30—H30A⋯O36ii 0.98 2.36 3.314 (3) 165
N15—H15A⋯O33iii 0.93 (4) 1.97 (4) 2.854 (3) 159 (3)
N15—H15A⋯O34iii 0.93 (4) 2.63 (4) 3.327 (3) 132 (3)
N15—H15A⋯S32iii 0.93 (4) 2.75 (4) 3.612 (2) 154 (3)
N15—H15B⋯O34iv 0.85 (4) 2.00 (4) 2.830 (3) 164 (4)
N22—H22A⋯O31v 0.83 (3) 2.12 (3) 2.928 (3) 162 (3)
N22—H22B⋯O33iii 0.83 (3) 2.31 (3) 3.018 (3) 144 (3)
N23—H23⋯O36 0.99 (4) 1.88 (5) 2.836 (3) 163 (4)
N23—H23⋯S32 0.99 (4) 2.72 (4) 3.683 (2) 166 (3)
N25—H25A⋯O28 0.87 (4) 2.00 (4) 2.827 (3) 159 (3)
N25—H25A⋯S27 0.87 (4) 2.86 (4) 3.558 (2) 139 (3)
N25—H25B⋯O29vi 0.83 (3) 2.12 (3) 2.931 (3) 167 (3)
N26—H26A⋯O31vi 0.85 (4) 2.10 (4) 2.916 (3) 163 (4)
N26—H26A⋯S27vi 0.85 (4) 3.01 (4) 3.799 (2) 156 (3)
N26—H26B⋯O29vii 0.89 (4) 2.46 (4) 2.925 (3) 113 (3)
N26—H26B⋯O36 0.89 (4) 2.45 (4) 3.174 (3) 139 (3)
C30—H30B⋯Cg(C)vii 0.98 2.96 3.405 (3) 109
Symmetry codes: (i) [-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]; (ii) x, y+1, z; (iii) [-x, -y+1, -z+1]; (iv) [x-1, y+1, z]; (v) [x-1, -y+{\script{3\over 2}}, z-{\script{1\over 2}}]; (vi) [-x+2, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]; (vii) [x, y-1, z].

The columnar structures are also consolidated by the other methane­sulfonate ion (red) containing the S32 atom, which is linked by two opposing amidino groups [N15—H15A⋯O33iii =2.854 (3) and N15—H15B⋯O34iv = 2.830 (3) Å], related by the inversion center, into an R44(12) ring. A weak C—H⋯π inter­action is also observed (Table 2[link]).

4. Database survey

The crystal structures of serine protease inhibitors have been reported for benzamidine (TEKTUY: Barker et al., 1996[Barker, J., Phillips, P. R., Wallbridge, M. G. H. & Powell, H. R. (1996). Acta Cryst. C52, 2617-2619.]), benzamidine HCl (DOHHAJ: Thailambal et al., 1986[Thailambal, V. G., Pattabhi, V. & Guru Row, T. N. (1986). Acta Cryst. C42, 587-589.]) and camostat mesylate (JAMREU: Matsumoto et al., 1989[Matsumoto, O., Taga, T. & Machida, K. (1989). Acta Cryst. C45, 913-915.]). Moreover, a search of the Cambridge Structural Database (CSD version 5.42, last updated May 2021; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) yielded another comparable structure, 4-guanidinio­benzoic acid HCl dihydrate (NIQCEW: Light et al., 2007[Light, M. E., Martinez, J. C. & Gale, P. A. (2007). CSD Communication (refcode NIQCEW). CCDC, Cambridge, England. https://doi.org/10.5517/ccpw2h3]). Another database search (PDB; 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.]) yielded the crystal structure of human TMPRSS2 in a covalent complex with nafamostat (PDB7MEQ: Fraser et al., 2021[Fraser, B., Beldar, S., Hutchinson, A., Li, Y., Seitova, A., Edwards, A. M., Benard, F., Arrowsmith, C. H. & Halabelian, L. (2021). doi: 10.2210/pdb7MEQ/pdb.]).

