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A novel and potentially active di­hydro­orotate de­hydrogenase (DHODH) inhibitor, namely 3-({(E)-[(E)-1-(biphenyl-4-yl)ethyl­idene]hydrazinyl­idene}meth­yl)-1H-indole (BEHI) aceto­nitrile disolvate, C23H19N3·2CH3CN, has been designed and synthesized. The structure of BEHI was characterized by elemental analysis, Q-TOF (quadrupole time-of-flight) MS, NMR, UV–Vis and single-crystal X-ray diffraction. The anti­tumour activity of the target mol­ecule was evaluated by the MTT method. Results indicated that BEHI exhibited rather potent cytotoxic activity against human A549 (IC50 = 20.5 µM) and mouse breast 4T1 (IC50 = 18.5 µM) cancer cell lines. Meanwhile, to rationalize its potencies in the target, BEHI was docked into DHODH and the inter­actions with the active site residues were analyzed. Single-crystal structure analysis indicated that hydrogen bonds are present only between BEHI and aceto­nitrile solvent mol­ecules in the asymmetric unit. The inter­play of weak π–π stacking and weak C(N)—H...π inter­actions between neighbouring BEHI mol­ecules play crucial roles in the formation of the final supra­molecular frameworks.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229617009044/fn3235sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229617009044/fn3235Isup2.hkl
Contains datablock I

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229617009044/fn3235Isup7.cml
Supplementary material

docx

Microsoft Word (DOCX) file https://doi.org/10.1107/S2053229617009044/fn3235sup3.docx
Supplementary material

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S2053229617009044/fn3235sup3.pdf
Fig. S1. 1H NMR spectrum of BEH.

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Portable Document Format (PDF) file https://doi.org/10.1107/S2053229617009044/fn3235sup4.pdf
Fig. S2 1H NMR spectrum of BEHI.

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Portable Document Format (PDF) file https://doi.org/10.1107/S2053229617009044/fn3235sup5.pdf
Fig. S3 13C NMR spectrum of BEHI.

CCDC reference: 1556543

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SMART (Bruker, 2000); data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXT2016 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: SHELXTL (Bruker, 2000), PLATON (Spek, 2009), DIAMOND (Brandenburg & Putz, 1999) and ORTEP-3 (Farrugia, 2012); software used to prepare material for publication: SHELXL2016 (Sheldrick, 2015b).

3-({(E)-[(E)-1-(Biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1H-indole acetonitrile disolvate top
Crystal data top
C23H19N3·2C2H3NDx = 1.171 Mg m3
Mr = 419.52Melting point: 462.8(2) K
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.1493 (4) ÅCell parameters from 380 reflections
b = 8.5209 (5) Åθ = 2.5–26.0°
c = 34.4887 (14) ŵ = 0.07 mm1
β = 96.648 (4)°T = 298 K
V = 2378.8 (2) Å3Block, light yellow
Z = 40.35 × 0.26 × 0.18 mm
F(000) = 888
Data collection top
Bruker SMART CCD area detector
diffractometer
5893 independent reflections
Radiation source: fine-focus sealed tube3167 reflections with I > 2σ(I)
Detector resolution: 10.24 pixels mm-1Rint = 0.076
phi and ω scansθmax = 29.1°, θmin = 3.3°
Absorption correction: multi-scan
(SADABS; Bruker, 2000)
h = 1010
Tmin = 0.976, Tmax = 0.989k = 1111
28460 measured reflectionsl = 4644
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.053Hydrogen site location: mixed
wR(F2) = 0.155H atoms treated by a mixture of independent and constrained refinement
S = 1.02 w = 1/[σ2(Fo2) + (0.065P)2]
where P = (Fo2 + 2Fc2)/3
5893 reflections(Δ/σ)max < 0.001
368 parametersΔρmax = 0.12 e Å3
0 restraintsΔρmin = 0.15 e Å3
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

