A new biologically active mol­ecular scaffold: crystal structure of 7-(3-hy­droxy­phen­yl)-4-methyl-2H-[1,2,4]triazolo[3,2-c][1,2,4]triazole and selective anti­proliferative activity of three isomeric triazolo–triazoles

A study of three isomeric com­pounds containing a phenolic moiety attached to the nitro­gen-rich triazolo–triazole bicycle is presented. In the three isomers, the phenolic OH group is in the ortho, meta and para positions. The crystal structure analysis of the meta isomer (C₁₀H₉N₅O) shows that the 2H-tautomer is present in the crystal and that the mol­ecule adopts a substanti­ally planar geometry. However, the conformation found in the crystal is different com­pared to the monoprotonated cation of the same com­pound previously investigated in several salts. The packing of the meta isomer is driven by the formation of strong hydrogen bonds and shows the formation of infinite planar ribbons, parallel to a, formed around 2₁ crystallographic axes. The three isomers were tested against some cancer cell lines and also against normal cell lines. The ortho isomer shows a weak anti­proliferative activity, the meta isomer shows significant anti­proliferative activity against some cancer lines and no activity against healthy cell lines, and the para isomer is active against all the tested cell lines.

Computing details

Data collection: COLLECT (Nonius, 1999); cell refinement: DIRAX/LSQ (Duisenberg et al., 2000); data reduction: EVALCCD (Duisenberg et al., 2003); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL2016 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2008); software used to prepare material for publication: WinGX (Farrugia, 2012).

3-(3-Hydroxyphenyl)-6-methyl-1H-[1,2,4]triazolo[3,2-c][1,2,4]triazole

Crystal data

C10H9N5O	Dx = 1.500 Mg m^−3
Mr = 215.22	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, Pbca	Cell parameters from 138 reflections
a = 12.251 (5) Å	θ = 3.6–23.8°
b = 7.457 (3) Å	µ = 0.11 mm^−1
c = 20.863 (6) Å	T = 173 K
V = 1906.0 (12) Å^3	Prism, colourless
Z = 8	0.40 × 0.40 × 0.10 mm
F(000) = 896