5. Synthesis and crystallization

Nafamostat mesylate (CAS No. 82956-11-4) was purchased from Tokyo Chemical Industry Co. Ltd (TCI). A small portion (ca 10 mg) was dissolved in a small volume of hot water (ca 100 µL), and acetone (ca 900 µL) was added slowly until it became cloudy white. On slow cooling to ambient temperature, colourless octa­hedral crystals suitable for X-ray measurements were obtained.

6. Refinement

Crystal data, data collection and structure refinement details at a low temperature (95 K) are summarized in Table 3[link]. All the H atoms were located in difference-Fourier maps. In the NH or NH2 groups, H atoms were freely refined. The C-bound H atoms were included in calculated positions and treated as riding atoms: C—H = 0.95–0.98 Å with Uiso(H) = 1.2–1.5Ueq(C).

Table 3
Experimental details

Crystal data
Chemical formula C19H19N5O22+·2CH3O3S−
Mr 539.58
Crystal system, space group Monoclinic, P21/c
Temperature (K) 95
a, b, c (Å) 11.0631 (1), 9.7215 (1), 21.9271 (3)
β (°) 96.746 (1)
V (Å3) 2341.93 (5)
Z 4
Radiation type Cu Kα
μ (mm−1) 2.59
Crystal size (mm) 0.4 × 0.3 × 0.3
 
Data collection
Diffractometer A Rigaku XtaLAB P200
Absorption correction Multi-scan (CrysAlis PRO; Rigaku, 2015[Rigaku (2015). CrysAlis PRO. Rigaku, The Woodlands, Texas, USA.])
Tmin, Tmax 0.46, 1
No. of measured, independent and observed [I > 2σ(I)] reflections 4675, 4675, 4457
Rint 0.058
(sin θ/λ)max (Å−1) 0.623
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.055, 0.126, 1.07
No. of reflections 4675
No. of parameters 363
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.64, −0.52
Computer programs: CrysAlis PRO (Rigaku, 2015[Rigaku (2015). CrysAlis PRO. Rigaku, The Woodlands, Texas, USA.]), SORTAV (Blessing, 1995[Blessing, R. H. (1995). Acta Cryst. A51, 33-38.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), ORTEP-3 for Windows and WinGX (Farrugia, 2012[Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849-854.]), Mercury (Macrae et al., 2020[Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226-235.]), PLATON (Spek, 2020[Spek, A. L. (2020). Acta Cryst. E76, 1-11.]) and publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).

Supporting information

CCDC reference: 2107852

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989021009245/tx2042sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989021009245/tx2042Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989021009245/tx2042Isup3.cml

checkCIF report


Computing details top

Data collection: CrysAlis PRO (Rigaku, 2015); cell refinement: CrysAlis PRO (Rigaku, 2015); data reduction: SORTAV (Blessing, 1995); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012), Mercury (Macrae et al., 2020); software used to prepare material for publication: PLATON (Spek, 2020), WinGX (Farrugia, 2012) and publCIF (Westrip, 2010).