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
xyzUiso*/Ueq
C10.1478 (2)0.5352 (2)0.19965 (5)0.0698 (5)
C20.2959 (3)0.5409 (3)0.17606 (6)0.0826 (6)
C30.3384 (2)0.4245 (3)0.14926 (5)0.0806 (5)
C40.2312 (2)0.3026 (2)0.14580 (5)0.0713 (5)
C50.0833 (2)0.2950 (2)0.16929 (4)0.0613 (4)
C60.03821 (18)0.41080 (17)0.19707 (4)0.0545 (4)
C70.11989 (18)0.40273 (17)0.22314 (4)0.0540 (4)
C80.1358 (2)0.46886 (19)0.26043 (4)0.0583 (4)
C90.28366 (19)0.46591 (19)0.28434 (5)0.0593 (4)
C100.42390 (17)0.39544 (17)0.27222 (4)0.0540 (4)
C110.4069 (2)0.3258 (2)0.23536 (5)0.0635 (4)
C120.2587 (2)0.3302 (2)0.21148 (5)0.0619 (4)
C130.58273 (18)0.39466 (18)0.29784 (4)0.0560 (4)
C140.7227 (3)0.2999 (3)0.28593 (7)0.0842 (6)
C150.7367 (2)0.5542 (2)0.38395 (5)0.0662 (4)
C160.8766 (2)0.56975 (19)0.41290 (5)0.0633 (4)
C170.8737 (3)0.6521 (3)0.44720 (5)0.0792 (5)
C181.1287 (2)0.5547 (2)0.44929 (5)0.0728 (5)
C191.2920 (3)0.5148 (3)0.46008 (7)0.0911 (7)
C201.3703 (3)0.4266 (3)0.43478 (7)0.0945 (7)
C211.2857 (2)0.3770 (3)0.39924 (6)0.0846 (6)
C221.1233 (2)0.4149 (2)0.38867 (5)0.0696 (5)
C231.0405 (2)0.50537 (19)0.41393 (4)0.0629 (4)
C241.1844 (4)0.9272 (4)0.61211 (7)0.1166 (8)
H24A1.07990.93110.62240.231 (19)*
H24B1.22911.03120.61140.191 (14)*
H24C1.25930.86190.62850.221 (17)*
C251.1617 (3)0.8632 (3)0.57327 (6)0.0886 (6)
C260.2515 (4)1.0066 (4)0.45680 (10)0.1259 (9)
H26A0.24601.04300.48300.27 (3)*
H26B0.16690.92960.45020.26 (2)*
H26C0.23541.09350.43900.243 (19)*
C270.4108 (4)0.9374 (3)0.45413 (7)0.1073 (8)
N10.58785 (15)0.47591 (17)0.32937 (4)0.0663 (4)
N20.74129 (15)0.47184 (17)0.35301 (4)0.0666 (4)
N31.0229 (2)0.6429 (2)0.46890 (5)0.0873 (5)
N40.5344 (4)0.8839 (4)0.45153 (8)0.1572 (11)
N51.1409 (3)0.8135 (3)0.54300 (6)0.1304 (8)
H10.119 (2)0.621 (2)0.2191 (5)0.093 (6)*
H20.367 (2)0.624 (2)0.1781 (6)0.094 (6)*
H30.447 (2)0.427 (2)0.1330 (5)0.085 (5)*
H3N1.049 (3)0.691 (3)0.4924 (7)0.113 (7)*
H40.259 (2)0.221 (2)0.1274 (5)0.082 (5)*
H50.0090 (18)0.204 (2)0.1671 (4)0.071 (5)*
H80.049 (2)0.5153 (19)0.2707 (5)0.069 (5)*
H90.2941 (19)0.513 (2)0.3102 (5)0.074 (5)*
H110.500 (2)0.277 (2)0.2264 (5)0.079 (5)*
H120.2510 (18)0.283 (2)0.1859 (5)0.076 (5)*
H14A0.751 (3)0.339 (3)0.2587 (8)0.126 (8)*
H14B0.696 (4)0.186 (4)0.2798 (9)0.167 (12)*
H14C0.820 (3)0.305 (3)0.3043 (6)0.107 (7)*
H150.633 (2)0.613 (2)0.3886 (5)0.083 (5)*
H170.785 (2)0.712 (3)0.4555 (6)0.096 (6)*
H191.348 (2)0.552 (2)0.4834 (6)0.093 (6)*
H201.489 (3)0.393 (2)0.4418 (5)0.096 (6)*
H211.344 (2)0.310 (2)0.3817 (6)0.091 (6)*
