organic compounds
Benznidazole
aPrograma de Pós-graduação em Ciências Farmacêuticas, Universidade Federal de Pernambuco, 50740-521 Recife, Brazil, bDepartamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15872, Spain, and cEd. CACTUS, Campus Sur, Unidade de Raios X, Universidad de Santiago de Compostela, 15782, Spain
*Correspondence e-mail: raiosxp@usc.es
The conformation of the title compound [systematic name: N-benzyl-2-(2-nitroimidazol-1-yl)acetamide], C12H12N4O3, can be described in terms of the relative orientation of three planar fragments, the imidazol group (A), benzyl group (B), and the acetamide fragment (C), with corresponding dihedral angles: A/C = 88.17 (4), B/C = 67.12 (5) and A/B = 21.11 (4)°. The crystal packing is enhanced by a network of strong intermolecular N—H⋯O hydrogen bonds.
Related literature
For related literature, see: Coura & Castro (2002); Lamas et al. (2006); Morilla et al. (2004); Silva et al. (2007).
Experimental
Crystal data
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Refinement
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Data collection: APEX2 (Bruker, 2007); cell APEX2; data reduction: APEX2; program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2006) and ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999) and PLATON (Spek, 2003).
Supporting information
10.1107/S1600536808005023/om2213sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: 10.1107/S1600536808005023/om2213Isup2.hkl
Benznidazole was supplied by Laboratório Farmacêutico do Estado de Pernambuco/LAFEPE batch 13871(Recife, Brazil). Purity was estimated by
(DSC-50 Shimadzu) and high-performance (HPLC Shimadzu) and found to be 99.9% (Silva et al., 2007). Yellow crystals suitable for X-ray analysis were grown from a solution of methanol and acetonitrile (1:1 v/v) at 298 K over a period of a few days in air.Data collection: APEX2 (Bruker, 2007); cell
APEX2 (Bruker, 2007); data reduction: APEX2 (Bruker, 2007); Absorption correction: SADABS (Bruker, 2001); program used to solve structure: SIR97 (Altomare et al., 1999); program used to structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 (Farrugia, 1997) and Mercury (Macrae et al., 2006); software used to prepare material for publication: WinGX (Farrugia, 1999); geometric calculations: PLATON (Spek, 2003).The H8 atom was located in a difference map and refined. The rest of the H atoms were positioned geometrically and refined with use of a riding model with C—H = 0.95 - 0.99Å and Uiso = 1.2 times Ueq of the bonded C. Friedel pairs were merged for the final refinement.
Data collection: APEX2 (Bruker, 2007); cell
APEX2 (Bruker, 2007); data reduction: APEX2 (Bruker, 2007); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999).C12H12N4O3 | F(000) = 272 |
Mr = 260.26 | Dx = 1.446 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.7107 Å |