[Amino({6-[(4-{[amino(iminiumyl)methyl]amino}phenyl)carbonyloxy]naphthalen-2-yl})methylidene]azanium bis(methanesulfonate) top
Crystal data top
C19H19N5O22+·2CH3O3S−F(000) = 1128
Mr = 539.58Dx = 1.53 Mg m−3
Monoclinic, P21/cCu Kα radiation, λ = 1.54184 Å
Hall symbol: -P 2ybcCell parameters from 17552 reflections
a = 11.0631 (1) Åθ = 5.0–73.5°
b = 9.7215 (1) ŵ = 2.59 mm−1
c = 21.9271 (3) ÅT = 95 K
β = 96.746 (1)°Octahedron, clear light colourless
V = 2341.93 (5) Å30.4 × 0.3 × 0.3 mm
Z = 4
Data collection top
A Rigaku XtaLAB P200
diffractometer		4675 independent reflections
Radiation source: fine-focus sealed X-ray tube4457 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.058
φ or ω oscillation scansθmax = 73.8°, θmin = 4.0°
Absorption correction: multi-scan
(CrysAlis PRO; Rigaku, 2015)		h = −13→13
Tmin = 0.46, Tmax = 1k = 0→11
4675 measured reflectionsl = 0→27
Refinement top
Refinement on F2Primary atom site location: dual
Least-squares matrix: fullSecondary atom site location: dual
R[F2 > 2σ(F2)] = 0.055Hydrogen site location: mixed
wR(F2) = 0.126H atoms treated by a mixture of independent and constrained refinement
S = 1.07 w = 1/[σ2(Fo2) + (0.0324P)2 + 4.9921P]
where P = (Fo2 + 2Fc2)/3
4675 reflections(Δ/σ)max = 0.001
363 parametersΔρmax = 0.64 e Å−3
0 restraintsΔρmin = −0.52 e Å−3
0 constraints
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
C10.1422 (2)0.5583 (3)0.56523 (13)0.0225 (5)
C20.0580 (2)0.5892 (3)0.60620 (13)0.0237 (5)
H20.0617780.5440660.6447990.028*
C3−0.0304 (2)0.6865 (3)0.58945 (12)0.0234 (5)
H3−0.0866370.7103280.6172870.028*
C4−0.0384 (2)0.7505 (3)0.53201 (12)0.0225 (5)
C5−0.1241 (2)0.8550 (3)0.51578 (12)0.0229 (5)
H5−0.1770170.8830650.5445970.027*
C6−0.1333 (2)0.9184 (3)0.45831 (13)0.0229 (5)
C7−0.0545 (2)0.8762 (3)0.41562 (12)0.0237 (5)
H7−0.0602460.9177180.3761620.028*
C80.0302 (2)0.7756 (3)0.43105 (12)0.0228 (5)
H80.0817460.7479360.4015560.027*
C90.0437 (2)0.7116 (3)0.48926 (12)0.0221 (5)
C100.1352 (2)0.6151 (3)0.50758 (12)0.0224 (5)
H100.1918080.5892510.4802710.027*
C120.3080 (2)0.4764 (3)0.63457 (12)0.0205 (5)
C14−0.2214 (2)1.0326 (3)0.44424 (12)0.0203 (5)
C160.4005 (2)0.3658 (3)0.64313 (12)0.0206 (5)
C170.4753 (2)0.3600 (3)0.69882 (12)0.0223 (5)
H170.4665340.4269780.7295540.027*
C180.5632 (2)0.2563 (3)0.70998 (12)0.0222 (5)
H180.613450.2520490.7481670.027*
C190.5758 (2)0.1599 (3)0.66434 (12)0.0217 (5)
C200.5019 (2)0.1658 (3)0.60820 (12)0.0237 (5)
H200.511470.1000930.5770620.028*
C210.4145 (2)0.2678 (3)0.59814 (12)0.0229 (5)
H210.3635370.2710470.5601520.027*
C240.7756 (2)0.0499 (3)0.69864 (12)0.0212 (5)