H221.0664 (19)0.382 (2)0.3637 (5)0.074 (5)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0843 (12)0.0597 (11)0.0643 (10)0.0098 (9)0.0037 (8)0.0079 (8)
C20.0895 (13)0.0822 (14)0.0740 (12)0.0282 (11)0.0002 (10)0.0089 (10)
C30.0760 (12)0.0916 (15)0.0712 (12)0.0118 (11)0.0039 (9)0.0053 (10)
C40.0805 (11)0.0673 (12)0.0637 (10)0.0010 (9)0.0011 (8)0.0101 (9)
C50.0745 (10)0.0540 (10)0.0556 (9)0.0026 (8)0.0079 (7)0.0017 (7)
C60.0664 (9)0.0480 (9)0.0502 (8)0.0020 (7)0.0112 (6)0.0027 (6)
C70.0649 (9)0.0449 (8)0.0531 (8)0.0041 (7)0.0110 (7)0.0001 (6)
C80.0610 (9)0.0568 (10)0.0587 (9)0.0001 (7)0.0132 (7)0.0075 (7)
C90.0659 (10)0.0584 (10)0.0547 (9)0.0030 (8)0.0115 (7)0.0084 (7)
C100.0617 (9)0.0467 (9)0.0546 (8)0.0025 (7)0.0116 (7)0.0012 (6)
C110.0702 (10)0.0623 (11)0.0594 (9)0.0066 (8)0.0141 (8)0.0045 (7)
C120.0744 (10)0.0586 (10)0.0530 (9)0.0036 (8)0.0093 (7)0.0082 (7)
C130.0639 (9)0.0504 (9)0.0552 (9)0.0032 (7)0.0139 (7)0.0043 (7)
C140.0711 (12)0.1059 (19)0.0751 (13)0.0178 (11)0.0068 (10)0.0137 (12)
C150.0712 (11)0.0617 (11)0.0659 (10)0.0047 (9)0.0090 (8)0.0017 (8)
C160.0733 (11)0.0586 (10)0.0582 (9)0.0081 (8)0.0092 (7)0.0006 (7)
C170.0902 (13)0.0800 (14)0.0674 (11)0.0047 (11)0.0089 (10)0.0079 (9)
C180.0828 (12)0.0729 (12)0.0612 (10)0.0135 (9)0.0017 (9)0.0036 (8)
C190.0868 (14)0.1062 (18)0.0752 (13)0.0170 (12)0.0118 (11)0.0055 (12)
C200.0773 (13)0.1102 (18)0.0932 (15)0.0061 (12)0.0015 (12)0.0142 (13)
C210.0811 (13)0.0898 (15)0.0847 (13)0.0006 (11)0.0174 (11)0.0083 (11)
C220.0752 (11)0.0710 (12)0.0628 (11)0.0079 (9)0.0087 (9)0.0029 (9)
C230.0732 (10)0.0586 (10)0.0564 (9)0.0163 (8)0.0052 (7)0.0067 (7)
C240.151 (2)0.120 (2)0.0767 (14)0.0237 (19)0.0050 (15)0.0135 (13)
C250.1088 (14)0.0845 (15)0.0727 (13)0.0190 (11)0.0108 (10)0.0018 (11)
C260.114 (2)0.133 (3)0.132 (2)0.0109 (19)0.0189 (15)0.027 (2)
C270.1092 (19)0.118 (2)0.0920 (15)0.0079 (17)0.0014 (13)0.0032 (13)
N10.0635 (8)0.0700 (9)0.0641 (8)0.0022 (7)0.0022 (6)0.0071 (7)
N20.0672 (8)0.0686 (9)0.0630 (8)0.0004 (7)0.0031 (6)0.0042 (7)
N30.1024 (12)0.0956 (13)0.0617 (10)0.0098 (9)0.0000 (9)0.0142 (9)
N40.1214 (18)0.180 (3)0.165 (2)0.0192 (18)0.0043 (16)0.033 (2)
N50.181 (2)0.1318 (19)0.0803 (13)0.0445 (15)0.0230 (12)0.0219 (13)
Geometric parameters (Å, º) top
C1—C21.376 (3)C15—C161.432 (2)
C1—C61.395 (2)C15—H151.013 (19)
C1—H11.00 (2)C16—C171.378 (2)
C2—C31.372 (3)C16—C231.440 (2)
C2—H20.92 (2)C17—N31.354 (3)
C3—C41.372 (3)C17—H170.96 (2)
C3—H30.990 (18)C18—N31.379 (3)
C4—C51.374 (2)C18—C191.382 (3)
C4—H40.952 (19)C18—C231.406 (2)
C5—C61.394 (2)C19—C201.364 (3)