Hall symbol: P 2yb | Cell parameters from 1992 reflections |
a = 4.6556 (1) Å | θ = 3.0–28.3° |
b = 10.9113 (2) Å | µ = 0.11 mm−1 |
c = 11.7681 (3) Å | T = 100 K |
β = 90.668 (1)° | Prism, colourless |
V = 597.76 (2) Å3 | 0.34 × 0.16 × 0.12 mm |
Z = 2 |
Bruker APEXII CCD diffractometer | 1287 independent reflections |
Radiation source: fine-focus sealed tube | 1216 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.012 |
ω and ϕ scans | θmax = 26.4°, θmin = 1.7° |
Absorption correction: multi-scan (SADABS; Bruker, 2001) | h = −5→5 |
Tmin = 0.861, Tmax = 0.987 | k = −13→13 |
11597 measured reflections | l = −14→14 |
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)] = 0.025 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.066 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.08 | w = 1/[σ2(Fo2) + (0.0385P)2 + 0.0782P] where P = (Fo2 + 2Fc2)/3 |
1287 reflections | (Δ/σ)max = 0.001 |
176 parameters | Δρmax = 0.14 e Å−3 |
1 restraint | Δρmin = −0.22 e Å−3 |
C12H12N4O3 | V = 597.76 (2) Å3 |
Mr = 260.26 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 4.6556 (1) Å | µ = 0.11 mm−1 |
b = 10.9113 (2) Å | T = 100 K |
c = 11.7681 (3) Å | 0.34 × 0.16 × 0.12 mm |
β = 90.668 (1)° |
Bruker APEXII CCD diffractometer | 1287 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2001) | 1216 reflections with I > 2σ(I) |
Tmin = 0.861, Tmax = 0.987 | Rint = 0.012 |
11597 measured reflections |
R[F2 > 2σ(F2)] = 0.025 | 1 restraint |
wR(F2) = 0.066 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.08 | Δρmax = 0.14 e Å−3 |
1287 reflections | Δρmin = −0.22 e Å−3 |
176 parameters |
Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s 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 > σ(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. |
x | y | z | Uiso*/Ueq | ||
C1 | 0.4003 (3) | 0.40584 (12) | 0.08674 (11) | 0.0161 (3) | |
C2 | 0.2787 (3) | 0.42354 (13) | −0.02020 (12) | 0.0185 (3) | |
H2 | 0.3368 | 0.4915 | −0.0649 | 0.022* | |
C3 | 0.0725 (3) | 0.34290 (15) | −0.06277 (12) | 0.0228 (3) | |
H3 | −0.0096 | 0.3558 | −0.1361 | 0.027* | |
C4 | −0.0126 (3) | 0.24393 (15) | 0.00205 (14) | 0.0249 (3) | |
H4 | −0.1559 | 0.1896 | −0.0263 | 0.03* | |
C5 | 0.1101 (3) | 0.22366 (13) | 0.10809 (13) | 0.0245 (3) | |
H5 | 0.0536 | 0.1548 | 0.1518 | 0.029* | |
C6 | 0.3162 (3) | 0.30441 (13) | 0.15048 (12) | 0.0199 (3) | |
H6 | 0.4003 | 0.2904 | 0.2233 | 0.024* | |
C7 | 0.6208 (3) | 0.49433 (14) | 0.13271 (12) | 0.0183 (3) | |
H7A | 0.7996 | 0.4494 | 0.1521 | 0.022* | |
H7B | 0.6664 | 0.5558 | 0.0737 | 0.022* | |
N8 | 0.5145 (3) | 0.55688 (11) | 0.23428 (10) | 0.0162 (3) | |
H8 | 0.338 (4) | 0.5619 (16) | 0.2452 (14) | 0.019 (4)* | |
C9 | 0.6898 (3) | 0.62199 (12) | 0.30060 (11) | 0.0136 (3) | |
O10 | 0.94844 (19) | 0.63427 (9) | 0.28473 (8) | 0.0174 (2) | |
