Hirshfeld analysis and mol­ecular docking with the RDR enzyme of 2-(5-chloro-2-oxoindolin-3-yl­idene)-N-methyl­hydrazinecarbo­thio­amide

Velasques, J.M.; Gervini, V.C.; Kickofel, L.; Farias, R.L. de; Oliveira, A.B. de

doi:10.1107/S2056989017005461

research communications

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ISSN: 2056-9890

Volume 73| Part 5| May 2017| Pages 702-707

https://doi.org/10.1107/S2056989017005461

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Hirshfeld analysis and molecular docking with the RDR enzyme of 2-(5-chloro-2-oxoindolin-3-ylidene)-N-methylhydrazinecarbothioamide

Jecika Maciel Velasques,^a ‡ Vanessa Carratu Gervini,^a ^* Lisliane Kickofel,^a Renan Lira de Farias ^b and Adriano Bof de Oliveira ^c

^aUniversidade Federal do Rio Grande (FURG), Escola de Química e Alimentos, Rio Grande, Brazil, ^bUniversidade Estadual Paulista (UNESP), Instituto de Química, Araraquara, Brazil, and ^cUniversidade Federal de Sergipe (UFS), Departamento de Química, São Cristóvão, Brazil
^*Correspondence e-mail: vanessa.gervini@gmail.com

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 4 April 2017; accepted 10 April 2017; online 13 April 2017)

The acetic acid-catalyzed reaction between 5-chloroisatin and 4-methylthiosemicarbazide yields the title compound, C₁₀H₉ClN₄OS (I) (common name: 5-chloroisatin-4-methylthiosemicarbazone). The molecule is nearly planar (r.m.s. deviation = 0.047 Å for all non-H atoms), with a maximum deviation of 0.089 (1) Å for the O atom. An S(6) ring motif formed by an intramolecular N—H⋯O hydrogen bond is observed. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming chains propagating along the a-axis direction. The chains are linked by N—H⋯S hydrogen bonds, forming a three-dimensional supramolecular structure. The three-dimensional framework is reinforced by C—H⋯π interactions. The absolute structure of the molecule in the crystal was determined by resonant scattering [Flack parameter = 0.006 (9)]. The crystal structure of the same compound, measured at 100 K, has been reported on previously [Qasem Ali et al. (2012 ). Acta Cryst. E68, o964–o965]. The Hirshfeld surface analysis indicates that the most important contributions for the crystal packing are the H⋯H (23.1%), H⋯C (18.4%), H⋯Cl (13.7%), H⋯S (12.0%) and H⋯O (11.3%) interactions. A molecular docking evaluation of the title compound with the ribonucleoside diphosphate reductase (RDR) enzyme was carried out. The title compound (I) and the active site of the selected enzyme show Cl⋯H—C(LYS140), Cg(aromatic ring)⋯H—C(SER71), H⋯O—C(GLU200) and Fe^III⋯O⋯Fe^III intermolecular interactions, which suggests a solid theoretical structure–activity relationship.

Keywords: crystal structure; isatin thiosemicarbazone derivative; hydrogen bonding; Hirshfeld surface analysis; RDR-thiosemicarbazone in silico evaluation.

CCDC reference: 1543340

1. Chemical context

Methods for the synthesis of isatin derivatives were first reported in the first half of the 19th century (Erdmann, 1841a ,b ; Laurent, 1841 ), while for thiosemicarbazone derivatives one of the first reports can be traced back to the early 1900's (Freund & Schander, 1902 ). Initially, thiosemicarbazone chemistry was not related to the pharmacological sciences. This has changed since the discovery that in vitro assays of sulfur-containing compounds showed that they are effective for Mycobacterium tuberculosis growth inhibition (Domagk et al., 1946 ). In the 1950's, the synthesis of isatin–thiosemicarbazone derivatives was reported (Campaigne & Archer, 1952 ) and in vitro assays indicated such compounds to be active against Cruzain, Falcipain-2 and Rhodesian (Chiyanzu et al., 2003 ). Nowadays, many isatin–thiosemicarbazone derivatives employed in medicinal chemistry. For example, 1-[(2-methylbenzimidazol-1-yl) methyl]-2-oxo-indolin-3-ylidene]amino]thiourea is an in vitro and in silico Chikungunya virus inhibitor (Mishra et al., 2016 ). The title compound (I), 5-chloroisatin-4-methylthiosemicarbazone, is an intermediate in the synthetic pathway of HIV-1 (human immunodeficiency virus type 1) RT (reverse transcriptase) inhibitor synthesis (Meleddu et al., 2017 ); a new crystal structure determination is reported here, the original work having been published by Qasem Ali et al. (2012). Thus, the crystal structure determination of isatin–thiosemicarbazone-based molecules is an intensive research area in medicinal chemistry and the main focus of our work.