C5—H50.991 (17)C19—H190.93 (2)
C6—C71.485 (2)C20—C211.400 (3)
C7—C121.389 (2)C20—H201.01 (2)
C7—C81.396 (2)C21—C221.370 (3)
C8—C91.379 (2)C21—H210.99 (2)
C8—H80.915 (17)C22—C231.395 (2)
C9—C101.397 (2)C22—H220.971 (17)
C9—H90.974 (18)C24—C251.438 (3)
C10—C111.395 (2)C24—H24A0.9600
C10—C131.480 (2)C24—H24B0.9600
C11—C121.381 (2)C24—H24C0.9600
C11—H110.947 (18)C25—N51.121 (2)
C12—H120.966 (17)C26—C271.438 (4)
C13—N11.2855 (18)C26—H26A0.9600
C13—C141.493 (2)C26—H26B0.9600
C14—H14A1.05 (3)C26—H26C0.9600
C14—H14B1.01 (4)C27—N41.118 (3)
C14—H14C0.96 (2)N1—N21.4119 (17)
C15—N21.281 (2)N3—H3N0.91 (2)
C2—C1—C6120.91 (17)N2—C15—H15120.6 (10)
C2—C1—H1119.6 (10)C16—C15—H15117.1 (10)
C6—C1—H1119.5 (10)C17—C16—C15123.67 (17)
C3—C2—C1120.52 (19)C17—C16—C23106.31 (15)
C3—C2—H2119.8 (12)C15—C16—C23130.00 (15)
C1—C2—H2119.7 (12)N3—C17—C16109.97 (19)
C4—C3—C2119.52 (18)N3—C17—H17121.9 (12)
C4—C3—H3119.9 (10)C16—C17—H17128.1 (12)
C2—C3—H3120.6 (10)N3—C18—C19129.75 (18)
C3—C4—C5120.54 (18)N3—C18—C23107.61 (16)
C3—C4—H4120.5 (10)C19—C18—C23122.6 (2)
C5—C4—H4119.0 (10)C20—C19—C18118.0 (2)
C4—C5—C6121.04 (17)C20—C19—H19121.5 (12)
C4—C5—H5119.5 (9)C18—C19—H19120.4 (12)
C6—C5—H5119.4 (9)C19—C20—C21120.5 (2)
C5—C6—C1117.46 (15)C19—C20—H20120.7 (11)
C5—C6—C7121.63 (14)C21—C20—H20118.8 (11)
C1—C6—C7120.91 (14)C22—C21—C20121.6 (2)
C12—C7—C8117.02 (14)C22—C21—H21119.5 (11)
C12—C7—C6121.61 (13)C20—C21—H21118.9 (11)
C8—C7—C6121.38 (14)C21—C22—C23119.10 (18)
C9—C8—C7121.66 (15)C21—C22—H22121.1 (10)
C9—C8—H8115.8 (10)C23—C22—H22119.8 (10)
C7—C8—H8122.5 (10)C22—C23—C18118.13 (17)
C8—C9—C10121.15 (15)C22—C23—C16135.19 (15)
C8—C9—H9121.2 (9)C18—C23—C16106.66 (16)
C10—C9—H9117.7 (9)C25—C24—H24A109.5
C11—C10—C9117.18 (14)C25—C24—H24B109.5
C11—C10—C13121.99 (14)H24A—C24—H24B109.5
C9—C10—C13120.82 (13)C25—C24—H24C109.5
C12—C11—C10121.31 (16)H24A—C24—H24C109.5
C12—C11—H11119.8 (10)H24B—C24—H24C109.5
C10—C11—H11118.9 (10)N5—C25—C24178.7 (3)
C11—C12—C7121.64 (15)C27—C26—H26A109.5
C11—C12—H12119.6 (9)C27—C26—H26B109.5
C7—C12—H12118.8 (9)H26A—C26—H26B109.5
N1—C13—C10116.29 (13)C27—C26—H26C109.5
N1—C13—C14124.95 (15)H26A—C26—H26C109.5
C10—C13—C14118.75 (15)H26B—C26—H26C109.5
C13—C14—H14A109.0 (13)N4—C27—C26179.1 (3)
C13—C14—H14B115.1 (17)C13—N1—N2114.52 (13)
H14A—C14—H14B101 (2)C15—N2—N1111.00 (13)
C13—C14—H14C113.0 (13)C17—N3—C18109.44 (16)
H14A—C14—H14C109.3 (18)C17—N3—H3N124.7 (14)
H14B—C14—H14C109 (2)C18—N3—H3N125.8 (14)
N2—C15—C16122.29 (17)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C14—H14C···N20.96 (2)2.34 (2)2.728 (3)103.3 (15)
