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Many heterocycles have been developed as drugs due to their capacity to inter­act productively with biological systems. The present study aimed to synthesize cocrystals of the heterocyclic anti­tubercular agent pyrazinamide (PYZ, 1, BCS III) and the commercially available anti­convulsant drug carbamazepine (CBZ, 2, BCS class II) to study the effect of cocrystallization on the stability and biological activities of these drugs. Two new cocrystals, namely, pyrazinamide–homophthalic acid (1/1) (PYZ:HMA, 3) and carbamazepine–5-chloro­salicylic acid (1/1) (CBZ:5-SA, 4), were synthesized. The single-crystal X-ray diffraction-based structure of carbamazepine–trans-cinnamic acid (1/1) (CBZ:TCA, 5) was also studied for the first time, along with the known cocrystal carbamazepine–nicotinamide (1/1) (CBZ:NA, 6). From a combination drug perspective, these are inter­esting pharmaceutical cocrystals to overcome the known side effects of PYZ (1) therapy, and the poor biopharmaceutical properties of CBZ (2). The purity and homogeneity of all the synthesized cocrystals were confirmed by single-crystal X-ray diffraction, powder X-ray diffraction and FT–IR analysis, followed by thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed inter­molecular inter­actions and the role of hydrogen bonding towards crystal stability were evaluated qu­anti­tatively via Hirshfeld surface analysis. The solubility of CBZ at pH 6.8 and 7.4 in 0.1 N HCl and H2O were com­pared with the values of cocrystal CBZ:5-SA (4). The solubility of CBZ:5-SA was found to be significantly improved at pH 6.8 and 7.4 in H2O. All the synthesized cocrystals 36 exhibited a potent urease inhibition (IC50 values range from 17.32 ± 0.89 to 12.3 ± 0.8 µM), several times more potent than standard aceto­hydroxamic acid (IC50 = 20.34 ± 0.43 µM). PYZ:HMA (3) also exhibited potent larvicidal activity against Aedes aegypti. Among the synthesized cocrystals, PYZ:HMA (3) and CBZ:TCA (5) were found to possess anti­leishmanial activity against the miltefosine-induced resistant strain of Leishmania major, with IC50 values of 111.98 ± 0.99 and 111.90 ± 1.44 µM, respectively, in com­parison with miltefosine (IC50 = 169.55 ± 0.20 µM).

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229623003753/ef3042sup1.cif
Contains datablocks PYZHMA, CBZ5SA, CBZTCA, CBZNA, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229623003753/ef3042PYZHMAsup2.hkl
Contains datablock PYZHMA

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229623003753/ef3042CBZ5SAsup3.hkl
Contains datablock CBZ5SA

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229623003753/ef3042CBZTCAsup4.hkl
Contains datablock CBZTCA

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229623003753/ef3042CBZNAsup5.hkl
Contains datablock CBZNA

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229623003753/ef3042PYZHMAsup6.cml
Supplementary material

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229623003753/ef3042CBZ5SAsup7.cml
Supplementary material

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229623003753/ef3042CBZTCAsup8.cml
Supplementary material

cml

Chemical Markup Language (CML) file https://doi.org/10.1107/S2053229623003753/ef3042CBZNAsup9.cml
Supplementary material

pdf

Portable Document Format (PDF) file https://doi.org/10.1107/S2053229623003753/ef3042sup10.pdf
Additional information, figures and tables

CCDC references: 2237311; 2234068; 2233995; 2233996

Computing details top

For all structures, data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT2014 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: PLATON (Spek, 2020).

