Synthesis, structure and anti­proliferative and optical activities of two new biphenyl-derived Schiff bases

Tan, X.-J.; Zhang, L.-Y.; Sun, Y.-K.; Zhou, X.-M.

doi:10.1107/S2053229618017989

Synthesis, structure and antiproliferative and optical activities of two new biphenyl-derived Schiff bases

X.-J. Tan, L.-Y. Zhang, Y.-K. Sun and X.-M. Zhou

Two novel Schiff bases derived from indole and biphenyl have been designed and synthesized, namely 3-((E)-{(E)-[1-(biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1-methyl-1H-indole (3-BEHMI) acetonitrile monosolvate, C₂₄H₂₁N₃·CH₃CN, and 3-((E)-{(E)-[1-(biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1-methyl-1H-indole (3-BEHEI) acetonitrile monosolvate, C₂₄H₂₁N₃·CH₃CN. Their structures were characterized by elemental analysis, quadrupole time-of-flight MS, NMR and UV–Vis spectroscopy. The single-crystal packing structure of 3-BEHMI is largely dominated by C—H

π interactions and weak van der Waals interactions. The in vitro cytotoxicity of the two title compounds have been evaluated against two tumour cell lines (A549 human lung cancer and 4T₁ mouse breast cancer) and two normal cell lines (MRC-5 normal lung cells and NIH 3T3 fibroblasts) by MTT assay. The results indicate that 3-BEHEI exhibits a slightly weaker antiproliferative capability (IC₅₀ = ∼50 µM) than the previously reported similar Schiff base 3-BEHI (IC₅₀ = ∼20 µM). This is in line with docking results. 3-BEHMI demonstrates a weak cytotoxic activity, with IC₅₀ values around 110 µM, which disagrees with its docking results. Overall, the tested compounds manifest relevant cytotoxicities on the selected cancer cell lines and normal cell lines. The UV–Vis and fluorescence spectra were recorded and reproduced through the TD-DFT method with four types of hybrid density functionals, including B3LYP, M062X, PBE1PBE and WB97XD.

Keywords: Schiff bases; biphenyl; indole; cytotoxicity; antiproliferative; crystal structure; optical activities.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229618017989/ov3117sup1.cif Contains datablocks I, global
	Structure factor file (CIF format) https://doi.org/10.1107/S2053229618017989/ov3117Isup2.hkl Contains datablock I
	Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229618017989/ov3117Isup3.cml Supplementary material
	Portable Document Format (PDF) file https://doi.org/10.1107/S2053229618017989/ov3117sup4.pdf Additional tables and figures

CCDC reference: 1886316

Computing details top

Data collection: SMART (Bruker, 2000); cell refinement: SMART (Bruker, 2000); data reduction: SAINT (Bruker, 2000); program(s) used to solve structure: SHELXS2016 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015b); molecular graphics: SHELXTL (Bruker, 2000) and PLATON (Spek, 2009); software used to prepare material for publication: SHELXL2016 (Sheldrick, 2015b).

3-((E)-{(E)-[1-(Biphenyl-4-yl)ethylidene]hydrazinylidene}methyl)-1-methyl-1H-indole acetonitrile monosolvate top

Crystal data top

C₂₄H₂₁N₃·C₂H₃N	F(000) = 832
M_r = 392.49	D_x = 1.184 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.1280 (2) Å	Cell parameters from 380 reflections
b = 8.2147 (1) Å	θ = 2.5–26.0°
c = 32.9809 (6) Å	µ = 0.07 mm⁻¹
β = 90.252 (2)°	T = 298 K
V = 2202.08 (7) Å³	Block, yellow
Z = 4	0.30 × 0.27 × 0.20 mm

Data collection top

Bruker SMART CCD area detector diffractometer	4300 independent reflections
Radiation source: fine-focus sealed tube	3623 reflections with I > 2σ(I)
Detector resolution: 10.13 pixels mm^-1	R_int = 0.040
phi and ω scans	θ_max = 26.1°, θ_min = 2.5°
Absorption correction: multi-scan (SADABS; Bruker, 2000)	h = −9→10
T_min = 0.971, T_max = 0.993	k = −10→9
26680 measured reflections	l = −34→40

Refinement top

Refinement on F²	Hydrogen site location: mixed
Least-squares matrix: full	Only H-atom displacement parameters refined
R[F² > 2σ(F²)] = 0.053	w = 1/[σ²(F_o²) + (0.0717P)² + 0.4656P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.151	(Δ/σ)_max < 0.001
S = 1.02	Δρ_max = 0.16 e Å⁻³
4300 reflections	Δρ_min = −0.16 e Å⁻³
344 parameters	Extinction correction: SHELXL2014 (Sheldrick, 2015b), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.021 (2)