2. Structural commentary

The present analysis of the title compound (I), measured at 200 K, is very similar to that measured by Qasem Ali et al. (2012) at 100 K. There is one intramolecular hydrogen bond, N3—H3N⋯O1 (Table 1), with an S(6) graph-set motif (Fig. 1). The molecule is almost planar (r.m.s. deviation = 0.047 Å for all non-H atoms), with maximum deviations of −0.089 (1), −0.073 (1) and 0.057 (1) Å for atoms O1, Cl1 and S1, respectively. In addition, the torsion angle for the N4—C9—N3—N2 unit is −0.8 (2)°.

Table 1
Hydrogen-bond geometry (Å, °)

Cg is the centroid of the C3–C8 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3N⋯O1	0.83 (2)	2.12 (3)	2.756 (2)	134 (2)
N1—H1N⋯O1ⁱ	0.79 (2)	2.04 (3)	2.824 (2)	175 (2)
N4—H4N⋯S1ⁱⁱ	0.88 (3)	2.72 (3)	3.518 (2)	152 (2)
C6—H6⋯Cgⁱⁱⁱ	0.95	2.61	3.410 (2)	142
Symmetry codes: (i) $[x+{\script{1\over 2}}, -y+{\script{3\over 2}}, -z+1]$ ; (ii) $[-x, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (iii) $[x+{\script{1\over 2}}, -y+{\script{1\over 2}}, -z+1]$ .

Figure 1
The molecular structure of the title compound (I)

(this work), showing the atom labelling and displacement ellipsoids drawn at the 50% probability level. The intramolecular hydrogen bond [graph-set motif S(6)] is shown as a dashed line (see Table 1

3. Supramolecular features

In the crystal, molecules are linked by N1—H1N⋯O1ⁱ hydrogen bonds, forming chains propagating along the a-axis direction. The chains are linked by N4—H4N⋯Sⁱⁱ hydrogen bonds, forming a three-dimensional supramolecular structure (Fig. 2, Table 1). The three-dimensional framework is reinforced by C6—H6⋯πⁱⁱⁱ interactions, as shown in Fig. 2 (see also Table 1). The crystal structure determined in this work and that of the originally published article (Qasem Ali et al., 2012) are, of course, similar.

Figure 2
A view along the a axis of the crystal packing of the title compound (I)

(this work). Details of the N—H⋯O and N—H⋯S hydrogen bonds (dashed lines) and the C—H⋯π interactions (blue arrows) are given in Table 1

. H atoms not involved in these interactions have been omitted for clarity.

4. Hirshfeld surface analysis

The Hirshfeld surface analysis (Hirshfeld, 1977 ) of the crystal structure of (I) suggests that the contribution of the H⋯H intermolecular interactions for the crystal structure cohesion amounts to 23.1%. The contributions of the other major intermolecular interactions are: H⋯C (18.4%), H⋯Cl (13.7%), H⋯S (12.0%) and H⋯O (11.3%). The minor observed contributions for the crystal packing are H⋯N (5.3%) and C⋯N (4.2%). The Hirshfeld surface graphical representation, d_norm, with transparency and labelled atoms indicates, in magenta, the locations of the strongest intermolecular contacts, e.g. the H6 and H2 atoms, which are important for the intermolecular hydrogen bonding (Fig. 3a). The H⋯H, H⋯C, H⋯Cl, H⋯S and H⋯O contributions to the crystal packing are shown as a Hirshfeld surface two-dimensional fingerprint plot with cyan dots. The d_e (y axis) and d_i (x axis) values are the closest external and internal distances (Å) from given points on the Hirshfeld surface contacts (Figs. 4a and 5) (Wolff et al., 2012 ).