C300.7107 (2)0.5832 (3)0.76962 (13)0.0245 (6)
H30A0.6612420.6370080.7381220.037*
H30B0.7342630.6413570.8055710.037*
H30C0.6632870.5046650.7816350.037*
C350.6293 (2)−0.4167 (3)0.57039 (13)0.0262 (6)
H35A0.717501−0.4033310.5782790.039*
H35B0.607172−0.4414660.5271880.039*
H35C0.604676−0.4907550.5966650.039*
N15−0.3033 (2)1.0565 (3)0.48204 (11)0.0238 (5)
N22−0.2175 (2)1.1128 (2)0.39642 (11)0.0214 (5)
N230.65733 (19)0.0475 (2)0.67377 (11)0.0242 (5)
N250.8365 (2)0.1631 (2)0.71094 (12)0.0242 (5)
N260.8283 (2)−0.0718 (2)0.70825 (12)0.0252 (5)
O110.23387 (15)0.46189 (19)0.57993 (8)0.0217 (4)
O130.29656 (16)0.5684 (2)0.67019 (9)0.0255 (4)
O280.80155 (16)0.44602 (19)0.68474 (8)0.0234 (4)
O290.91327 (16)0.64512 (19)0.72854 (9)0.0252 (4)
O310.90733 (15)0.43603 (19)0.78786 (8)0.0221 (4)
O330.42506 (16)−0.2921 (2)0.57331 (10)0.0308 (5)
O340.59193 (17)−0.1572 (2)0.54595 (9)0.0282 (4)
O360.59191 (19)−0.2314 (2)0.65057 (9)0.0308 (4)
S270.84252 (5)0.52334 (6)0.73995 (3)0.01897 (15)
S320.55448 (5)−0.26334 (6)0.58663 (3)0.01882 (15)
H22A−0.168 (3)1.102 (3)0.3710 (14)0.017 (7)*
H25B0.902 (3)0.162 (3)0.7333 (14)0.019 (7)*
H22B−0.266 (3)1.177 (3)0.3897 (13)0.019 (7)*
H25A0.806 (3)0.244 (4)0.7016 (17)0.039 (10)*
H26B0.787 (3)−0.150 (4)0.7025 (17)0.045 (10)*
H15A−0.354 (3)1.132 (4)0.4725 (17)0.043 (10)*
H26A0.905 (4)−0.078 (4)0.7167 (18)0.051 (11)*
H15B−0.323 (3)0.994 (4)0.5063 (18)0.043 (10)*
H230.627 (4)−0.042 (5)0.6577 (19)0.062 (12)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0136 (11)0.0182 (13)0.0341 (14)0.0017 (9)−0.0030 (10)−0.0012 (10)
C20.0163 (12)0.0241 (14)0.0307 (14)−0.0010 (10)0.0023 (10)0.0018 (11)
C30.0134 (11)0.0253 (14)0.0324 (14)0.0000 (10)0.0060 (10)−0.0028 (11)
C40.0129 (11)0.0224 (13)0.0319 (14)−0.0016 (10)0.0021 (10)−0.0035 (11)
C50.0141 (11)0.0245 (14)0.0306 (13)−0.0018 (10)0.0047 (10)−0.0030 (11)
C60.0126 (11)0.0194 (13)0.0359 (14)−0.0009 (9)0.0002 (10)−0.0011 (11)
C70.0184 (12)0.0250 (14)0.0271 (13)−0.0014 (10)0.0005 (10)0.0011 (10)
C80.0160 (12)0.0217 (13)0.0301 (13)0.0023 (10)0.0008 (10)−0.0031 (10)
C90.0156 (11)0.0249 (14)0.0256 (13)−0.0039 (10)0.0015 (10)−0.0012 (10)
C100.0177 (12)0.0224 (14)0.0277 (13)−0.0004 (10)0.0051 (10)−0.0012 (10)
C120.0138 (11)0.0196 (13)0.0286 (13)−0.0014 (9)0.0050 (10)−0.0004 (10)
C140.0114 (11)0.0187 (13)0.0303 (13)−0.0028 (9)0.0000 (9)−0.0012 (10)
C160.0126 (11)0.0201 (13)0.0293 (13)−0.0013 (9)0.0033 (9)0.0019 (10)
C170.0170 (12)0.0255 (14)0.0244 (12)−0.0037 (10)0.0018 (10)0.0002 (10)
C180.0182 (12)0.0219 (13)0.0259 (13)−0.0015 (10)0.0000 (10)−0.0001 (10)
C190.0144 (11)0.0218 (13)0.0290 (13)−0.0016 (10)0.0029 (10)0.0020 (10)
