Crystal structure of (3E)-5-nitro-3-(2-phenyl­hydrazinyl­idene)-1H-indol-2(3H)-one

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

doi:10.1107/S2056989016020375

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 73| Part 2| February 2017| Pages 168-172

https://doi.org/10.1107/S2056989016020375

Open

access

Crystal structure of (3E)-5-nitro-3-(2-phenylhydrazinylidene)-1H-indol-2(3H)-one

Jecika Maciel Velasques,^a Vanessa Carratu Gervini,^a ^* Adaílton João Bortoluzzi,^b Renan Lira de Farias ^c and Adriano Bof de Oliveira ^d

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

Edited by C. Rizzoli, Universita degli Studi di Parma, Italy (Received 17 December 2016; accepted 22 December 2016; online 13 January 2017)

The reaction between 5-nitroisatin and phenylhydrazine in acidic ethanol yields the title compound, C₁₄H₁₀N₄O₃, whose molecular structure deviates slightly from a planar geometry (r.m.s. deviation = 0.065 Å for the mean plane through all non-H atoms). An intramolecular N—H⋯O hydrogen bond is present, forming a ring of graph-set motif S(6). In the crystal, molecules are linked by N—H⋯O and C—H⋯O hydrogen-bonding interactions into a two-dimensional network along (120), and rings of graph-set motif R₂²(8), R₂²(26) and R₄⁴(32) are observed. Additionally, a Hirshfeld surface analysis suggests that the molecules are stacked along [100] through C=O⋯Cg interactions and indicates that the most important contributions for the crystal structure are O⋯H (28.5%) and H⋯H (26.7%) interactions. An in silico evaluation of the title compound with the DHFR enzyme (dihydrofolate reductase) was performed. The isatin–hydrazone derivative and the active site of the selected enzyme show N—H⋯O(ASP29), N—H⋯O(ILE96) and Cg⋯Cg(PHE33) interactions.

Keywords: crystal structure; isatin–hydrazone derivative; two-dimensional hydrogen-bonded network; Hirshfeld surface calculation; in silico evaluation.

CCDC reference: 1524161

1. Chemical context

The first reports on isatin and the synthesis of isatin derivatives were published independently in Germany and France over 170 years ago (Erdmann, 1841a ,b ; Laurent, 1841 ). After the 19th Century, isatin chemistry changed rapidly into a major group of compounds with a wide range of applications in different scientific disciplines, with special attention to medicinal chemistry. For example, the synthesis, in silico evaluation and in vitro inhibition of Chikungunya virus replication by an isatin–thiosemicarbazone derivative was performed recently (Mishra et al., 2016 ). Other isatin derivatives synthesized in the 1950s (Campaigne & Archer, 1952 ) had their pharmacological properties in vitro successfully tested against Cruzain, Falcipain-2 and Rhodesian in the 2000s (Chiyanzu et al., 2003 ), and the crystal structure of one of the derivatives was determined by X-ray diffraction in the 2010s (Pederzolli et al., 2011 ). The crystal structure determination of isatin-based molecules is an intensive research field, especially in medicinal chemistry. As part of our studies in this area, we now describe the synthesis and structure of the title compound, (I).

2. Structural commentary

For the title compound, the molecular structure matches the asymmetric unit and one intramolecular N4—H5⋯O1 interaction of graph-set S(6) is observed (Fig. 1). The molecule is nearly planar with an r.m.s. deviation from the mean plane of the non–H atoms of 0.065 Å and a maximum deviation of 0.1907 (9) Å for atom O2 of the nitro group. The dihedral angle between the indole unit and the phenyl ring is 0.9 (4)°. The plane through the nitro group is rotated by 6.21 (6)° with respect to the indole ring.

Figure 1
The molecular structure of the title compound, showing displacement ellipsoids drawn at the 50% probability level. The intramolecular hydrogen bond is shown as a dashed line.