Figure 3
The Hirshfeld surface graphical representation (d_norm) for the asymmetric unit of: (a) the title compound (I)

(this work) and (b) 5-chloroisatin-thiosemicarbazone (II) (de Bittencourt et al., 2014

). The surface regions with strongest intermolecular interactions are drawn in magenta colour.

Figure 4
Hirshfeld surface two-dimensional fingerprint plots for the crystal structures of: (a) the title compound (I)

(this work) and (b) 5-chloroisatin-thiosemicarbazone (II) (de Bittencourt et al., 2014

), showing the H⋯S contacts in detail (cyan dots). The contribution of the H⋯S interactions to the molecular cohesion of the crystal structures amounts to 12.0 and 17.2%, respectively. The d_e (y axis) and d_i (x axis) values are the closest external and internal distances (Å) from given points on the Hirshfeld surface contacts.

Figure 5
Hirshfeld surface two-dimensional fingerprint plots for the title compound (I)

(this work), showing the (a) H⋯H, (b) H⋯C, (c) H⋯Cl and (d) H⋯O contacts in detail (cyan dots). The contributions of the interactions to the crystal packing amount to 23.1, 18.4, 13.7 and 11.3%, respectively. The d_e (y axis) and d_i (x axis) values are the closest external and internal distances (Å) from given points on the Hirshfeld surface contacts.

5. Molecular docking

Finally, for an interaction between the 5-chloroisatin-4-methylthiosemicarbazone (this work) and a biological target, the ribonucleoside diphosphate reductase (RDR), a lock-and-key supramolecular analysis was carried out (Chen, 2015 ). The RDR enzyme was selected for this work due its importance in cell proliferation. It catalyzes the conversion of ribonucleotides to deoxyribonucleotides, which is the rate-limiting step for DNA synthesis. In addition, a thiosemicarbazone derivative, the 3-amino-pyridine-2-carboxaldehyde thiosemicarbazone, shows RDR inhibition and biological activity is suggested by its coordination with the Fe ions of the enzyme active site (Popović-Bijelić et al., 2011 ). The commercial name for this thiosemicarbazone derivative is Triapine. Its source until 2009 was Vion Pharmaceuticals Inc., New Haven, CT, United States. Since 2017, Trethera Corporation, Santa Monica, CA, and Nanotherapeutics Inc., Alachua, FL, have had a worldwide agreement for the development, production and commercialization of Triapine formulations and for its applications in hematological malignancies (Nanotherapeutics, 2017 ). This illustrates that academic institutions, public and private research facilities and industry have a high level of interest in thiosemicarbazone derivatives and in studies concerning RDR–thiosemicarbazone interactions.

The semi-empirical equilibrium energy of the title compound (this work) was obtained using the PM6 Hamiltonian (Stewart, 2013 ), but the experimental bond lengths were conserved. The crystal structure of the RDR enzyme (PDB code: 1W68) was downloaded from the Protein Data Bank (Strand et al., 2004 ). The calculated parameters were: heat of formation = 98.697 kcal mol⁻¹, gradient normal = 0.68005, HOMO = −8.934 eV, LUMO = −1.598 eV and energy gap = 7.336 eV. The title compound (I) and the active site of the selected enzyme matches and structure–activity relationship can be assumed by the following observed intermolecular interactions: Cl1⋯H—C(LYS140) = 2.538 Å, Cg(aromatic ring)⋯H—C(SER71) = 2.714 Å, H5⋯O—C(GLU200) = 1.663 Å, Fe1⋯O1 = 2.567 Å and Fe2⋯O1 = 2.511 Å. The in silico evaluation suggests through the graphical representation the bridging O1 atom connecting the two Fe^III metal centers by intermolecular interactions (Fig. 6).

Figure 6
Graphical representation of a lock-and-key model for the title compound (I)

(this work) and the RDR enzyme active site, with selected amino acid residues. The interactions are shown as dashed lines and the figure in the stick model is simplified for clarity.