C200.0166 (12)0.0250 (14)0.0290 (13)0.0003 (10)0.0010 (10)0.0008 (11)
C210.0209 (12)0.0217 (13)0.0270 (13)−0.0021 (10)0.0069 (10)0.0000 (10)
C240.0142 (11)0.0256 (14)0.0247 (12)0.0026 (10)0.0057 (9)0.0020 (10)
C300.0151 (12)0.0286 (15)0.0301 (14)0.0051 (10)0.0035 (10)0.0020 (11)
C350.0194 (12)0.0225 (14)0.0359 (15)0.0023 (10)0.0004 (11)0.0014 (11)
N150.0169 (10)0.0226 (12)0.0324 (12)0.0037 (9)0.0054 (9)0.0062 (10)
N220.0149 (10)0.0217 (12)0.0280 (12)0.0019 (9)0.0037 (9)0.0004 (9)
N230.0137 (10)0.0245 (12)0.0334 (12)0.0027 (9)−0.0012 (9)−0.0001 (10)
N250.0160 (11)0.0187 (12)0.0378 (13)0.0028 (9)0.0037 (10)0.0035 (10)
N260.0146 (11)0.0202 (12)0.0409 (14)0.0014 (9)0.0034 (9)0.0005 (10)
O110.0142 (8)0.0238 (10)0.0267 (9)0.0021 (7)0.0002 (7)−0.0028 (7)
O130.0184 (9)0.0270 (10)0.0310 (10)0.0029 (7)0.0019 (7)−0.0023 (8)
O280.0234 (9)0.0202 (9)0.0264 (9)0.0013 (7)0.0021 (7)−0.0010 (7)
O290.0202 (9)0.0200 (10)0.0358 (10)−0.0005 (7)0.0059 (8)0.0036 (8)
O310.0136 (8)0.0236 (10)0.0288 (9)0.0045 (7)0.0012 (7)0.0060 (7)
O330.0126 (9)0.0248 (10)0.0547 (13)0.0006 (7)0.0027 (8)0.0066 (9)
O340.0288 (10)0.0214 (10)0.0358 (11)0.0005 (8)0.0102 (8)0.0067 (8)
O360.0398 (11)0.0225 (10)0.0282 (10)0.0011 (8)−0.0038 (8)0.0013 (8)
S270.0124 (3)0.0184 (3)0.0264 (3)0.0017 (2)0.0034 (2)0.0019 (2)
S320.0117 (3)0.0167 (3)0.0281 (3)0.0007 (2)0.0021 (2)0.0025 (2)
Geometric parameters (Å, º) top
C1—O111.391 (3)C35—S321.762 (3)
C1—C21.401 (4)C35—H35C0.98
C1—C101.373 (4)C35—H35B0.98
C10—H100.95C35—H35A0.98
C12—O131.204 (3)C4—C91.430 (4)
C12—O111.377 (3)C4—C51.407 (4)
C12—C161.481 (3)C5—H50.95
C14—N221.311 (3)C5—C61.396 (4)
C14—N151.319 (3)C6—C71.413 (4)
C16—C211.393 (4)C6—C141.486 (3)
C16—C171.393 (4)C7—H70.95
C17—H170.95C7—C81.369 (4)
C17—C181.402 (4)C8—H80.95
C18—H180.95C8—C91.412 (4)
C18—C191.390 (4)C9—C101.403 (4)
C19—N231.417 (3)N15—H15B0.85 (4)
C19—C201.397 (4)N15—H15A0.93 (4)
C2—H20.95N22—H22B0.83 (3)
C2—C31.379 (4)N22—H22A0.83 (3)
C20—H200.95N23—H230.99 (4)
C20—C211.384 (4)N25—H25B0.83 (3)
C21—H210.95N25—H25A0.87 (4)
C24—N261.325 (3)N26—H26B0.89 (4)
C24—N251.302 (4)N26—H26A0.85 (4)
C24—N231.357 (3)O28—S271.4515 (19)
C3—H30.95O29—S271.4570 (19)
C3—C41.398 (4)O31—S271.4700 (18)
C30—S271.764 (3)O33—S321.4545 (18)
C30—H30C0.98O34—S321.4553 (19)
C30—H30B0.98O36—S321.448 (2)
C30—H30A0.98
C10—C1—O11116.5 (2)C21—C20—H20120.2
C10—C1—C2122.3 (2)C19—C20—H20120.2
O11—C1—C2121.2 (2)C20—C21—C16120.7 (3)
C3—C2—C1118.7 (2)C20—C21—H21119.6
C3—C2—H2120.6C16—C21—H21119.6
C1—C2—H2120.6N25—C24—N26121.0 (2)
C2—C3—C4120.8 (2)N25—C24—N23123.3 (2)
C2—C3—H3119.6N26—C24—N23115.7 (2)
C4—C3—H3119.6S27—C30—H30A109.5