Pyrazine-2-carboxamide; 2-(carboxymethyl)benzoic acid (PYZHMA) top
Crystal data top
C5H5N3O·C9H8O4F(000) = 632
Mr = 303.27Dx = 1.469 Mg m3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
a = 15.3082 (9) ÅCell parameters from 9936 reflections
b = 5.2020 (3) Åθ = 4.8–72.6°
c = 18.6832 (11) ŵ = 0.96 mm1
β = 112.809 (2)°T = 100 K
V = 1371.46 (14) Å3Plate, colourless
Z = 40.20 × 0.17 × 0.06 mm
Data collection top
Bruker APEXII CCD
diffractometer
2701 independent reflections
Radiation source: Cu2409 reflections with I > 2σ(I)
φ and ω scansθmax = 72.6°, θmin = 3.2°
Absorption correction: multi-scan
(SADABS; Bruker, 2016)
h = 1817
Tmin = 0.831, Tmax = 0.944k = 06
2701 measured reflectionsl = 023
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.061H-atom parameters constrained
wR(F2) = 0.225 w = 1/[σ2(Fo2) + (0.1217P)2 + 2.2971P]
where P = (Fo2 + 2Fc2)/3
S = 1.20(Δ/σ)max < 0.001
2701 reflectionsΔρmax = 0.39 e Å3
202 parametersΔρmin = 0.31 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. Refined as a 2-component twin.