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	1.0305 (2)	−0.0658 (2)	0.16179 (5)	0.0580 (4)
C2	1.1581 (2)	−0.0543 (2)	0.13436 (6)	0.0695 (5)
C3	1.2654 (3)	0.0741 (3)	0.13619 (6)	0.0781 (6)
C4	1.2440 (3)	0.1923 (3)	0.16526 (6)	0.0819 (6)
C5	1.1167 (2)	0.1816 (2)	0.19267 (6)	0.0680 (5)
C6	1.00710 (19)	0.05118 (18)	0.19154 (4)	0.0510 (4)
C7	0.86788 (18)	0.04172 (17)	0.22050 (4)	0.0493 (3)
C8	0.87657 (19)	0.1149 (2)	0.25885 (5)	0.0537 (4)
C9	0.74443 (19)	0.1122 (2)	0.28499 (5)	0.0535 (4)
C10	0.59637 (18)	0.03798 (17)	0.27413 (4)	0.0482 (3)
C11	0.5885 (2)	−0.0368 (2)	0.23637 (5)	0.0574 (4)
C12	0.7214 (2)	−0.0350 (2)	0.21020 (5)	0.0570 (4)
C13	0.45344 (18)	0.04005 (18)	0.30195 (4)	0.0501 (3)
C14	0.2979 (2)	−0.0395 (3)	0.28876 (6)	0.0825 (6)
H14A	0.3158	−0.1543	0.2857	0.179 (16)*
H14B	0.2629	0.0060	0.2633	0.115 (9)*
H14C	0.2145	−0.0214	0.3088	0.094 (7)*
C15	0.3693 (2)	0.1851 (2)	0.39525 (5)	0.0636 (4)
C16	0.2504 (2)	0.2018 (2)	0.42686 (5)	0.0616 (4)
C17	0.0815 (2)	0.1469 (2)	0.42844 (5)	0.0599 (4)
C18	−0.0230 (2)	0.0630 (2)	0.40208 (6)	0.0686 (5)
C19	−0.1814 (3)	0.0321 (3)	0.41404 (8)	0.0835 (6)
C20	−0.2386 (3)	0.0810 (3)	0.45228 (9)	0.0940 (8)
C21	−0.1384 (3)	0.1627 (3)	0.47869 (7)	0.0852 (7)
C22	0.0210 (2)	0.1956 (2)	0.46654 (5)	0.0682 (5)
C23	0.2810 (3)	0.2782 (3)	0.46332 (6)	0.0735 (5)
C24	0.1338 (4)	0.3442 (4)	0.52775 (6)	0.0999 (9)
H24A	0.0406	0.4156	0.5292	0.122 (9)*
H24B	0.2323	0.4040	0.5339	0.21 (2)*
H24C	0.1211	0.2573	0.5469	0.140 (11)*
C25	0.2584 (5)	0.7005 (5)	0.39055 (10)	0.1204 (10)
H25A	0.2202	0.8091	0.3853	0.32 (3)*
H25B	0.1659	0.6307	0.3956	0.21 (2)*
H25C	0.3180	0.6611	0.3675	0.198 (19)*
C26	0.3626 (3)	0.7014 (4)	0.42481 (8)	0.0950 (7)
N1	0.47564 (16)	0.11150 (19)	0.33626 (4)	0.0608 (4)
N2	0.33775 (17)	0.11183 (19)	0.36187 (4)	0.0608 (4)
N3	0.1452 (2)	0.2767 (2)	0.48697 (4)	0.0763 (5)
N4	0.4440 (3)	0.7039 (6)	0.45186 (9)	0.1703 (16)
H1	0.959 (2)	−0.153 (2)	0.1602 (5)	0.066 (5)*
H2	1.169 (2)	−0.140 (3)	0.1140 (6)	0.077 (6)*
H3	1.359 (3)	0.077 (3)	0.1186 (6)	0.086 (6)*
H4	1.323 (3)	0.283 (3)	0.1675 (6)	0.088 (6)*
H5	1.105 (3)	0.266 (3)	0.2116 (7)	0.092 (7)*
H8	0.977 (2)	0.176 (2)	0.2677 (5)	0.063 (5)*
H9	0.753 (2)	0.159 (2)	0.3112 (6)	0.067 (5)*
H11	0.489 (2)	−0.082 (2)	0.2283 (5)	0.065 (5)*
H12	0.707 (2)	−0.081 (2)	0.1825 (6)	0.075 (6)*
H15	0.477 (3)	0.236 (3)	0.3994 (6)	0.080 (6)*
H18	0.011 (2)	0.029 (2)	0.3748 (6)	0.061 (5)*