3. Supramolecular features

In the crystal, the molecules are connected by centrosymmetric pairs of N1—H1⋯O1ⁱ interactions (Table 1) into dimers with graph-set motif $[R_{2}^{2}]$ (8). In addition, C10—H6⋯O3ⁱⁱ and C12—H8⋯O2ⁱⁱⁱ interactions complete a two-dimensional hydrogen-bonded network with rings of graph-set motif $[R_{2}^{2}]$ (26) and $[R_{4}^{4}]$ (32) (Fig. 2, Table 1). As suggested by Hirshfeld surface analysis, the dimensionality of the structure increases to three-dimensional through the C=O⋯Cg interactions [C1⋯Cg = 3.5427 (7) Å, O1⋯Cg = 3.2004 (7) Å; Cg is the centroid of the C9–C14 ring], building a chain along [100] (Fig. 3). The separation between the C1 and C14 atoms of adjacent molecules in the chain is 3.1744 (11) Å, which is shorter than the sum of the van der Waals radii for carbon atoms (Bondi, 1964 ; Rowland & Taylor, 1996 ).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N4—H5⋯O1	0.88	2.03	2.7479 (10)	137
N1—H1⋯O1ⁱ	0.88	1.96	2.8310 (10)	171
C10—H6⋯O3ⁱⁱ	0.95	2.63	3.5542 (13)	166
C12—H8⋯O2ⁱⁱⁱ	0.95	2.47	3.3943 (13)	163
Symmetry codes: (i) -x+2, -y, -z+1; (ii) x, y, z+1; (iii) -x, -y+1, -z+1.

Figure 2
A packing diagram of the title compound, showing the N—H⋯O and C—H⋯O interactions (dashed lines) connecting the molecules into a two-dimensional network in the (120) plane. The graph-set motifs for the crystal packing are: R1 = $[R_{2}^{2}]$ (8), R2 = $[R_{2}^{2}]$ (26) and R3 = $[R_{4}^{4}]$ (32).

Figure 3
A packing diagram of the title compound showning the C⋯Cg interactions (as dashed lines) building a chain along [100]. [Symmetry codes: (iv) x − 1, y, z; (v) x + 1, y, z.]

4. Hirshfeld surface analysis

The Hirshfeld surface analysis of the crystal structure indicates that the contribution of O⋯H intermolecular interactions to the crystal packing amounts to 28.5% and the H⋯H interactions amount to 26.7%. Other important intermolecular contacts for the cohesion of the structure are (in %): H⋯C = 17.7, H⋯N = 8.9, C⋯O = 8.2, C⋯C = 5.5 and C⋯N = 3.3. The Hirshfeld surface graphical representation with transparency and labelled atoms (Figs. 4 and 5) indicates, in magenta, the locations of the strongest intermolecular contacts. The H1, H8, O1 and O2 atoms are the most important for the intermolecular hydrogen bonding, while the C1 and C14 atoms are the most important for C⋯C interactions. The O⋯H contribution to the crystal packing is shown as a Hirshfeld surface fingerprint two-dimensional plot with cyan dots (Wolff et al., 2012 ). The d_e (y axis) and d_i (x axis) values are the closest external and internal distances (in Å) from given points on the Hirshfeld surface (Fig. 6). The magenta colour on graphical representations of the Hirshfeld surface matches the N1—H1⋯O1ⁱ, C10—H6⋯O3ⁱⁱ and C12—H8⋯O2ⁱⁱⁱ interactions described above. In the same way, the C⋯Cg interactions can be seen more clearly on the C1=O1 and C14 atoms.

Figure 4
A Hirshfeld surface graphical representation (d_norm) for the title compound. The surface is drawn with transparency and all atoms are labelled. The surface regions with strongest intermolecular interactions for atoms H1, O1 and C14 are shown in magenta.