6. Comparison with a related structure

Isatin–thiosemicarbazone derivatives have molecular structural features in common, viz. nearly a planar geometry as a result of the sp²-hybridized C and N atoms of the main fragment. For a comparison with the title compound [5-chloroisatin-4-methylthiosemicarbazone (I); this work], 5-chloroisatin-thiosemicarbazone, (II), was selected (de Bittencourt et al., 2014 ) as both structures have the same main entity. The molecular structural difference is the substitution of one H atom of the amine group of (II) by a methyl group in the title compound (I). Although the molecular basis for the two compounds is the same, there are significant differences in the crystal packing. For compound (I), the unit cell is chiral and the molecules are linked by hydrogen bonding into a three-dimensional network (Figs. 2 and 7a), while for compound (II) the unit cell is centrosymmetric and the hydrogen bonding is observed in a planar arrangement, with the molecules stacked along the [001] direction (Fig. 7b). The terminal methyl group in (I) decreases the possibility of H-atom contacts with S and O acceptors, while in compound (II), the presence of the terminal unsubstituted amine increases the chances for hydrogen bonding, as suggested by the Hirshfeld surface analysis, d_norm, for the two molecules (Fig. 3a,b). The Hirshfeld surface two-dimensional fingerprint plot shows that the contribution of the H⋯S intermolecular interaction to the crystal cohesion amounts to 12.0% in the title compound (I), while for the 5-chloroisatin-thiosemicarbazone (II) it amounts to 17.2% (Fig. 5a,b). The relationship between thiosemicarbazone derivatives, the molecular assembly, the geometry of the H⋯S interactions and their contribution to the crystal structures can be seen in a recently published article (de Oliveira et al., 2017 ).

Figure 7
Section of the crystal structures of: (a) the title compound (I)

(this work), and (b) 5-chloroisatin–thiosemicarbazone (II) (de Bittencourt et al., 2014

), showing the molecular stacking along the [001] direction. The crystal packing of both compounds is viewed along the b axis, and the figures are simplified for clarity.

7. Synthesis and crystallization

The starting materials are commercially available and were used without further purification. The synthesis of the title compound was adapted from a previously reported procedure (Freund & Schander, 1902). In an acetic acid-catalyzed reaction, a mixture of 5-cloroisatin (3 mmol) and 4-methyl-3-thiosemicarbazide (3 mmol) in ethanol (40 ml) was stirred and refluxed for 5 h. On cooling, a solid was obtained which was filtered off. Yellow prismatic crystals of the title compound were grown in tetrahydrofuran by slow evaporation of the solvent.

8. Refinement

Crystal data, data collection and structure refinement details for the title compound (I) are summarized in Table 2. The NH H atoms were located in difference-Fourier maps and freely refined. The C-bound H atoms were positioned with idealized geometry and refined using a riding model: C—H = 0.95–0.98 Å with U_iso(H) = 1.5U_eq(C-methyl) and 1.2U_eq(C) for other H atoms. The absolute structure of the molecule in the crystal was determined by resonant scattering [Flack parameter = 0.006 (9)].

Table 2
Experimental details

Crystal data
Chemical formula	C₁₀H₉ClN₄OS
M_r	268.72
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	200
a, b, c (Å)	6.2584 (1), 10.1734 (2), 18.7183 (3)
V (Å³)	1191.78 (4)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.48
Crystal size (mm)	0.46 × 0.16 × 0.12

Data collection
Diffractometer	Bruker APEXII CCD area detector
Absorption correction	Multi-scan (SADABS; Bruker, 2014 )
T_min, T_max	0.697, 0.749
No. of measured, independent and observed [I > 2σ(I)] reflections	10426, 2342, 2295
R_int	0.013
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.020, 0.056, 1.05
No. of reflections	2342
No. of parameters	167
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.19, −0.15
Absolute structure	Flack x determined using 940 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.006 (9)
Computer programs: APEX2 and SAINT (Bruker, 2014), SHELXT2014 (Sheldrick, 2015a ), SHELXL2016 (Sheldrick, 2015b ), Mercury (Macrae et al., 2008 ), DIAMOND (Brandenburg, 2006 ), GOLD (Chen, 2015), MOPAC (Stewart, 2013), Crystal Explorer (Wolff et al., 2012), publCIF (Westrip, 2010 ) and enCIFer (Allen et al., 2004 ).