For data collection and structure determination, suitable-sized crystals were mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the diffraction data. The SAINT (Bruker, 1998) program was utilized to reduce the collected data, followed by direct methods and Fourier transformation techniques to solve the structures. The refined structures were subjected to full-matrix least-square calculations on F2 using the SHELXL program, with non-H atoms being refined anisotropically and placed at geometrically idealized positions (Sheldrick, 2015b).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.81778 (14)0.1424 (4)0.55153 (12)0.0142 (5)
O20.57323 (15)0.0654 (4)0.28945 (12)0.0172 (5)
O30.57199 (15)0.1657 (4)0.40542 (12)0.0173 (5)
H3C0.6104360.2789730.4041030.026*
O40.48236 (15)0.1382 (4)0.10418 (12)0.0170 (5)
O50.37276 (14)0.0291 (4)0.15013 (12)0.0140 (5)
H50.3606080.0857220.1160360.021*
N10.84566 (18)0.1608 (5)0.39119 (14)0.0147 (5)
N20.70078 (17)0.4682 (5)0.40127 (14)0.0155 (6)
N30.91888 (17)0.2280 (5)0.49235 (14)0.0143 (5)
H3B0.9449640.3583190.5233040.017*
H3A0.9386850.1857160.4555570.017*
C10.80965 (19)0.1217 (5)0.44526 (16)0.0115 (6)
C20.7381 (2)0.2740 (6)0.45111 (16)0.0137 (6)
H20.7153100.2402160.4908090.016*
C30.7365 (2)0.5082 (6)0.34753 (17)0.0161 (6)
H30.7115850.6440020.3113090.019*
C40.8093 (2)0.3574 (6)0.34273 (16)0.0152 (6)
H40.8336400.3952090.3042130.018*
C50.85015 (19)0.0961 (6)0.50110 (16)0.0121 (6)
C60.5426 (2)0.0312 (6)0.33989 (16)0.0137 (6)
C70.4696 (2)0.1652 (6)0.33570 (16)0.0133 (6)
C80.4395 (2)0.3514 (5)0.27599 (16)0.0118 (6)
C90.3697 (2)0.5265 (6)0.27490 (17)0.0146 (6)
H90.3486950.6531150.2351890.018*
C100.3304 (2)0.5198 (6)0.33026 (19)0.0179 (7)
H100.2829200.6405300.3281420.021*
C110.3604 (2)0.3369 (6)0.38888 (18)0.0184 (7)
H110.3336540.3320330.4270450.022*
C120.4296 (2)0.1615 (6)0.39129 (17)0.0163 (6)
H120.4502000.0365210.4314930.020*
C130.4783 (2)0.3717 (5)0.21315 (16)0.0127 (6)
H13A0.5483060.3662620.2379510.015*
H13B0.4602480.5414360.1877160.015*
C140.4456 (2)0.1663 (5)0.15115 (16)0.0119 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0144 (10)0.0174 (10)0.0125 (10)0.0035 (8)0.0070 (8)0.0022 (8)
O20.0172 (10)0.0192 (11)0.0155 (10)0.0041 (8)0.0066 (8)0.0005 (8)
O30.0181 (11)0.0194 (11)0.0137 (10)0.0057 (8)0.0054 (8)0.0041 (8)
O40.0194 (11)0.0190 (11)0.0177 (10)0.0046 (9)0.0129 (9)0.0033 (8)
O50.0133 (10)0.0162 (10)0.0138 (10)0.0038 (8)0.0066 (8)0.0031 (8)
N10.0149 (12)0.0162 (12)0.0117 (11)0.0000 (10)0.0036 (10)0.0004 (9)
N20.0123 (12)0.0160 (12)0.0137 (12)0.0012 (10)0.0002 (9)0.0021 (10)
N30.0142 (12)0.0163 (12)0.0135 (12)0.0037 (10)0.0066 (9)0.0032 (9)
C10.0115 (13)0.0117 (13)0.0096 (13)0.0002 (10)0.0024 (10)0.0001 (10)
C20.0120 (13)0.0161 (14)0.0105 (13)0.0010 (11)0.0016 (10)0.0008 (11)
C30.0165 (14)0.0161 (14)0.0114 (13)0.0006 (11)0.0008 (11)0.0020 (10)
C40.0172 (14)0.0189 (14)0.0083 (13)0.0024 (11)0.0036 (11)0.0009 (10)
C50.0108 (13)0.0134 (13)0.0096 (12)0.0017 (10)0.0010 (10)0.0017 (10)
C60.0119 (13)0.0134 (13)0.0117 (13)0.0023 (11)0.0003 (10)0.0013 (10)