Figure 5
A Hirshfeld surface graphical representation (d_norm) for the title compound. The surface is drawn with transparency and all atoms are labelled. The surface regions with strongest intermolecular interactions for atoms H8, O2 and C1 are shown in magenta.

Figure 6
Hirshfeld surface fingerprint two-dimensional plot for the 5-nitroisatin-3-phenylhydrazone crystal structure showing the O⋯H contacts in detail (cyan dots). The O⋯H contribution for the crystal packing amounts to 28.5%, being the most important intermolecular connection. The d_e (y axis) and d_i (x axis) values are the closest external and internal distances [in Å] from given points on the Hirshfeld surface.

5. Molecular docking evaluation

Finally, for a lock-and-key supramolecular analysis, a molecular docking evaluation between the title compound and the DHFR enzyme (dihydrofolate reductase) was carried out. Initially, the semi-empirical equilibrium energy of the small molecule was obtained using the PM6 Hamiltonian, but the experimental bond lengths were conserved. The calculated parameters were: heat of formation = 149.41 kJ mol⁻¹, gradient normal = 0.763, HOMO = −8.96 eV, LUMO =-1.66 eV and energy gap = 7.30 eV. The target prediction for 5-nitroisatin-3-phenylhydrazone was calculated with the SwissTargetPrediction webserver based on the bioisosteric similarity to the isatin entity (Gfeller et al., 2013 ). As result of this screening, the title compound showed a promising theoretical structure–activity relationship to kinase proteins sites. The Frequency Target Class for kinases amounts to 44%, while the second best result for phosphatases amounts to 13%. The interactions with enzymes are important features for biologically active molecules, e.g. inhibition of tumor cell proliferation, activation of cell apoptosis mechanisms and blocking of bacterial membrane synthesis. Based on a search for a biological target with pharmacological background, the dihydrofolate reductase was selected for the in silico evaluation (Chen, 2015 ; Dias et al., 2014 ; Verdonk et al., 2003 ), biological target code: DHFR (Protein Data Bank ID: 4KM0; Wei et al., 2005 ). The isatin–hydrazone derivative and the active site of the selected enzyme matches and the structure–activity relationship can be assumed by the following observed intermolecular interactions: N1—H1⋯O(ASP29) (1.928 Å), N4—H5⋯O(ILE96) (1.925 Å) and Cg⋯Cg(PHE33) (3.567 Å) (Fig. 7).

Figure 7
Intermolecular interactions between the title compound and the dihydrofolate reductase enzyme. The interactions are shown as dashed lines and the figure is simplified for clarity.

6. Comparison with a related structure

A recently published article (Bittencourt et al., 2016 ) reports the structure of (3E)-5-nitro-3-(2-phenylhydrazinylidene)-1H-indol-2(3H)-one, which may be compared with that of the title compound. The molecular structure deviates slightly from the ideal planar geometry and the C⋯C contacts between the planes are observed. The molecules are linked by N—H⋯O and C—H⋯Cl interactions into a two-dimensional hydrogen-bonded polymer, a quite similar structure to the title compound. The in silico evaluation of 5-chloroisatin-phenylhydrazone, a molecule with similar crystal packing to the title compound, with and the DNA topoisomerase IIα enzyme was performed and the global free energy of −26.59 kJ mol⁻¹ was found. The evaluation agrees with the literature data for molecular docking and cytotoxic activity of hydrazone derivatives against breast cancer cells (Dandawate et al., 2012 ) and supports research on the structural determination of other isatin-based molecules. The title compound is commercially available, but its structural analysis by X–ray single crystal diffraction, Hirshfeld surface calculation and molecular docking evaluation are presented in this work for the first time.

7. Synthesis and crystallization

All starting materials are commercially available and were used without further purification. The synthesis of the title compound was adapted from a procedure reported previously (Fonseca et al., 2011 ). The glacial acetic acid-catalysed reaction of 5-nitroisatin (2.6 mmol) and phenylhydrazine (2.6 mmol) in ethanol (40 mL) was refluxed for 4 h. After cooling and filtering, an irregular solid was isolated. Single crystals suitable for X-ray diffraction were obtained from a DMF/methanol solution (1:1 v/v) on slow evaporation of the solvent.

8. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. Hydrogen atoms were located in a difference Fourier map, but were positioned with idealized geometry and refined isotropically using a riding model, with U_iso(H) = 1.2U_eq(C, N), and with C—H = 0.95 Å and N—H = 0.88 Å.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₄H₁₀N₄O₃
M_r	282.26
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	200
a, b, c (Å)	5.7504 (4), 9.7190 (6), 12.1976 (7)
α, β, γ (°)	111.196 (2), 96.759 (2), 98.497 (2)
V (Å³)	617.69 (7)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.11
Crystal size (mm)	0.48 × 0.16 × 0.10

Data collection
Diffractometer	Bruker APEXII CCD area detector
Absorption correction	Multi-scan (SADABS; Bruker, 2013 )
T_min, T_max	0.949, 0.989
No. of measured, independent and observed [I > 2σ(I)] reflections	11325, 3971, 3281
R_int	0.017
(sin θ/λ)_max (Å⁻¹)	0.726

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.039, 0.117, 1.03
No. of reflections	3971
No. of parameters	190
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.37, −0.26
Computer programs: APEX2 and SAINT (Bruker, 2013), SHELXS97 and SHELXL97 (Sheldrick, 2008 ), DIAMOND (Brandenburg, 2006 ), GOLD (Verdonk et al., 2003), Crystal Explorer (Wolff, et al., 2012), publCIF (Westrip, 2010 ) and enCIFer (Allen et al., 2004 ).

Supporting information

CCDC reference: 1524161

Crystal structure: contains datablocks I, publication_text. DOI: https://doi.org/10.1107/S2056989016020375/rz5203sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989016020375/rz5203Isup2.hkl

SwissTargetPrediction Report for 5-nitroisatin-3-phenylhydrazone. DOI: https://doi.org/10.1107/S2056989016020375/rz5203sup3.pdf

Supporting information file. DOI: https://doi.org/10.1107/S2056989016020375/rz5203Isup4.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2006), GOLD (Verdonk et al., 2003) and Crystal Explorer (Wolff, et al., 2012); software used to prepare material for publication: publCIF (Westrip, 2010) and enCIFer (Allen et al., 2004).

(3E)-5-nitro-3-(2-phenylhydrazinylidene)-1H-indol-2(3H)-one top

Crystal data top

C₁₄H₁₀N₄O₃	Z = 2
M_r = 282.26	F(000) = 292
Triclinic, P1	D_x = 1.518 Mg m⁻³
a = 5.7504 (4) Å	Mo Kα radiation, λ = 0.71073 Å
b = 9.7190 (6) Å	Cell parameters from 2154 reflections
c = 12.1976 (7) Å	θ = 2.3–31.0°
α = 111.196 (2)°	µ = 0.11 mm⁻¹
β = 96.759 (2)°	T = 200 K
γ = 98.497 (2)°	Prism, yellow
V = 617.69 (7) Å³	0.48 × 0.16 × 0.10 mm

Data collection top

Bruker APEXII CCD area detector diffractometer	3971 independent reflections
Radiation source: fine-focus sealed tube, Bruker APEX2 CCD	3281 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.017
φ and ω scans	θ_max = 31.1°, θ_min = 1.8°
Absorption correction: multi-scan (SADABS; Bruker, 2013)	h = −8→8
T_min = 0.949, T_max = 0.989	k = −14→14
11325 measured reflections	l = −17→17

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.039	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.117	H-atom parameters constrained
S = 1.03	w = 1/[σ²(F_o²) + (0.0693P)² + 0.1171P] where P = (F_o² + 2F_c²)/3
3971 reflections	(Δ/σ)_max < 0.001
190 parameters	Δρ_max = 0.37 e Å⁻³
0 restraints	Δρ_min = −0.26 e Å⁻³