Supporting information

CCDC reference: 1543340

Crystal structure: contains datablocks I, Global. DOI: https://doi.org/10.1107/S2056989017005461/su5363sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989017005461/su5363Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989017005461/su5363Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: SAINT (Bruker, 2014); data reduction: SAINT (Bruker, 2014); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2008), DIAMOND (Brandenburg, 2006), GOLD (Chen, 2015), MOPAC (Stewart, 2013) and Crystal Explorer (Wolff et al., 2012); software used to prepare material for publication: SHELXL2016 (Sheldrick, 2015b), publCIF (Westrip, 2010) and enCIFer (Allen et al., 2004).

2-(5-Chloro-2-oxoindolin-3-ylidene)-N-methylhydrazinecarbothioamide top

Crystal data top

C₁₀H₉ClN₄OS	D_x = 1.498 Mg m⁻³
M_r = 268.72	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 9936 reflections
a = 6.2584 (1) Å	θ = 3.0–40.9°
b = 10.1734 (2) Å	µ = 0.48 mm⁻¹
c = 18.7183 (3) Å	T = 200 K
V = 1191.78 (4) Å³	Prism, yellow
Z = 4	0.46 × 0.16 × 0.12 mm
F(000) = 552

Data collection top

Bruker APEXII CCD area detector diffractometer	2295 reflections with I > 2σ(I)
Radiation source: fine-focus sealed X-ray tube, Bruker APEXII CCD	R_int = 0.013
φ and ω scans	θ_max = 26.0°, θ_min = 2.2°
Absorption correction: multi-scan (SADABS; Bruker, 2014)	h = −7→5
T_min = 0.697, T_max = 0.749	k = −12→12
10426 measured reflections	l = −23→23
2342 independent reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.020	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.056	w = 1/[σ²(F_o²) + (0.0338P)² + 0.2804P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max = 0.001
2342 reflections	Δρ_max = 0.19 e Å⁻³
167 parameters	Δρ_min = −0.15 e Å⁻³
0 restraints	Absolute structure: Flack x determined using 940 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.006 (9)