C11 | 0.5490 (3) | 0.67480 (13) | 0.40651 (12) | 0.0169 (3) | |
H11A | 0.3579 | 0.7085 | 0.3859 | 0.02* | |
H11B | 0.5211 | 0.6087 | 0.4629 | 0.02* | |
N12 | 0.7269 (2) | 0.77163 (10) | 0.45668 (9) | 0.0155 (2) | |
C13 | 0.7665 (3) | 0.89028 (13) | 0.42442 (11) | 0.0173 (3) | |
N14 | 0.9577 (3) | 0.94933 (12) | 0.48657 (10) | 0.0212 (3) | |
C15 | 1.0495 (3) | 0.86385 (13) | 0.56313 (12) | 0.0202 (3) | |
H15 | 1.1901 | 0.8781 | 0.6208 | 0.024* | |
C16 | 0.9113 (3) | 0.75456 (13) | 0.54557 (11) | 0.0178 (3) | |
H16 | 0.939 | 0.681 | 0.5875 | 0.021* | |
N17 | 0.6082 (3) | 0.94740 (12) | 0.33348 (10) | 0.0239 (3) | |
O18 | 0.4426 (2) | 0.88404 (11) | 0.27695 (9) | 0.0306 (3) | |
O19 | 0.6452 (3) | 1.05789 (11) | 0.31808 (11) | 0.0419 (3) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0137 (6) | 0.0156 (7) | 0.0191 (6) | 0.0026 (6) | 0.0028 (5) | −0.0051 (5) |
C2 | 0.0202 (7) | 0.0166 (7) | 0.0187 (7) | 0.0025 (6) | 0.0021 (5) | −0.0016 (5) |
C3 | 0.0208 (7) | 0.0276 (8) | 0.0199 (7) | 0.0040 (7) | −0.0040 (6) | −0.0089 (6) |
C4 | 0.0191 (7) | 0.0216 (8) | 0.0340 (8) | −0.0045 (6) | 0.0008 (6) | −0.0137 (6) |
C5 | 0.0251 (8) | 0.0152 (8) | 0.0333 (8) | −0.0025 (6) | 0.0055 (6) | −0.0029 (6) |
C6 | 0.0212 (7) | 0.0192 (8) | 0.0193 (7) | −0.0006 (6) | 0.0004 (5) | −0.0023 (6) |
C7 | 0.0161 (7) | 0.0196 (7) | 0.0193 (7) | −0.0006 (6) | 0.0030 (5) | −0.0047 (6) |
N8 | 0.0106 (6) | 0.0182 (6) | 0.0198 (6) | −0.0003 (5) | 0.0016 (4) | −0.0057 (5) |
C9 | 0.0153 (7) | 0.0096 (6) | 0.0159 (6) | 0.0013 (5) | 0.0000 (5) | 0.0008 (5) |
O10 | 0.0134 (5) | 0.0189 (5) | 0.0198 (4) | −0.0008 (4) | 0.0010 (4) | −0.0031 (4) |
C11 | 0.0160 (6) | 0.0155 (7) | 0.0194 (7) | −0.0036 (6) | 0.0012 (5) | −0.0059 (5) |
N12 | 0.0168 (6) | 0.0139 (6) | 0.0159 (5) | −0.0011 (5) | 0.0020 (4) | −0.0024 (5) |
C13 | 0.0221 (7) | 0.0133 (7) | 0.0164 (6) | 0.0005 (6) | −0.0001 (5) | −0.0013 (5) |
N14 | 0.0281 (7) | 0.0169 (6) | 0.0187 (6) | −0.0036 (6) | −0.0021 (5) | −0.0029 (5) |
C15 | 0.0236 (8) | 0.0176 (7) | 0.0194 (7) | 0.0005 (6) | −0.0037 (6) | −0.0044 (5) |
C16 | 0.0210 (7) | 0.0153 (7) | 0.0171 (6) | 0.0029 (6) | −0.0014 (5) | −0.0014 (5) |
N17 | 0.0325 (8) | 0.0211 (7) | 0.0179 (6) | 0.0008 (6) | −0.0037 (5) | 0.0002 (5) |
O18 | 0.0347 (6) | 0.0323 (7) | 0.0244 (5) | −0.0023 (5) | −0.0114 (5) | −0.0012 (5) |
O19 | 0.0699 (10) | 0.0196 (6) | 0.0358 (6) | −0.0031 (6) | −0.0180 (6) | 0.0077 (5) |
O10—C9 | 1.2281 (16) | C15—C16 | 1.370 (2) |
N17—O18 | 1.2260 (17) | C15—H15 | 0.95 |
N17—O19 | 1.2316 (18) | C4—C3 | 1.383 (2) |
N17—C13 | 1.4348 (18) | C4—C5 | 1.384 (2) |
N12—C16 | 1.3581 (18) | C4—H4 | 0.95 |
N12—C13 | 1.3622 (19) | C5—C6 | 1.391 (2) |
N12—C11 | 1.4628 (17) | C5—H5 | 0.95 |
N8—C9 | 1.3286 (17) | C3—H3 | 0.95 |
N8—C7 | 1.4675 (17) | C7—C1 | 1.505 (2) |
N8—H8 | 0.836 (18) | C7—H7A | 0.99 |