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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > 2sigma(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.74444 (16)	0.10997 (10)	0.47144 (8)	0.01734 (17)
C2	0.58388 (16)	0.19030 (10)	0.42434 (8)	0.01692 (17)
C3	0.63293 (16)	0.17378 (10)	0.30690 (8)	0.01701 (17)
C4	0.53990 (17)	0.22036 (10)	0.21904 (8)	0.01863 (18)
H2	0.4130	0.2737	0.2283	0.022*
C5	0.64117 (17)	0.18525 (11)	0.11683 (8)	0.02053 (19)
C6	0.8299 (2)	0.10968 (12)	0.10014 (9)	0.0255 (2)
H3	0.8968	0.0921	0.0299	0.031*
C7	0.92000 (19)	0.06009 (12)	0.18685 (9)	0.0240 (2)
H4	1.0462	0.0062	0.1767	0.029*
C8	0.81885 (16)	0.09218 (10)	0.28844 (8)	0.01844 (17)
C9	0.26077 (16)	0.34671 (10)	0.65458 (8)	0.01776 (17)
C10	0.25473 (19)	0.34151 (12)	0.76695 (9)	0.0244 (2)
H6	0.3603	0.2920	0.7976	0.029*
C11	0.0939 (2)	0.40895 (13)	0.83359 (9)	0.0296 (2)
H7	0.0883	0.4047	0.9099	0.036*
C12	−0.0597 (2)	0.48282 (13)	0.78973 (10)	0.0284 (2)
H8	−0.1711	0.5280	0.8354	0.034*
C13	−0.04899 (19)	0.49000 (11)	0.67893 (9)	0.0248 (2)
H9	−0.1521	0.5418	0.6494	0.030*
C14	0.11070 (18)	0.42243 (11)	0.61027 (9)	0.02091 (19)
H10	0.1173	0.4278	0.5344	0.025*
N1	0.87794 (14)	0.05403 (9)	0.38620 (7)	0.01994 (17)
H1	0.9867	0.0010	0.3923	0.024*
N2	0.54638 (17)	0.23011 (10)	0.02105 (8)	0.02622 (19)
N3	0.43091 (14)	0.26487 (9)	0.47905 (7)	0.01813 (16)
N4	0.41836 (15)	0.27045 (9)	0.58791 (7)	0.01990 (17)
H5	0.5115	0.2250	0.6195	0.024*
O1	0.75650 (12)	0.09474 (8)	0.56864 (6)	0.02078 (15)
O2	0.36881 (18)	0.28657 (11)	0.03076 (8)	0.0393 (2)
O3	0.64526 (18)	0.20633 (12)	−0.06636 (8)	0.0416 (2)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0163 (4)	0.0189 (4)	0.0187 (4)	0.0066 (3)	0.0039 (3)	0.0081 (3)
C2	0.0171 (4)	0.0202 (4)	0.0165 (4)	0.0077 (3)	0.0050 (3)	0.0084 (3)
C3	0.0160 (4)	0.0198 (4)	0.0176 (4)	0.0072 (3)	0.0050 (3)	0.0081 (3)
C4	0.0187 (4)	0.0222 (4)	0.0182 (4)	0.0089 (3)	0.0055 (3)	0.0091 (3)
C5	0.0229 (5)	0.0257 (4)	0.0165 (4)	0.0093 (4)	0.0049 (3)	0.0103 (3)
C6	0.0278 (5)	0.0344 (5)	0.0206 (4)	0.0158 (4)	0.0107 (4)	0.0125 (4)
C7	0.0242 (5)	0.0326 (5)	0.0217 (4)	0.0162 (4)	0.0100 (4)	0.0121 (4)
C8	0.0183 (4)	0.0217 (4)	0.0179 (4)	0.0084 (3)	0.0047 (3)	0.0085 (3)
C9	0.0181 (4)	0.0201 (4)	0.0169 (4)	0.0075 (3)	0.0053 (3)	0.0071 (3)
C10	0.0269 (5)	0.0326 (5)	0.0187 (4)	0.0138 (4)	0.0066 (4)	0.0120 (4)
C11	0.0357 (6)	0.0389 (6)	0.0195 (4)	0.0163 (5)	0.0127 (4)	0.0117 (4)
C12	0.0293 (5)	0.0329 (5)	0.0256 (5)	0.0152 (4)	0.0133 (4)	0.0085 (4)
C13	0.0250 (5)	0.0260 (4)	0.0274 (5)	0.0138 (4)	0.0085 (4)	0.0107 (4)
C14	0.0235 (5)	0.0236 (4)	0.0208 (4)	0.0112 (3)	0.0076 (3)	0.0111 (3)
N1	0.0203 (4)	0.0257 (4)	0.0196 (4)	0.0133 (3)	0.0068 (3)	0.0111 (3)
N2	0.0310 (5)	0.0332 (4)	0.0206 (4)	0.0144 (4)	0.0074 (3)	0.0136 (3)
N3	0.0184 (4)	0.0215 (3)	0.0171 (3)	0.0076 (3)	0.0056 (3)	0.0085 (3)
N4	0.0216 (4)	0.0265 (4)	0.0172 (3)	0.0130 (3)	0.0069 (3)	0.0108 (3)
O1	0.0218 (3)	0.0259 (3)	0.0201 (3)	0.0108 (3)	0.0059 (3)	0.0122 (3)
O2	0.0468 (5)	0.0577 (6)	0.0299 (4)	0.0370 (5)	0.0134 (4)	0.0241 (4)
O3	0.0475 (5)	0.0687 (6)	0.0280 (4)	0.0299 (5)	0.0198 (4)	0.0305 (4)