C70.0131 (13)0.0146 (14)0.0103 (13)0.0012 (11)0.0025 (11)0.0014 (10)
C80.0112 (13)0.0128 (13)0.0102 (13)0.0033 (10)0.0026 (10)0.0031 (10)
C90.0127 (13)0.0143 (14)0.0151 (14)0.0006 (11)0.0034 (11)0.0012 (11)
C100.0152 (13)0.0179 (15)0.0225 (15)0.0017 (12)0.0093 (12)0.0011 (12)
C110.0175 (15)0.0256 (16)0.0159 (14)0.0007 (12)0.0108 (12)0.0011 (12)
C120.0165 (14)0.0196 (15)0.0116 (13)0.0007 (11)0.0041 (11)0.0016 (11)
C130.0126 (13)0.0127 (13)0.0121 (13)0.0020 (11)0.0041 (11)0.0009 (11)
C140.0110 (13)0.0134 (13)0.0104 (13)0.0014 (10)0.0031 (10)0.0027 (10)
Geometric parameters (Å, º) top
O1—C51.246 (4)C3—H30.9500
O2—C61.217 (4)C4—H40.9500
O3—C61.328 (4)C6—C71.493 (4)
O3—H3C0.8400C7—C121.395 (4)
O4—C141.221 (4)C7—C81.413 (4)
O5—C141.318 (3)C8—C91.398 (4)
O5—H50.8400C8—C131.511 (4)
N1—C41.336 (4)C9—C101.383 (4)
N1—C11.341 (4)C9—H90.9500
N2—C31.333 (4)C10—C111.388 (4)
N2—C21.342 (4)C10—H100.9500
N3—C51.318 (4)C11—C121.386 (4)
N3—H3B0.8800C11—H110.9500
N3—H3A0.8800C12—H120.9500
C1—C21.390 (4)C13—C141.511 (4)
C1—C51.502 (4)C13—H13A0.9900
C2—H20.9500C13—H13B0.9900
C3—C41.394 (4)
C6—O3—H3C109.5C12—C7—C6119.1 (3)
C14—O5—H5109.5C8—C7—C6121.3 (3)
C4—N1—C1116.2 (3)C9—C8—C7118.2 (3)
C3—N2—C2116.9 (3)C9—C8—C13118.1 (3)
C5—N3—H3B120.0C7—C8—C13123.7 (3)
C5—N3—H3A120.0C10—C9—C8121.6 (3)
H3B—N3—H3A120.0C10—C9—H9119.2
N1—C1—C2122.7 (3)C8—C9—H9119.2
N1—C1—C5117.3 (3)C9—C10—C11120.1 (3)
C2—C1—C5120.1 (3)C9—C10—H10120.0
N2—C2—C1120.7 (3)C11—C10—H10120.0
N2—C2—H2119.7C12—C11—C10119.4 (3)
C1—C2—H2119.7C12—C11—H11120.3
N2—C3—C4122.2 (3)C10—C11—H11120.3
N2—C3—H3118.9C11—C12—C7121.2 (3)
C4—C3—H3118.9C11—C12—H12119.4
N1—C4—C3121.4 (3)C7—C12—H12119.4
N1—C4—H4119.3C8—C13—C14115.7 (2)
C3—C4—H4119.3C8—C13—H13A108.4
O1—C5—N3124.3 (3)C14—C13—H13A108.4
O1—C5—C1119.5 (3)C8—C13—H13B108.4
N3—C5—C1116.2 (3)C14—C13—H13B108.4
O2—C6—O3122.8 (3)H13A—C13—H13B107.4
O2—C6—C7124.3 (3)O4—C14—O5123.2 (3)
O3—C6—C7112.8 (2)O4—C14—C13121.9 (3)
C12—C7—C8119.6 (3)O5—C14—C13114.8 (2)
C4—N1—C1—C20.5 (4)C12—C7—C8—C90.1 (4)
C4—N1—C1—C5179.2 (2)C6—C7—C8—C9178.9 (3)
C3—N2—C2—C10.9 (4)C12—C7—C8—C13180.0 (3)
N1—C1—C2—N20.8 (4)C6—C7—C8—C131.0 (4)
C5—C1—C2—N2179.6 (2)C7—C8—C9—C100.1 (4)
C2—N2—C3—C40.1 (4)C13—C8—C9—C10179.8 (3)
C1—N1—C4—C31.5 (4)C8—C9—C10—C110.2 (5)
N2—C3—C4—N11.4 (5)C9—C10—C11—C120.1 (5)
N1—C1—C5—O1178.8 (2)C10—C11—C12—C70.1 (5)
C2—C1—C5—O11.5 (4)C8—C7—C12—C110.3 (4)
N1—C1—C5—N30.8 (4)C6—C7—C12—C11178.8 (3)
C2—C1—C5—N3178.8 (3)C9—C8—C13—C14106.2 (3)
O2—C6—C7—C12170.5 (3)C7—C8—C13—C1473.7 (4)
O3—C6—C7—C1210.1 (4)C8—C13—C14—O4168.8 (3)
O2—C6—C7—C88.5 (4)C8—C13—C14—O513.8 (4)
O3—C6—C7—C8170.9 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O5—H5···O1i0.841.812.636 (3)168
O3—H3C···N2ii0.841.922.764 (3)179
N3—H3B···O4iii0.882.012.879 (3)167
N3—H3A···O4iv0.882.142.853 (3)137
C4—H4···O2v0.952.663.596 (4)169
C3—H3···O2vi0.952.503.201 (4)130
Symmetry codes: (i) x1/2, y1/2, z1/2; (ii) x, y1, z; (iii) x+1/2, y1/2, z+1/2; (iv) x+3/2, y1/2, z+1/2; (v) x+3/2, y+1/2, z+1/2; (vi) x, y+1, z.
2-Azatricyclo[9.4.0.03,8]pentadeca- 1(11),3,5,7,9,12,14-heptaene-2-carboxamide; 5-chloro-2-hydroxybenzoic acid (CBZ5SA) top