Data collection

Bruker–Nonius KappaCCD diffractometer	2171 independent reflections
Radiation source: normal-focus sealed tube	1351 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.071
Detector resolution: 9 pixels mm^-1	θmax = 27.6°, θmin = 3.3°
CCD rotation images, thick slices scans	h = −15→14
Absorption correction: multi-scan (SADABS; Bruker, 2001)	k = −8→9
Tmin = 0.950, Tmax = 0.981	l = −26→26
14282 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.056	Hydrogen site location: mixed
wR(F^2) = 0.118	H atoms treated by a mixture of independent and constrained refinement
S = 1.07	w = 1/[σ^2(Fo^2) + (0.0463P)^2 + 0.6519P] where P = (Fo^2 + 2Fc^2)/3
2171 reflections	(Δ/σ)max < 0.001
152 parameters	Δρmax = 0.22 e Å^−3
0 restraints	Δρmin = −0.22 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.64043 (16)	0.4373 (3)	−0.12741 (9)	0.0257 (5)
C2	0.68973 (18)	0.5154 (3)	−0.18050 (10)	0.0314 (5)
H2	0.766890	0.513131	−0.184963	0.038*
C3	0.62617 (17)	0.5961 (3)	−0.22650 (10)	0.0342 (6)
H3	0.659875	0.651763	−0.262361	0.041*
C4	0.51393 (17)	0.5970 (3)	−0.22113 (10)	0.0315 (5)
H4	0.470861	0.653220	−0.253225	0.038*
C5	0.46382 (16)	0.5162 (3)	−0.16903 (9)	0.0270 (5)
C6	0.52748 (16)	0.4378 (3)	−0.12145 (9)	0.0258 (5)
H6	0.493856	0.384822	−0.085050	0.031*
C7	0.71111 (15)	0.3614 (3)	−0.07796 (9)	0.0241 (5)
C8	0.77250 (15)	0.2236 (3)	0.00878 (10)	0.0248 (5)
C9	0.64025 (15)	0.1345 (3)	0.06245 (10)	0.0259 (5)
C10	0.57846 (17)	0.0455 (3)	0.11475 (10)	0.0358 (6)
H10A	0.500249	0.049097	0.104975	0.054*
H10B	0.592117	0.108240	0.155243	0.054*
H10C	0.602226	−0.079517	0.118569	0.054*
N1	0.81769 (13)	0.3690 (2)	−0.07994 (8)	0.0285 (4)
N2	0.85626 (14)	0.2823 (2)	−0.02622 (8)	0.0279 (4)
H2N	0.9308 (18)	0.281 (3)	−0.0182 (10)	0.034*
N3	0.75169 (13)	0.1352 (2)	0.06233 (8)	0.0269 (4)
N4	0.59113 (12)	0.2149 (2)	0.01296 (8)	0.0253 (4)
N5	0.68080 (12)	0.2726 (2)	−0.02216 (8)	0.0231 (4)
O1	0.35366 (12)	0.5210 (2)	−0.16658 (8)	0.0408 (4)
H1O	0.330 (2)	0.461 (3)	−0.1305 (12)	0.049*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0267 (11)	0.0256 (11)	0.0246 (11)	−0.0013 (8)	0.0017 (8)	−0.0068 (10)
C2	0.0278 (12)	0.0397 (12)	0.0268 (11)	−0.0038 (9)	0.0043 (9)	−0.0052 (10)
C3	0.0376 (14)	0.0420 (13)	0.0229 (11)	−0.0068 (10)	0.0040 (9)	0.0004 (11)
C4	0.0351 (13)	0.0365 (12)	0.0229 (11)	0.0002 (10)	−0.0017 (9)	0.0024 (10)
C5	0.0230 (12)	0.0305 (11)	0.0277 (12)	0.0002 (8)	0.0008 (9)	−0.0047 (10)
C6	0.0270 (12)	0.0273 (11)	0.0232 (11)	−0.0020 (9)	0.0031 (9)	−0.0018 (9)
C7	0.0207 (12)	0.0256 (11)	0.0260 (11)	−0.0022 (8)	0.0035 (8)	−0.0069 (10)
C8	0.0182 (10)	0.0280 (11)	0.0283 (12)	0.0004 (9)	−0.0016 (9)	−0.0063 (10)
C9	0.0214 (12)	0.0285 (11)	0.0279 (12)	0.0024 (8)	0.0000 (8)	−0.0035 (10)
C10	0.0276 (12)	0.0443 (13)	0.0355 (13)	0.0050 (10)	0.0006 (10)	0.0096 (11)
N1	0.0229 (10)	0.0336 (10)	0.0288 (10)	−0.0018 (7)	−0.0004 (7)	−0.0040 (9)
N2	0.0158 (9)	0.0362 (10)	0.0318 (10)	−0.0014 (8)	−0.0008 (8)	−0.0042 (9)
N3	0.0205 (10)	0.0311 (9)	0.0291 (10)	0.0004 (7)	−0.0017 (7)	−0.0034 (8)
N4	0.0202 (9)	0.0308 (9)	0.0249 (10)	−0.0016 (7)	0.0032 (7)	−0.0013 (8)
N5	0.0177 (9)	0.0248 (9)	0.0269 (10)	−0.0015 (7)	−0.0005 (7)	−0.0046 (8)
O1	0.0243 (9)	0.0600 (11)	0.0381 (9)	0.0026 (7)	−0.0004 (7)	0.0150 (9)

Geometric parameters (Å, º)