C9—C11 | 1.5278 (18) | C7—H7B | 0.99 |
C2—C1 | 1.3875 (19) | C1—C6 | 1.396 (2) |
C2—C3 | 1.391 (2) | C11—H11A | 0.99 |
C2—H2 | 0.95 | C11—H11B | 0.99 |
N14—C13 | 1.3144 (19) | C16—H16 | 0.95 |
N14—C15 | 1.3620 (19) | C6—H6 | 0.95 |
O18—N17—O19 | 124.07 (13) | C4—C3—H3 | 120.1 |
O18—N17—C13 | 118.30 (12) | C2—C3—H3 | 120.1 |
O19—N17—C13 | 117.62 (13) | N8—C7—C1 | 110.86 (11) |
C16—N12—C13 | 104.99 (12) | N8—C7—H7A | 109.5 |
C16—N12—C11 | 124.17 (12) | C1—C7—H7A | 109.5 |
C13—N12—C11 | 130.67 (12) | N8—C7—H7B | 109.5 |
C9—N8—C7 | 121.09 (12) | C1—C7—H7B | 109.5 |
C9—N8—H8 | 118.2 (12) | H7A—C7—H7B | 108.1 |
C7—N8—H8 | 119.9 (11) | C2—C1—C6 | 118.93 (13) |
O10—C9—N8 | 124.46 (12) | C2—C1—C7 | 120.41 (13) |
O10—C9—C11 | 120.91 (12) | C6—C1—C7 | 120.65 (12) |
N8—C9—C11 | 114.48 (11) | N12—C11—C9 | 110.81 (11) |
C1—C2—C3 | 120.75 (13) | N12—C11—H11A | 109.5 |
C1—C2—H2 | 119.6 | C9—C11—H11A | 109.5 |
C3—C2—H2 | 119.6 | N12—C11—H11B | 109.5 |
C13—N14—C15 | 103.74 (12) | C9—C11—H11B | 109.5 |
N14—C15—C16 | 110.69 (12) | H11A—C11—H11B | 108.1 |
N14—C15—H15 | 124.7 | N12—C16—C15 | 106.76 (13) |
C16—C15—H15 | 124.7 | N12—C16—H16 | 126.6 |
C3—C4—C5 | 120.29 (14) | C15—C16—H16 | 126.6 |
C3—C4—H4 | 119.9 | C5—C6—C1 | 120.41 (13) |
C5—C4—H4 | 119.9 | C5—C6—H6 | 119.8 |
C4—C5—C6 | 119.86 (14) | C1—C6—H6 | 119.8 |
C4—C5—H5 | 120.1 | N14—C13—N12 | 113.81 (12) |
C6—C5—H5 | 120.1 | N14—C13—N17 | 122.74 (13) |
C4—C3—C2 | 119.74 (13) | N12—C13—N17 | 123.42 (12) |
C7—N8—C9—O10 | −1.0 (2) | C11—N12—C16—C15 | 176.45 (12) |
C7—N8—C9—C11 | −176.53 (13) | N14—C15—C16—N12 | −0.46 (16) |
C13—N14—C15—C16 | 0.00 (16) | C4—C5—C6—C1 | 0.0 (2) |
C3—C4—C5—C6 | 1.1 (2) | C2—C1—C6—C5 | −1.1 (2) |
C5—C4—C3—C2 | −1.1 (2) | C7—C1—C6—C5 | 179.30 (13) |
C1—C2—C3—C4 | 0.0 (2) | C15—N14—C13—N12 | 0.48 (16) |
C9—N8—C7—C1 | 167.75 (12) | C15—N14—C13—N17 | 178.56 (13) |
C3—C2—C1—C6 | 1.1 (2) | C16—N12—C13—N14 | −0.77 (16) |
C3—C2—C1—C7 | −179.29 (13) | C11—N12—C13—N14 | −176.13 (13) |
N8—C7—C1—C2 | 116.20 (14) | C16—N12—C13—N17 | −178.83 (13) |
N8—C7—C1—C6 | −64.20 (17) | C11—N12—C13—N17 | 5.8 (2) |
C16—N12—C11—C9 | −97.72 (15) | O18—N17—C13—N14 | 177.06 (14) |
C13—N12—C11—C9 | 76.86 (17) | O19—N17—C13—N14 | −3.8 (2) |
O10—C9—C11—N12 | 20.40 (18) | O18—N17—C13—N12 | −5.0 (2) |
N8—C9—C11—N12 | −163.87 (11) | O19—N17—C13—N12 | 174.08 (14) |
C13—N12—C16—C15 | 0.70 (14) |
D—H···A | D—H | H···A | D···A | D—H···A |
N8—H8···O10i | 0.835 (19) | 2.037 (18) | 2.837 (2) | 160.2 (17) |
Symmetry code: (i) x−1, y, z. |
Experimental details
Crystal data | |
Chemical formula | C12H12N4O3 |
Mr | 260.26 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 100 |
a, b, c (Å) | 4.6556 (1), 10.9113 (2), 11.7681 (3) |
β (°) | 90.668 (1) |
V (Å3) | 597.76 (2) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.11 |
Crystal size (mm) | 0.34 × 0.16 × 0.12 |