Crystal data top
C15H12N2O·C7H5ClO3F(000) = 848
Mr = 408.83Dx = 1.401 Mg m3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
a = 5.1567 (3) ÅCell parameters from 9986 reflections
b = 21.1373 (10) Åθ = 3.3–68.3°
c = 17.8054 (9) ŵ = 2.02 mm1
β = 92.826 (2)°T = 285 K
V = 1938.41 (18) Å3PLATE, colourless
Z = 40.52 × 0.11 × 0.05 mm
Data collection top
Bruker APEXII CCD
diffractometer
2994 reflections with I > 2σ(I)
Radiation source: CuRint = 0.062
φ and ω scansθmax = 68.2°, θmin = 3.3°
Absorption correction: multi-scan
(SADABS; Bruker, 2016)
h = 66
Tmin = 0.424, Tmax = 0.907k = 2525
24609 measured reflectionsl = 2121
3545 independent reflections
Refinement top
Refinement on F2Hydrogen site location: mixed
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.044 w = 1/[σ2(Fo2) + (0.0554P)2 + 0.7152P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.119(Δ/σ)max = 0.001
S = 1.03Δρmax = 0.24 e Å3
3545 reflectionsΔρmin = 0.34 e Å3
276 parametersExtinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
0 restraintsExtinction coefficient: 0.0150 (9)
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. For data collection and structure determination, suitable-sized crystals were mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the diffraction data. The SAINT (Bruker, 1998) program was utilized to reduce the collected data, followed by direct methods and Fourier transformation techniques to solve the structures. The refined structures were subjected to full-matrix least-square calculations on F2 using the SHELXL program, with non-H atoms being refined anisotropically and placed at geometrically idealized positions (Sheldrick, 2015b).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Cl1.21944 (16)0.43407 (3)0.86940 (5)0.0982 (3)
O10.1000 (3)0.30786 (6)0.61414 (6)0.0470 (3)
O20.4486 (3)0.44255 (7)0.58391 (8)0.0621 (4)
O30.4702 (3)0.37096 (6)0.67534 (8)0.0540 (4)
O40.7627 (5)0.53683 (9)0.58902 (10)0.0932 (7)
H4A0.6374880.5159410.5732880.140*
N10.1371 (3)0.27012 (7)0.51362 (7)0.0379 (3)
N20.0267 (4)0.37143 (8)0.51371 (10)0.0503 (4)
C10.1689 (3)0.21011 (8)0.54975 (9)0.0371 (4)
C20.3481 (4)0.20436 (10)0.60481 (10)0.0461 (4)
H20.4474230.2390350.6178390.055*
C30.3787 (4)0.14700 (11)0.64023 (11)0.0544 (5)
H30.4995420.1428430.6769830.065*
C40.2296 (4)0.09577 (11)0.62106 (12)0.0581 (6)
H40.2499550.0571750.6451410.070*
C50.0514 (4)0.10150 (10)0.56663 (12)0.0534 (5)
H50.0491860.0667490.5546260.064*
C60.0188 (3)0.15895 (8)0.52890 (10)0.0408 (4)
C70.1638 (4)0.16245 (9)0.46865 (11)0.0470 (4)
H70.3137870.1381550.4745980.056*
C80.1367 (4)0.19699 (9)0.40614 (11)0.0475 (5)
H80.2700260.1939640.3730160.057*
C90.0779 (4)0.23900 (9)0.38356 (10)0.0423 (4)
C100.1555 (5)0.24507 (11)0.30731 (11)0.0562 (5)
H100.0664350.2227560.2716640.067*
C110.3595 (5)0.28311 (12)0.28397 (11)0.0626 (6)
H110.4086840.2857630.2331130.075*
C120.4915 (4)0.31735 (11)0.33561 (12)0.0576 (6)
H120.6281940.3435600.3196150.069*
C130.4202 (4)0.31267 (9)0.41165 (11)0.0474 (4)
H130.5097290.3354870.4467570.057*
C140.2158 (3)0.27400 (8)0.43495 (9)0.0378 (4)