H19	−0.255 (3)	−0.020 (3)	0.3967 (8)	0.098 (8)*
H20	−0.343 (3)	0.055 (3)	0.4605 (8)	0.110 (8)*
H21	−0.178 (3)	0.200 (3)	0.5051 (7)	0.087 (6)*
H23	0.382 (3)	0.330 (3)	0.4728 (7)	0.085 (7)*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0615 (9)	0.0530 (8)	0.0596 (9)	−0.0038 (7)	0.0094 (7)	−0.0029 (7)
C2	0.0754 (12)	0.0713 (11)	0.0619 (10)	−0.0031 (9)	0.0181 (9)	−0.0093 (8)
C3	0.0750 (12)	0.0913 (14)	0.0682 (11)	−0.0166 (10)	0.0258 (9)	−0.0039 (10)
C4	0.0851 (14)	0.0897 (14)	0.0711 (12)	−0.0353 (11)	0.0204 (10)	−0.0111 (10)
C5	0.0772 (12)	0.0658 (10)	0.0610 (10)	−0.0173 (9)	0.0134 (8)	−0.0101 (8)
C6	0.0539 (8)	0.0511 (8)	0.0482 (8)	0.0003 (6)	0.0034 (6)	0.0025 (6)
C7	0.0534 (8)	0.0451 (7)	0.0494 (8)	0.0011 (6)	0.0043 (6)	0.0013 (6)
C8	0.0489 (8)	0.0601 (9)	0.0521 (8)	−0.0023 (7)	0.0017 (6)	−0.0053 (7)
C9	0.0513 (8)	0.0612 (9)	0.0481 (8)	0.0003 (7)	0.0012 (6)	−0.0064 (7)
C10	0.0494 (8)	0.0467 (7)	0.0485 (7)	0.0017 (6)	0.0025 (6)	0.0025 (6)
C11	0.0564 (9)	0.0603 (9)	0.0556 (9)	−0.0122 (7)	0.0036 (7)	−0.0050 (7)
C12	0.0634 (9)	0.0587 (9)	0.0490 (8)	−0.0097 (7)	0.0067 (7)	−0.0066 (7)
C13	0.0493 (8)	0.0507 (8)	0.0502 (8)	0.0022 (6)	0.0024 (6)	0.0048 (6)
C14	0.0559 (10)	0.1263 (19)	0.0655 (11)	−0.0202 (11)	0.0096 (8)	−0.0145 (11)
C15	0.0576 (10)	0.0771 (11)	0.0562 (9)	0.0025 (8)	0.0027 (7)	−0.0002 (8)
C16	0.0635 (10)	0.0715 (10)	0.0498 (8)	0.0101 (8)	0.0038 (7)	0.0021 (7)
C17	0.0630 (9)	0.0626 (9)	0.0542 (8)	0.0175 (7)	0.0099 (7)	0.0112 (7)
C18	0.0685 (11)	0.0664 (10)	0.0709 (11)	0.0105 (8)	0.0068 (9)	0.0065 (9)
C19	0.0694 (12)	0.0785 (13)	0.1027 (16)	0.0024 (10)	0.0053 (12)	0.0108 (12)
C20	0.0701 (14)	0.0964 (16)	0.1156 (19)	0.0116 (12)	0.0287 (13)	0.0255 (15)
C21	0.0844 (14)	0.0926 (15)	0.0789 (13)	0.0264 (12)	0.0319 (12)	0.0192 (11)
C22	0.0747 (11)	0.0717 (11)	0.0583 (9)	0.0230 (9)	0.0146 (8)	0.0125 (8)
C23	0.0758 (12)	0.0872 (13)	0.0574 (10)	0.0115 (10)	0.0012 (9)	−0.0036 (9)
C24	0.135 (2)	0.1115 (18)	0.0537 (11)	0.0424 (18)	0.0092 (12)	−0.0068 (12)
C25	0.125 (2)	0.129 (3)	0.107 (2)	0.014 (2)	−0.0211 (19)	−0.0079 (18)
C26	0.0777 (14)	0.124 (2)	0.0833 (15)	0.0088 (13)	0.0163 (12)	−0.0233 (14)
N1	0.0506 (7)	0.0789 (9)	0.0530 (7)	−0.0036 (6)	0.0094 (6)	−0.0055 (6)
N2	0.0523 (7)	0.0771 (9)	0.0529 (7)	−0.0003 (6)	0.0087 (6)	−0.0022 (6)
N3	0.0914 (12)	0.0889 (11)	0.0487 (8)	0.0250 (9)	0.0101 (7)	−0.0006 (7)
N4	0.1039 (19)	0.301 (5)	0.1065 (19)	0.023 (2)	−0.0050 (16)	−0.055 (2)