Geometric parameters (Å, º) top

C1—O1	1.2421 (11)	C9—C14	1.3942 (12)
C1—N1	1.3669 (11)	C9—N4	1.4029 (11)
C1—C2	1.4848 (12)	C10—C11	1.3845 (14)
C2—N3	1.3119 (11)	C10—H6	0.9500
C2—C3	1.4490 (12)	C11—C12	1.3913 (16)
C3—C4	1.3882 (12)	C11—H7	0.9500
C3—C8	1.4144 (12)	C12—C13	1.3863 (15)
C4—C5	1.3900 (13)	C12—H8	0.9500
C4—H2	0.9500	C13—C14	1.3919 (13)
C5—C6	1.3923 (13)	C13—H9	0.9500
C5—N2	1.4631 (12)	C14—H10	0.9500
C6—C7	1.3902 (13)	N1—H1	0.8800
C6—H3	0.9500	N2—O2	1.2267 (12)
C7—C8	1.3838 (13)	N2—O3	1.2316 (12)
C7—H4	0.9500	N3—N4	1.3202 (11)
C8—N1	1.3915 (11)	N4—H5	0.8800
C9—C10	1.3939 (13)

O1—C1—N1	126.00 (8)	C14—C9—N4	121.93 (8)
O1—C1—C2	127.42 (8)	C11—C10—C9	119.56 (9)
N1—C1—C2	106.58 (7)	C11—C10—H6	120.2
N3—C2—C3	126.40 (8)	C9—C10—H6	120.2
N3—C2—C1	126.92 (8)	C10—C11—C12	120.53 (9)
C3—C2—C1	106.67 (7)	C10—C11—H7	119.7
C4—C3—C8	119.72 (8)	C12—C11—H7	119.7
C4—C3—C2	134.01 (8)	C13—C12—C11	119.47 (9)
C8—C3—C2	106.26 (7)	C13—C12—H8	120.3
C3—C4—C5	116.83 (8)	C11—C12—H8	120.3
C3—C4—H2	121.6	C12—C13—C14	120.93 (9)
C5—C4—H2	121.6	C12—C13—H9	119.5
C4—C5—C6	123.62 (9)	C14—C13—H9	119.5
C4—C5—N2	118.74 (8)	C13—C14—C9	118.93 (9)
C6—C5—N2	117.64 (8)	C13—C14—H10	120.5
C7—C6—C5	119.64 (9)	C9—C14—H10	120.5
C7—C6—H3	120.2	C1—N1—C8	110.92 (7)
C5—C6—H3	120.2	C1—N1—H1	124.5
C8—C7—C6	117.46 (9)	C8—N1—H1	124.5
C8—C7—H4	121.3	O2—N2—O3	123.29 (9)
C6—C7—H4	121.3	O2—N2—C5	118.18 (8)
C7—C8—N1	127.81 (8)	O3—N2—C5	118.50 (9)
C7—C8—C3	122.66 (8)	C2—N3—N4	116.98 (8)
N1—C8—C3	109.53 (8)	N3—N4—C9	121.85 (8)