C9—H9···N10.974 (18)2.430 (15)2.770 (2)100.0 (11)
C17—H17···N40.96 (2)2.50 (2)3.416 (4)159.6 (16)
N3—H3N···N50.91 (2)2.10 (2)3.000 (3)171.2 (19)
Table 2. Selected ππ interaction geometry for BEHI top
d is the the centroid–centroid distance; α is the dihedral angle; β is the slippage angles between the centroid–centroid distance and the normal to plane I; γ is the slippage angles between the centroid–centroid distance and the normal to tplane J; e is the the perpendicular distance of centroid I to plane J; f is the perpendicular distance of centroid J to plane I.
ππ interactions (I J)d (Å)α (°)β (°)γ (°)e (Å)f (Å)
Cg1Cg1#14.4695 (11)0.0044.6344.633.1813.181
Cg1Cg2#25.1886 (11)86.4223.3164.572.2284.765
Cg1Cg4#15.1826 (12)0.7851.9452.533.1533.195
Cg2Cg3#35.3543 (10)29.1736.8160.772.6144.287
Cg2Cg3#45.2907 (11)89.1228.7062.192.4694.641
Cg2Cg4#25.7358 (12)87.1333.3766.052.3284.790
Cg3Cg2#45.0087 (11)89.1211.2886.910.2704.912
Cg3Cg3#25.6496 (10)59.9632.0662.682.5934.788
Cg4Cg1#15.1827 (12)0.7852.5351.943.1953.153
Cg4Cg2#25.1006 (12)87.1321.0985.280.4204.759
Notes: ring 1 is N3—C17—C16—C23—C18, ring 2 is C1–C6, ring 3 is C7–C12 and ring 4 is C18–C23. Symmetry codes: (#1) -x, -y+2, -z; (#2) -x+1, y+1/2, -z+1/2; (#3) x+1, y, z; (#4) -x+2, y-1/2, -z+1/2.
Selected C—H···π and N—H···π interaction geometry for BEHI. top
H···Cg is the distance between a H atom and the centroid of the benzene ring; H-Perp is the perpendicular distances of a H atom to the benzene-ring plane; γ is the slipping angle between the X—H distance and the normal to the benzene plane; X—H···Cg is the X—H···centroid angle; X···Cg is the X—centroid distance.
C—H···π interactionsH···Cg (Å)H-Perp (Å)γ (°)X—H···Cg (°)X···Cg (Å)
C1—H1···Cg3#12.958 (17)2.9179.61139.9 (12)3.7795 (18)
C4—H4···Cg4#22.877 (17)2.80512.83157.8 (13)3.7748 (19)
C14—H14A···Cg2#33.13 (3)2.78527.15172.7 (18)4.170 (3)
C14—H14B···Cg3#22.66 (3)2.61910.54159 (2)3.618 (3)
N3—H3N···Cg1#43.39 (2)3.19819.29106.5 (17)3.7496 (19)
C24—H24A···Cg2#23.2203.08616.60154.404.107 (3)
C26—H26C···Cg4#53.2152.80029.42149.584.072 (4)
Notes: ring 1 is N3—C17—C16—C23—C18; ring 2 is C1–C6; ring 3 is C7–C12; ring 4 is C18–C23. Symmetry codes: (#1) -x+2, y+1/2, -z+1/2; (#2) -x+1, y-1/2, -z+1/2; (#3) x-1, y, z; (#4) -x, -y+2, -z; (#5) x+1, y, z.
Inhibition of A549 and 4T1 cells growth by BEHI compared with Brequinar sodium top
CompoundA549 cells, IC504T1 cells, IC50
BEHI20.5±0.6 µM18.5±0.4 µM
Brequinar sodium12.3±0.5 nM9.5±0.4 nM
 

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