Geometric parameters (Å, º) top

C1—C2	1.383 (2)	C15—N2	1.280 (2)
C1—C6	1.387 (2)	C15—C16	1.431 (2)
C1—H1	0.924 (19)	C15—H15	0.98 (2)
C2—C3	1.370 (3)	C16—C23	1.378 (3)
C2—H2	0.98 (2)	C16—C17	1.446 (2)
C3—C4	1.376 (3)	C17—C18	1.395 (3)
C3—H3	0.96 (2)	C17—C22	1.409 (2)
C4—C5	1.380 (3)	C18—C19	1.372 (3)
C4—H4	0.99 (2)	C18—H18	0.982 (18)
C5—C6	1.394 (2)	C19—C20	1.405 (4)
C5—H5	0.94 (2)	C19—H19	0.93 (3)
C6—C7	1.486 (2)	C20—C21	1.366 (4)
C7—C12	1.388 (2)	C20—H20	0.92 (3)
C7—C8	1.402 (2)	C21—C22	1.384 (3)
C8—C9	1.380 (2)	C21—H21	0.98 (2)
C8—H8	1.000 (19)	C22—N3	1.382 (3)
C9—C10	1.395 (2)	C23—N3	1.354 (2)
C9—H9	0.949 (19)	C23—H23	0.98 (2)
C10—C11	1.390 (2)	C24—N3	1.458 (3)
C10—C13	1.4836 (19)	C24—H24A	0.9600
C11—C12	1.386 (2)	C24—H24B	0.9600
C11—H11	0.927 (18)	C24—H24C	0.9600
C12—H12	0.99 (2)	C25—C26	1.410 (4)
C13—N1	1.287 (2)	C25—H25A	0.9600
C13—C14	1.487 (2)	C25—H25B	0.9600
C14—H14A	0.9600	C25—H25C	0.9600
C14—H14B	0.9600	C26—N4	1.108 (3)
C14—H14C	0.9600	N1—N2	1.4063 (17)

C2—C1—C6	121.41 (16)	N2—C15—C16	122.58 (17)
C2—C1—H1	119.2 (11)	N2—C15—H15	119.7 (12)
C6—C1—H1	119.4 (11)	C16—C15—H15	117.7 (12)
C3—C2—C1	120.21 (17)	C23—C16—C15	124.00 (18)
C3—C2—H2	121.6 (12)	C23—C16—C17	106.18 (16)
C1—C2—H2	118.2 (12)	C15—C16—C17	129.82 (16)
C2—C3—C4	119.46 (17)	C18—C17—C22	118.83 (18)
C2—C3—H3	120.0 (13)	C18—C17—C16	135.01 (16)
C4—C3—H3	120.4 (13)	C22—C17—C16	106.16 (17)
C3—C4—C5	120.57 (18)	C19—C18—C17	118.8 (2)
C3—C4—H4	120.0 (13)	C19—C18—H18	118.4 (11)
C5—C4—H4	119.4 (13)	C17—C18—H18	122.7 (11)
C4—C5—C6	120.84 (17)	C18—C19—C20	121.3 (3)
C4—C5—H5	117.6 (14)	C18—C19—H19	120.7 (15)
C6—C5—H5	121.5 (14)	C20—C19—H19	117.9 (15)
C1—C6—C5	117.51 (15)	C21—C20—C19	120.9 (2)
C1—C6—C7	121.71 (14)	C21—C20—H20	118.4 (17)
C5—C6—C7	120.76 (14)	C19—C20—H20	120.7 (17)
C12—C7—C8	117.10 (14)	C20—C21—C22	117.9 (2)
C12—C7—C6	121.40 (13)	C20—C21—H21	121.7 (13)
C8—C7—C6	121.46 (13)	C22—C21—H21	120.4 (13)
C9—C8—C7	121.35 (14)	N3—C22—C21	129.5 (2)
C9—C8—H8	117.7 (10)	N3—C22—C17	108.34 (17)
C7—C8—H8	120.9 (10)	C21—C22—C17	122.2 (2)
C8—C9—C10	121.31 (14)	N3—C23—C16	110.70 (19)
C8—C9—H9	120.3 (11)	N3—C23—H23	120.4 (13)
C10—C9—H9	118.4 (11)	C16—C23—H23	128.9 (13)
C11—C10—C9	117.35 (14)	N3—C24—H24A	109.5
C11—C10—C13	121.76 (14)	N3—C24—H24B	109.5
C9—C10—C13	120.89 (13)	H24A—C24—H24B	109.5
C12—C11—C10	121.38 (15)	N3—C24—H24C	109.5
C12—C11—H11	120.4 (11)	H24A—C24—H24C	109.5
C10—C11—H11	118.0 (11)	H24B—C24—H24C	109.5
C11—C12—C7	121.49 (14)	C26—C25—H25A	109.5
C11—C12—H12	118.4 (11)	C26—C25—H25B	109.5
C7—C12—H12	119.8 (11)	H25A—C25—H25B	109.5
N1—C13—C10	116.23 (13)	C26—C25—H25C	109.5
N1—C13—C14	125.00 (15)	H25A—C25—H25C	109.5
C10—C13—C14	118.77 (14)	H25B—C25—H25C	109.5
C13—C14—H14A	109.5	N4—C26—C25	179.2 (4)
C13—C14—H14B	109.5	C13—N1—N2	114.83 (13)
H14A—C14—H14B	109.5	C15—N2—N1	111.13 (14)
C13—C14—H14C	109.5	C23—N3—C22	108.62 (16)
H14A—C14—H14C	109.5	C23—N3—C24	125.6 (2)
H14B—C14—H14C	109.5	C22—N3—C24	125.7 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C9—H9···N1	0.949 (19)	2.440 (18)	2.769 (2)	100.1 (13)
C14—H14C···N2	0.96	2.29	2.731 (2)	107