C10—C9—C14	120.56 (9)	N3—N4—H5	119.1
C10—C9—N4	117.49 (8)	C9—N4—H5	119.1

O1—C1—C2—N3	2.70 (16)	C14—C9—C10—C11	1.64 (16)
N1—C1—C2—N3	−177.67 (9)	N4—C9—C10—C11	−176.92 (9)
O1—C1—C2—C3	−178.71 (9)	C9—C10—C11—C12	−0.59 (17)
N1—C1—C2—C3	0.91 (10)	C10—C11—C12—C13	−0.70 (18)
N3—C2—C3—C4	−2.73 (17)	C11—C12—C13—C14	0.97 (17)
C1—C2—C3—C4	178.67 (10)	C12—C13—C14—C9	0.06 (16)
N3—C2—C3—C8	176.72 (9)	C10—C9—C14—C13	−1.37 (15)
C1—C2—C3—C8	−1.87 (10)	N4—C9—C14—C13	177.12 (9)
C8—C3—C4—C5	−1.17 (14)	O1—C1—N1—C8	−179.93 (9)
C2—C3—C4—C5	178.23 (10)	C2—C1—N1—C8	0.44 (10)
C3—C4—C5—C6	−1.17 (15)	C7—C8—N1—C1	177.81 (10)
C3—C4—C5—N2	179.09 (8)	C3—C8—N1—C1	−1.68 (11)
C4—C5—C6—C7	2.57 (17)	C4—C5—N2—O2	−5.61 (15)
N2—C5—C6—C7	−177.69 (9)	C6—C5—N2—O2	174.63 (10)
C5—C6—C7—C8	−1.48 (16)	C4—C5—N2—O3	175.99 (10)
C6—C7—C8—N1	179.74 (10)	C6—C5—N2—O3	−3.77 (15)
C6—C7—C8—C3	−0.83 (16)	C3—C2—N3—N4	−177.84 (8)
C4—C3—C8—C7	2.21 (15)	C1—C2—N3—N4	0.47 (14)
C2—C3—C8—C7	−177.34 (9)	C2—N3—N4—C9	−179.85 (8)
C4—C3—C8—N1	−178.26 (8)	C10—C9—N4—N3	177.74 (9)
C2—C3—C8—N1	2.18 (10)	C14—C9—N4—N3	−0.80 (15)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N4—H5···O1	0.88	2.03	2.7479 (10)	137
N1—H1···O1ⁱ	0.88	1.96	2.8310 (10)	171
C10—H6···O3ⁱⁱ	0.95	2.63	3.5542 (13)	166
C12—H8···O2ⁱⁱⁱ	0.95	2.47	3.3943 (13)	163

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

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 scholarships. RLF thanks the São Paulo State University, Brazil, for the access to the computer facilities to perform the in silico evaluation.