C3—C4—C5121.2 (2)S27—C30—H30B109.5
C3—C4—C9119.7 (2)H30A—C30—H30B109.5
C5—C4—C9119.1 (2)S27—C30—H30C109.5
C6—C5—C4121.5 (2)H30A—C30—H30C109.5
C6—C5—H5119.3H30B—C30—H30C109.5
C4—C5—H5119.3S32—C35—H35A109.5
C5—C6—C7119.0 (2)S32—C35—H35B109.5
C5—C6—C14119.6 (2)H35A—C35—H35B109.5
C7—C6—C14121.3 (2)S32—C35—H35C109.5
C8—C7—C6120.1 (2)H35A—C35—H35C109.5
C8—C7—H7120H35B—C35—H35C109.5
C6—C7—H7120C14—N15—H15A116 (2)
C7—C8—C9122.3 (2)C14—N15—H15B120 (3)
C7—C8—H8118.8H15A—N15—H15B121 (3)
C9—C8—H8118.8C14—N22—H22A123 (2)
C10—C9—C8123.3 (2)C14—N22—H22B121 (2)
C10—C9—C4118.7 (2)H22A—N22—H22B116 (3)
C8—C9—C4117.9 (2)C24—N23—C19127.7 (2)
C1—C10—C9119.6 (2)C24—N23—H23115 (2)
C1—C10—H10120.2C19—N23—H23117 (2)
C9—C10—H10120.2C24—N25—H25B121 (2)
O13—C12—O11122.9 (2)C24—N25—H25A122 (2)
O13—C12—C16125.5 (2)H25B—N25—H25A116 (3)
O11—C12—C16111.6 (2)C24—N26—H26B122 (2)
N22—C14—N15119.1 (2)C24—N26—H26A120 (3)
N22—C14—C6121.9 (2)H26B—N26—H26A117 (4)
N15—C14—C6119.0 (2)C12—O11—C1118.4 (2)
C17—C16—C21119.3 (2)O28—S27—O29113.51 (11)
C17—C16—C12118.1 (2)O28—S27—O31112.04 (11)
C21—C16—C12122.6 (2)O29—S27—O31111.41 (11)
C16—C17—C18120.7 (2)O28—S27—C30106.72 (12)
C16—C17—H17119.7O29—S27—C30106.21 (12)
C18—C17—H17119.7O31—S27—C30106.39 (12)
C19—C18—C17119.0 (2)O36—S32—O33113.48 (13)
C19—C18—H18120.5O36—S32—O34111.82 (12)
C17—C18—H18120.5O33—S32—O34110.96 (12)
C18—C19—C20120.6 (2)O36—S32—C35106.84 (13)
C18—C19—N23122.1 (2)O33—S32—C35105.73 (12)
C20—C19—N23117.2 (2)O34—S32—C35107.57 (12)
C21—C20—C19119.7 (3)
Hydrogen-bond geometry (Å, º) top
Cg(C) is the center of gravity of phenyl ring C.
D—H···AD—HH···AD···AD—H···A
C18—H18···O13i0.952.643.419 (3)140
C30—H30A···O36ii0.982.363.314 (3)165
N15—H15A···O33iii0.93 (4)1.97 (4)2.854 (3)159 (3)
N15—H15A···O34iii0.93 (4)2.63 (4)3.327 (3)132 (3)
N15—H15A···S32iii0.93 (4)2.75 (4)3.612 (2)154 (3)
N15—H15B···O34iv0.85 (4)2.00 (4)2.830 (3)164 (4)
N22—H22A···O31v0.83 (3)2.12 (3)2.928 (3)162 (3)
N22—H22B···O33iii0.83 (3)2.31 (3)3.018 (3)144 (3)
N23—H23···O360.99 (4)1.88 (5)2.836 (3)163 (4)
N23—H23···S320.99 (4)2.72 (4)3.683 (2)166 (3)
N25—H25A···O280.87 (4)2.00 (4)2.827 (3)159 (3)
N25—H25A···S270.87 (4)2.86 (4)3.558 (2)139 (3)
N25—H25B···O29vi0.83 (3)2.12 (3)2.931 (3)167 (3)
N26—H26A···O31vi0.85 (4)2.10 (4)2.916 (3)163 (4)
N26—H26A···S27vi0.85 (4)3.01 (4)3.799 (2)156 (3)
N26—H26B···O29vii0.89 (4)2.46 (4)2.925 (3)113 (3)
N26—H26B···O360.89 (4)2.45 (4)3.174 (3)139 (3)
C30—H30B···Cg(C)vii0.982.963.405 (3)109
Symmetry codes: (i) −x+1, y−1/2, −z+3/2; (ii) x, y+1, z; (iii) −x, −y+1, −z+1; (iv) x−1, y+1, z; (v) x−1, −y+3/2, z−1/2; (vi) −x+2, y−1/2, −z+3/2; (vii) x, y−1, z.
 