Crystallographic data and structure refinements summary for 3-BEHMI top

Compound	3-BEHMI
Chemical formula	C₂₄H₂₁N₃.C₂H₃N
M_r	392.49
Crystal habit	block/yellow
Crystal system	Monoclinic
Space group	P2₁/c
a (Å)	8.1280 (2)
b (Å)	8.21470 (10)
c (Å)	32.9809 (6)
α (°)	90.00
β (°)	90.252 (2)
γ (°)	90.00
V /Å³	2202.08 (7)
Z	4
Dcalc. (Mg m^-3)	1.184
µ (mm^-1)	0.071
T (K)	298
F(000)	832
R_int	0.0395
R₁ [I>2σ(I)]	0.0525
wR₂/reflections	0.151/4300
S	1.024

Computer programs: SMART (Bruker, 2000), SAINT (Bruker, 2000), SHELXT2016 (Sheldrick, 2015a), SHELXL2016 (Sheldrick, 2015b), SHELXTL (Bruker, 2000), PLATON (Spek, 2009), DIAMOND (Brandenburg & Putz, 1999) and ORTEP-3 (Farrugia, 2012).

Selected C—H···π interaction geometry for 3-BEHEI [the H–centroid distance (H···Cg), the perpendicular distance of H to plane I (H-Perp), slippage angles between H···Cg and the normal to the plane I (γ), the C—H···Cg angles (C—H···Cg), the C–centroid distance (C···Cg), the angles between C—H bond line and plane I (C—H···π)] (Å, °) top

Notation	C—H···π (plane I)	H···Cg	H-Perp	γ	C—H···Cg	C···Cg	C—H···π
a	C2—H2···Cg1ⁱ	2.80 (2)	2.679	16.69	159.7 (13)	3.729 (2)	60.31
b	C24—H24C···Cg1ⁱⁱ	3.0934	2.713	28.71	146.48	3.930 (3)	60.80

Ring 1 consists of atoms C17–C22 Symmetry codes: (i) -x+1, y-1/2, -z+1/2; (ii) -x+2, -y+1, -.

Inhibition of A549, 4T₁ and MRC-5, NIH 3T3 cells growth by the title compounds, compared with 3-BEHEI and Brequinar sodium top

Compound	A549 cells, IC₅₀	4T₁ cells, IC₅₀	MRC-5 cells, IC₅₀	NIH 3T3 fibroblasts, IC₅₀
3-BEHMI	108.5±0.9 µM	112.0±1.0 µM	145.0±1.5 µM	159.0±1.5 µM
3-BEHEI	50.5±0.7 µM	52.0±0.9 µM	78.5±0.9 µM	79.0±1.2 µM
3-BEHI	21.5±0.6 µM	18.0±0.6 µM	28.0±0.7 µM	22.0±0.8 µM
Brequinar sodium	12.6±0.5 nM	9.9±0.4 nM	18.0±0.3 nM	15.5±0.5 nM

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Synthesis, structure and anti­proliferative and optical activities of two new biphenyl-derived Schiff bases

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Synthesis, structure and antiproliferative and optical activities of two new biphenyl-derived Schiff bases