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

	x	y	z	U_iso*/U_eq
C1	0.4431 (3)	0.63210 (18)	0.56919 (9)	0.0229 (4)
C2	0.3885 (3)	0.51360 (17)	0.61332 (9)	0.0200 (4)
C3	0.5539 (3)	0.41669 (18)	0.59914 (9)	0.0199 (4)
C4	0.5853 (3)	0.28884 (18)	0.62247 (9)	0.0215 (3)
H4	0.487362	0.247309	0.653982	0.026*
C5	0.7655 (3)	0.22425 (18)	0.59789 (9)	0.0246 (4)
C6	0.9124 (3)	0.2840 (2)	0.55278 (10)	0.0278 (4)
H6	1.036794	0.237337	0.538476	0.033*
C7	0.8793 (3)	0.4117 (2)	0.52828 (10)	0.0271 (4)
H7	0.977419	0.452902	0.496717	0.033*
C8	0.6980 (3)	0.47585 (18)	0.55173 (9)	0.0226 (4)
C9	−0.0829 (3)	0.58961 (18)	0.70690 (9)	0.0216 (4)
C10	−0.2880 (3)	0.4484 (2)	0.78682 (11)	0.0345 (4)
H10A	−0.260071	0.490692	0.832924	0.052*
H10B	−0.301350	0.353251	0.793692	0.052*
H10C	−0.421127	0.483020	0.766648	0.052*
Cl1	0.80561 (8)	0.06052 (5)	0.62274 (3)	0.03753 (15)
N1	0.6267 (3)	0.60279 (16)	0.53459 (8)	0.0254 (3)
H1N	0.684 (4)	0.652 (2)	0.5082 (14)	0.037 (7)*
N2	0.2289 (3)	0.49844 (14)	0.65623 (7)	0.0210 (3)
N3	0.0946 (3)	0.60072 (16)	0.66389 (8)	0.0236 (3)
H3N	0.110 (4)	0.669 (2)	0.6405 (12)	0.031 (6)*
N4	−0.1123 (3)	0.47545 (16)	0.73815 (8)	0.0244 (3)
H4N	−0.014 (4)	0.415 (3)	0.7332 (13)	0.040 (7)*
O1	0.3382 (2)	0.73458 (13)	0.56517 (7)	0.0295 (3)
S1	−0.24203 (8)	0.72186 (5)	0.71392 (3)	0.03074 (13)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0266 (9)	0.0228 (9)	0.0194 (8)	−0.0015 (7)	−0.0011 (7)	0.0016 (7)
C2	0.0213 (8)	0.0188 (8)	0.0198 (8)	0.0008 (7)	−0.0020 (6)	0.0005 (6)
C3	0.0189 (8)	0.0235 (9)	0.0174 (7)	−0.0005 (7)	−0.0008 (6)	−0.0016 (7)
C4	0.0212 (8)	0.0240 (9)	0.0194 (7)	0.0020 (7)	0.0004 (7)	0.0010 (7)
C5	0.0249 (9)	0.0249 (8)	0.0241 (8)	0.0059 (9)	−0.0053 (7)	−0.0014 (7)
C6	0.0201 (9)	0.0358 (10)	0.0275 (9)	0.0053 (8)	0.0005 (7)	−0.0074 (8)
C7	0.0221 (9)	0.0352 (10)	0.0240 (8)	−0.0047 (8)	0.0051 (7)	−0.0038 (8)
C8	0.0245 (10)	0.0248 (9)	0.0185 (7)	−0.0041 (7)	−0.0002 (7)	−0.0022 (6)
C9	0.0178 (8)	0.0240 (9)	0.0231 (8)	0.0004 (7)	−0.0022 (7)	−0.0042 (7)
C10	0.0261 (10)	0.0391 (11)	0.0382 (10)	−0.0029 (9)	0.0065 (9)	0.0058 (9)
Cl1	0.0386 (3)	0.0307 (3)	0.0433 (3)	0.0154 (2)	−0.0012 (2)	0.0053 (2)
N1	0.0305 (9)	0.0239 (8)	0.0219 (7)	−0.0032 (7)	0.0054 (6)	0.0032 (6)
N2	0.0202 (8)	0.0197 (6)	0.0230 (7)	0.0018 (6)	−0.0012 (6)	−0.0014 (5)
N3	0.0239 (8)	0.0193 (7)	0.0277 (8)	0.0042 (6)	0.0044 (6)	0.0017 (6)
N4	0.0192 (8)	0.0246 (8)	0.0294 (8)	0.0016 (7)	0.0017 (6)	0.0008 (6)
O1	0.0366 (8)	0.0230 (7)	0.0289 (6)	0.0061 (6)	−0.0009 (6)	0.0066 (5)
S1	0.0266 (2)	0.0249 (2)	0.0407 (3)	0.0070 (2)	0.0042 (2)	−0.00341 (19)

Geometric parameters (Å, º) top

C1—O1	1.234 (2)	C7—H7	0.9500
C1—N1	1.352 (3)	C8—N1	1.404 (2)
C1—C2	1.501 (2)	C9—N4	1.313 (2)
C2—N2	1.291 (2)	C9—N3	1.376 (2)
C2—C3	1.454 (2)	C9—S1	1.6792 (18)
C3—C4	1.386 (3)	C10—N4	1.455 (2)
C3—C8	1.401 (3)	C10—H10A	0.9800
C4—C5	1.384 (3)	C10—H10B	0.9800
C4—H4	0.9500	C10—H10C	0.9800
C5—C6	1.388 (3)	N1—H1N	0.79 (3)
C5—Cl1	1.7475 (19)	N2—N3	1.345 (2)
C6—C7	1.393 (3)	N3—H3N	0.83 (3)
C6—H6	0.9500	N4—H4N	0.87 (3)
C7—C8	1.381 (3)