Acknowledgements

The author thanks Tokai University for a research grant, which partially supported this work.

References

First citationBarker, J., Phillips, P. R., Wallbridge, M. G. H. & Powell, H. R. (1996). Acta Cryst. C52, 2617–2619.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
 First citationBerman, 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.  Web of Science CrossRef PubMed CAS Google Scholar
 First citationBlessing, R. H. (1995). Acta Cryst. A51, 33–38.  CrossRef CAS Web of Science IUCr Journals Google Scholar
 First citationFarrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.  Web of Science CrossRef CAS IUCr Journals Google Scholar
 First citationFraser, B., Beldar, S., Hutchinson, A., Li, Y., Seitova, A., Edwards, A. M., Benard, F., Arrowsmith, C. H. & Halabelian, L. (2021). doi: 10.2210/pdb7MEQ/pdb.  Google Scholar
 First citationFujii, S. & Hitomi, Y. (1981). Biochim. Biophys. Acta Enzymology, 661, 342–345.  CrossRef CAS Web of Science Google Scholar
 First citationGroom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179.  Web of Science CrossRef IUCr Journals Google Scholar
 First citationHoffmann, M., Schroeder, S., Kleine-Weber, H., Müller, M. A., Drosten, C. & Pöhlmann, S. (2020). Antimicrob. Agents Chemother. 64, e00754–20.  Web of Science CrossRef PubMed Google Scholar
 First citationLight, M. E., Martinez, J. C. & Gale, P. A. (2007). CSD Communication (refcode NIQCEW). CCDC, Cambridge, England. https://doi.org/10.5517/ccpw2h3  Google Scholar
 First citationMacrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235.  Web of Science CrossRef CAS IUCr Journals Google Scholar
 First citationMatsumoto, O., Taga, T. & Machida, K. (1989). Acta Cryst. C45, 913–915.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
 First citationRigaku (2015). CrysAlis PRO. Rigaku, The Woodlands, Texas, USA.  Google Scholar
 First citationSheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
 First citationSheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
 First citationSpek, A. L. (2020). Acta Cryst. E76, 1–11.  Web of Science CrossRef IUCr Journals Google Scholar
 First citationTakeda, K., Kakugawa, Y., Kobari, M. & Matsuno, S. (1989). Gastroenterol. Jpn. 24, 340.  CrossRef PubMed Google Scholar
 First citationTamura, Y., Hirado, M., Okamura, K., Minato, Y. & Fujii, S. (1977). Biochim. Biophys. Acta Enzymology, 484, 417–422.  CrossRef CAS Web of Science Google Scholar
 First citationThailambal, V. G., Pattabhi, V. & Guru Row, T. N. (1986). Acta Cryst. C42, 587–589.  CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
 First citationWestrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.  Web of Science CrossRef CAS IUCr Journals Google Scholar
 First citationYamamoto, M., Kiso, M., Sakai-Tagawa, Y., Iwatsuki-Horimoto, K., Imai, M., Takeda, M., Kinoshita, N., Ohmagari, N., Gohda, J., Semba, K., Matsuda, Z., Kawaguchi, Y., Kawaoka, Y. & Inoue, J. (2020). Viruses, 12, 629–638.  Web of Science CrossRef CAS Google Scholar
 First citationYamamoto, M., Matsuyama, S., Li, X., Takeda, M., Kawaguchi, Y., Inoue, J. & Matsuda, Z. (2016). Antimicrob. Agents Chemother. 60, 6532–6539.  Web of Science CrossRef CAS PubMed Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 77| Part 10| October 2021| Pages 999-1002
https://doi.org/10.1107/S2056989021009245
Follow Acta Cryst. E
Sign up for e-alerts
E-alerts
Follow Acta Cryst. on Twitter
Twitter
Follow us on facebook
Facebook
Sign up for RSS feeds
RSS