Data collection | |
Diffractometer | Bruker APEXII CCD diffractometer |
Absorption correction | Multi-scan (SADABS; Bruker, 2001) |
Tmin, Tmax | 0.861, 0.987 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 11597, 1287, 1216 |
Rint | 0.012 |
(sin θ/λ)max (Å−1) | 0.626 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.025, 0.066, 1.08 |
No. of reflections | 1287 |
No. of parameters | 176 |
No. of restraints | 1 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.14, −0.22 |
Computer programs: APEX2 (Bruker, 2007), SIR97 (Altomare et al., 1999), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 1997), WinGX (Farrugia, 1999).
O10—C9 | 1.2281 (16) | N12—C11 | 1.4628 (17) |
N17—O18 | 1.2260 (17) | N8—C9 | 1.3286 (17) |
N17—O19 | 1.2316 (18) | N8—C7 | 1.4675 (17) |
N17—C13 | 1.4348 (18) | C9—C11 | 1.5278 (18) |
C9—N8—C7 | 121.09 (12) | N12—C11—C9 | 110.81 (11) |
N8—C7—C1 | 110.86 (11) | N12—C13—N17 | 123.42 (12) |
D—H···A | D—H | H···A | D···A | D—H···A |
N8—H8···O10i | 0.835 (19) | 2.037 (18) | 2.837 (2) | 160.2 (17) |
Symmetry code: (i) x−1, y, z. |
Acknowledgements
The authors thank LAFEPE/Brazil, CNPq/Brazil and Xunta de Galicia (project No. PGIDT01BIO20302PR) for supporting this work.
References
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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.
The title compound, Benznidazole, is the drug of choice in the treatment of Chagas disease, a protozoan infection caused by the parasite Trypanosoma cruzi. This illness constitutes a major public health problem for developing nations, affecting sundries Latin America countries, being considered a neglected disease according to World Health Organization (Coura & Castro, 2002; Lamas et al., 2006). In spite of the epidemiological importance of this disease, currently the only available therapeutic agent is Benznidazole, especially effective in the acute phase of infection (Morilla et al., 2004).
The conformation of the title compound (Fig. 1) can be described by the mutual orientation of three approximately planar fragments, A, B and C: one imidazole group (fragment A: N12, C13, N14, C15, C16, N17, O18 and O19 atoms) for which the maximum deviation from the least-squares plane is -0.067 (1) Å, the benzene group (fragment B: C1, C2, C3, C4, C5, C6 and C7 atoms) whose maximum deviation from the mentioned planarity is -0.013 (2), and the central acetamide (fragment C: N8, C9, O10 and C11 atoms), with a deviation of 0.024 (1) Å. The corresponding dihedral angles are: A/C = 88.17 (4)°, B/C = 67.12 (5)° and A/B = 21.11 (4)°.
The strategy of self-assembly through weak interactions is of central importance for efficient and specific biological reactions. In our case we can find one strong intermolecular O···HN hydrogen bond between N(8)–H(8) and O(10) that almost lies along the "a" axis (Fig. 2).