O1—C1—N1	127.53 (18)	C7—C8—N1	128.59 (18)
O1—C1—C2	126.21 (17)	C3—C8—N1	109.59 (16)
N1—C1—C2	106.26 (16)	N4—C9—N3	116.50 (16)
N2—C2—C3	125.68 (16)	N4—C9—S1	126.19 (14)
N2—C2—C1	127.93 (16)	N3—C9—S1	117.30 (13)
C3—C2—C1	106.39 (15)	N4—C10—H10A	109.5
C4—C3—C8	120.74 (17)	N4—C10—H10B	109.5
C4—C3—C2	132.84 (17)	H10A—C10—H10B	109.5
C8—C3—C2	106.41 (16)	N4—C10—H10C	109.5
C5—C4—C3	117.17 (17)	H10A—C10—H10C	109.5
C5—C4—H4	121.4	H10B—C10—H10C	109.5
C3—C4—H4	121.4	C1—N1—C8	111.32 (16)
C4—C5—C6	122.28 (18)	C1—N1—H1N	123.1 (19)
C4—C5—Cl1	118.75 (15)	C8—N1—H1N	125.5 (19)
C6—C5—Cl1	118.95 (15)	C2—N2—N3	117.21 (15)
C5—C6—C7	120.64 (18)	N2—N3—C9	120.21 (15)
C5—C6—H6	119.7	N2—N3—H3N	121.4 (17)
C7—C6—H6	119.7	C9—N3—H3N	118.2 (17)
C8—C7—C6	117.32 (17)	C9—N4—C10	123.53 (17)
C8—C7—H7	121.3	C9—N4—H4N	118.4 (17)
C6—C7—H7	121.3	C10—N4—H4N	117.8 (17)
C7—C8—C3	121.81 (18)

O1—C1—C2—N2	−2.4 (3)	C6—C7—C8—N1	−179.15 (17)
N1—C1—C2—N2	178.37 (18)	C4—C3—C8—C7	−2.1 (3)
O1—C1—C2—C3	178.15 (18)	C2—C3—C8—C7	178.33 (16)
N1—C1—C2—C3	−1.04 (19)	C4—C3—C8—N1	177.97 (16)
N2—C2—C3—C4	2.7 (3)	C2—C3—C8—N1	−1.55 (19)
C1—C2—C3—C4	−177.88 (19)	O1—C1—N1—C8	−179.07 (18)
N2—C2—C3—C8	−177.86 (17)	C2—C1—N1—C8	0.1 (2)
C1—C2—C3—C8	1.57 (19)	C7—C8—N1—C1	−178.94 (18)
C8—C3—C4—C5	1.1 (2)	C3—C8—N1—C1	0.9 (2)
C2—C3—C4—C5	−179.57 (18)	C3—C2—N2—N3	178.33 (16)
C3—C4—C5—C6	1.1 (3)	C1—C2—N2—N3	−1.0 (3)
C3—C4—C5—Cl1	−177.22 (13)	C2—N2—N3—C9	177.74 (16)
C4—C5—C6—C7	−2.3 (3)	N4—C9—N3—N2	−0.8 (2)
Cl1—C5—C6—C7	176.06 (14)	S1—C9—N3—N2	179.76 (13)
C5—C6—C7—C8	1.2 (3)	N3—C9—N4—C10	178.17 (17)
C6—C7—C8—C3	1.0 (3)	S1—C9—N4—C10	−2.4 (3)

Hydrogen-bond geometry (Å, º) top

Cg is the centroid of the C3–C8 ring.

D—H···A	D—H	H···A	D···A	D—H···A
N3—H3N···O1	0.83 (2)	2.12 (3)	2.756 (2)	134 (2)
N1—H1N···O1ⁱ	0.79 (2)	2.04 (3)	2.824 (2)	175 (2)
N4—H4N···S1ⁱⁱ	0.88 (3)	2.72 (3)	3.518 (2)	152 (2)
C6—H6···Cgⁱⁱⁱ	0.95	2.61	3.410 (2)	142

Symmetry codes: (i) x+1/2, −y+3/2, −z+1; (ii) −x, y−1/2, −z+3/2; (iii) x+1/2, −y+1/2, −z+1.

Footnotes

‡Current address: Universidade Estadual Paulista (UNESP), Instituto de Química, Araraquara, Brazil.

Acknowledgements

ABO is an associate researcher in the project `Dinitrosyl complexes containing thiol and/or thiosemicarbazone: synthesis, characterization and treatment against cancer', founded by FAPESP, Proc. 2015/12098–0, and acknowledges Professor José C. M. Pereira (São Paulo State University, Brazil) for his support in this work. ABO also acknowledges VCG for the invitation to be a visiting professor at the Federal University of Rio Grande, Brazil, where part of this work was developed. JMV and RLF thank the CAPES foundation for the scholarships. The authors acknowledge Professor A. J. Bortoluzzi for access to the experimental facilities and the data collection (Federal University of Santa Catarina, Brazil).

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