C1—C6	1.389 (3)	C8—N3	1.322 (3)
C1—C2	1.390 (3)	C8—N2	1.333 (3)
C1—C7	1.461 (3)	C8—N5	1.346 (2)
C2—C3	1.375 (3)	C9—N4	1.337 (3)
C2—H2	0.9500	C9—N3	1.365 (3)
C3—C4	1.380 (3)	C9—C10	1.485 (3)
C3—H3	0.9500	C10—H10A	0.9800
C4—C5	1.386 (3)	C10—H10B	0.9800
C4—H4	0.9500	C10—H10C	0.9800
C5—O1	1.351 (3)	N1—N2	1.377 (2)
C5—C6	1.391 (3)	N2—H2N	0.93 (2)
C6—H6	0.9500	N4—N5	1.389 (2)
C7—N1	1.308 (3)	O1—H1O	0.92 (3)
C7—N5	1.390 (2)
C6—C1—C2	120.19 (19)	N3—C8—N5	112.32 (16)
C6—C1—C7	121.89 (18)	N2—C8—N5	106.88 (18)
C2—C1—C7	117.88 (18)	N4—C9—N3	116.55 (18)
C3—C2—C1	119.6 (2)	N4—C9—C10	122.58 (17)
C3—C2—H2	120.2	N3—C9—C10	120.86 (19)
C1—C2—H2	120.2	C9—C10—H10A	109.5
C2—C3—C4	120.7 (2)	C9—C10—H10B	109.5
C2—C3—H3	119.7	H10A—C10—H10B	109.5
C4—C3—H3	119.7	C9—C10—H10C	109.5
C3—C4—C5	120.2 (2)	H10A—C10—H10C	109.5
C3—C4—H4	119.9	H10B—C10—H10C	109.5
C5—C4—H4	119.9	C7—N1—N2	107.25 (17)
O1—C5—C4	117.43 (18)	C8—N2—N1	109.62 (16)
O1—C5—C6	122.95 (18)	C8—N2—H2N	130.9 (13)
C4—C5—C6	119.60 (19)	N1—N2—H2N	119.3 (13)
C1—C6—C5	119.72 (19)	C8—N3—C9	101.32 (16)
C1—C6—H6	120.1	C9—N4—N5	100.98 (15)
C5—C6—H6	120.1	C8—N5—N4	108.83 (16)
N1—C7—N5	108.30 (17)	C8—N5—C7	107.94 (15)
N1—C7—C1	123.56 (19)	N4—N5—C7	143.23 (16)
N5—C7—C1	128.14 (17)	C5—O1—H1O	109.4 (15)
N3—C8—N2	140.80 (18)
C6—C1—C2—C3	1.2 (3)	C7—N1—N2—C8	−0.6 (2)
C7—C1—C2—C3	−176.81 (18)	N2—C8—N3—C9	179.7 (3)
C1—C2—C3—C4	−1.3 (3)	N5—C8—N3—C9	−0.5 (2)
C2—C3—C4—C5	0.0 (3)	N4—C9—N3—C8	0.3 (2)
C3—C4—C5—O1	−179.8 (2)	C10—C9—N3—C8	179.31 (18)
C3—C4—C5—C6	1.5 (3)	N3—C9—N4—N5	0.0 (2)
C2—C1—C6—C5	0.3 (3)	C10—C9—N4—N5	−179.02 (18)
C7—C1—C6—C5	178.19 (17)	N3—C8—N5—N4	0.5 (2)
O1—C5—C6—C1	179.72 (19)	N2—C8—N5—N4	−179.65 (15)
C4—C5—C6—C1	−1.6 (3)	N3—C8—N5—C7	−179.00 (16)
C6—C1—C7—N1	−175.36 (19)	N2—C8—N5—C7	0.9 (2)
C2—C1—C7—N1	2.6 (3)	C9—N4—N5—C8	−0.25 (19)
C6—C1—C7—N5	4.1 (3)	C9—N4—N5—C7	178.9 (2)
C2—C1—C7—N5	−177.93 (19)	N1—C7—N5—C8	−1.3 (2)
N5—C7—N1—N2	1.2 (2)	C1—C7—N5—C8	179.16 (19)
C1—C7—N1—N2	−179.26 (17)	N1—C7—N5—N4	179.5 (2)
N3—C8—N2—N1	179.6 (2)	C1—C7—N5—N4	0.0 (4)
N5—C8—N2—N1	−0.2 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C6—H6···N4	0.95	2.68	3.352 (3)	128
C10—H10A···N1^i	0.98	2.38	3.338 (3)	167
N2—H2N···N4^ii	0.93 (2)	1.97 (2)	2.891 (3)	172.6 (19)
O1—H1O···N3^i	0.92 (3)	1.86 (3)	2.765 (2)	167 (2)

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