Funding information

Funding for this research was provided by: Fundação de Amparo à Pesquisa do Estado de São Paulo (award No. 2015/12098–0); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior

References

Allen, F. H., Johnson, O., Shields, G. P., Smith, B. R. & Towler, M. (2004). J. Appl. Cryst. 37, 335–338. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Bittencourt, V. C. D., Almeida, R. M. F. C., Bortoluzzi, A. J., Gervini, V. C. & de Oliveira, A. B. (2016). IUCrData, 1, x160258. Google Scholar
Bondi, A. (1964). J. Phys. Chem. 68, 441–451. CrossRef CAS Web of Science Google Scholar
Brandenburg, K. (2006). DIAMOND. Crystal Impact GbR, Bonn, Germany. Google Scholar
Bruker (2013). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Campaigne, E. & Archer, W. L. (1952). J. Am. Chem. Soc. 74, 5801. CrossRef Google Scholar
Chen, Y.-C. (2015). Trends Pharmacol. Sci. 36, 78–95. CrossRef Google Scholar
Chiyanzu, I., Hansell, E., Gut, J., Rosenthal, P. J., McKerrow, J. H. & Chibale, K. (2003). Bioorg. Med. Chem. Lett. 13, 3527–3530. Web of Science CrossRef PubMed CAS Google Scholar
Dandawate, P., Khan, E., Padhye, S., Gaba, H., Sinha, S., Deshpande, J., Venkateswara Swamy, K., Khetmalas, M., Ahmad, A. & Sarkar, F. H. (2012). Bioorg. Med. Chem. Lett. 22, 3104–3108. Web of Science CrossRef CAS PubMed Google Scholar
Dias, M. V. B., Tyrakis, P., Domingues, R. R., Leme, A. F. P. & Blundell, T. L. (2014). Cell, 22, 94–103. CAS Google Scholar
Erdmann, O. L. (1841a). Ann. Chim. Phys. 3, 355–371. Google Scholar
Erdmann, O. L. (1841b). J. Prakt. Chem. 22, 257–299. CrossRef Google Scholar
Fonseca, A. de S., Storino, T. G., Carratu, V. S., Locatelli, A. & Oliveira, A. B. de (2011). Acta Cryst. E67, o3256. Web of Science CSD CrossRef IUCr Journals Google Scholar
Gfeller, D., Michielin, O. & Zoete, V. (2013). Bioinformatics, 29, 3073–3079. Web of Science CrossRef CAS Google Scholar
Laurent, A. (1841). Ann. Chim. Phys. 3, 371–383. Google Scholar
Mishra, P., Kumar, A., Mamidi, P., Kumar, S., Basantray, I., Saswat, T., Das, I., Nayak, T. K., Chattopadhyay, S., Subudhi, B. B. & Chattopadhyay, S. (2016). Sci. Rep. 6, 20122. Web of Science CrossRef Google Scholar
Pederzolli, F. R. S., Bresolin, L., Carratu, V. S., Locatelli, A. & Oliveira, A. B. de (2011). Acta Cryst. E67, o1804. Web of Science CSD CrossRef IUCr Journals Google Scholar
Rowland, R. S. & Taylor, R. (1996). J. Phys. Chem. 100, 7384–7391. CSD CrossRef CAS Web of Science Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Verdonk, M. L., Cole, J. C., Hartshorn, M. J., Murray, C. W. & Taylor, R. D. (2003). Proteins, 52, 609–623. Web of Science CSD CrossRef PubMed CAS Google Scholar
Wei, H., Ruthenburg, A. J., Bechis, S. K. & Verdine, G. L. (2005). J. Biol. Chem. 280, 37041–37047. Web of Science CrossRef PubMed CAS Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
Wolff, S. K., Grimwood, D. J., McKinnon, J. J., Turner, M. J., Jayatilaka, D. & Spackman, M. A. (2012). Crystal Explorer. University of Western Australia. 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.