C150.0022 (3)0.31659 (8)0.54956 (9)0.0357 (4)
H3A0.335 (6)0.3510 (14)0.6490 (16)0.087 (9)*
H1A0.138 (4)0.3990 (11)0.5338 (12)0.052 (6)*
H1B0.038 (4)0.3754 (10)0.4707 (13)0.053 (6)*
C160.5489 (4)0.42198 (8)0.64295 (10)0.0430 (4)
C170.7677 (3)0.45485 (8)0.68269 (10)0.0405 (4)
C180.8629 (4)0.51091 (10)0.65335 (11)0.0536 (5)
C191.0674 (5)0.54195 (11)0.69094 (12)0.0623 (6)
H191.1303100.5794230.6713950.075*
C201.1777 (4)0.51822 (10)0.75634 (12)0.0534 (5)
H201.3164550.5390410.7808310.064*
C211.0816 (4)0.46307 (9)0.78576 (12)0.0511 (5)
C220.8794 (4)0.43162 (9)0.74970 (11)0.0480 (5)
H220.8165900.3945090.7701870.058*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl0.1061 (6)0.0770 (5)0.1047 (6)0.0120 (4)0.0639 (5)0.0219 (4)
O10.0591 (8)0.0449 (7)0.0362 (6)0.0171 (6)0.0051 (6)0.0006 (5)
O20.0770 (10)0.0582 (9)0.0491 (8)0.0251 (7)0.0171 (7)0.0096 (7)
O30.0598 (8)0.0447 (8)0.0561 (8)0.0183 (6)0.0107 (7)0.0080 (6)
O40.1345 (17)0.0828 (12)0.0590 (10)0.0615 (12)0.0295 (10)0.0294 (9)
N10.0474 (8)0.0349 (7)0.0312 (7)0.0080 (6)0.0004 (6)0.0000 (6)
N20.0648 (11)0.0403 (9)0.0446 (10)0.0163 (8)0.0090 (8)0.0040 (7)
C10.0400 (9)0.0371 (9)0.0333 (8)0.0086 (7)0.0059 (7)0.0017 (7)
C20.0482 (10)0.0507 (11)0.0393 (9)0.0040 (8)0.0014 (8)0.0038 (8)
C30.0506 (11)0.0650 (13)0.0475 (11)0.0101 (10)0.0017 (8)0.0174 (9)
C40.0558 (12)0.0540 (12)0.0633 (13)0.0142 (10)0.0078 (10)0.0254 (10)
C50.0533 (11)0.0420 (10)0.0639 (12)0.0018 (9)0.0079 (9)0.0091 (9)
C60.0384 (9)0.0411 (9)0.0419 (9)0.0069 (7)0.0070 (7)0.0020 (7)
C70.0418 (9)0.0442 (10)0.0549 (11)0.0009 (8)0.0014 (8)0.0059 (8)
C80.0479 (10)0.0493 (11)0.0462 (10)0.0100 (8)0.0111 (8)0.0105 (8)
C90.0493 (10)0.0423 (10)0.0354 (9)0.0142 (8)0.0027 (7)0.0020 (7)
C100.0726 (14)0.0613 (13)0.0348 (10)0.0166 (11)0.0019 (9)0.0040 (9)
C110.0757 (14)0.0750 (15)0.0358 (10)0.0263 (12)0.0118 (10)0.0088 (10)
C120.0526 (11)0.0611 (13)0.0573 (12)0.0149 (10)0.0147 (9)0.0194 (10)
C130.0453 (10)0.0489 (11)0.0478 (10)0.0082 (8)0.0009 (8)0.0075 (8)
C140.0430 (9)0.0379 (9)0.0323 (8)0.0127 (7)0.0017 (7)0.0023 (7)
C150.0371 (8)0.0362 (9)0.0341 (8)0.0040 (7)0.0049 (7)0.0034 (7)
C160.0488 (10)0.0381 (9)0.0421 (10)0.0050 (8)0.0025 (8)0.0029 (7)
C170.0439 (9)0.0353 (9)0.0424 (9)0.0034 (7)0.0035 (7)0.0047 (7)
C180.0681 (13)0.0510 (11)0.0415 (10)0.0188 (10)0.0010 (9)0.0010 (9)
C190.0743 (14)0.0574 (13)0.0553 (12)0.0308 (11)0.0035 (10)0.0012 (10)
C200.0456 (10)0.0530 (12)0.0614 (12)0.0086 (9)0.0003 (9)0.0166 (10)
C210.0488 (10)0.0452 (10)0.0581 (12)0.0059 (8)0.0097 (9)0.0056 (9)
C220.0495 (10)0.0370 (10)0.0567 (11)0.0022 (8)0.0053 (9)0.0022 (8)
Geometric parameters (Å, º) top
Cl—C211.730 (2)C7—C81.333 (3)
O1—C151.246 (2)C7—H70.9300
O2—C161.228 (2)C8—C91.460 (3)
O3—C161.297 (2)C8—H80.9300
O3—H3A0.92 (3)C9—C141.398 (3)
O4—C181.349 (3)C9—C101.402 (3)
O4—H4A0.8200C10—C111.372 (4)
N1—C151.358 (2)C10—H100.9300
N1—C11.435 (2)C11—C121.376 (3)
N1—C141.441 (2)C11—H110.9300
N2—C151.332 (2)C12—C131.389 (3)
N2—H1A0.88 (2)C12—H120.9300
N2—H1B0.82 (2)C13—C141.381 (3)
C1—C21.385 (3)C13—H130.9300
C1—C61.391 (3)C16—C171.476 (3)
C2—C31.379 (3)C17—C221.389 (3)
C2—H20.9300C17—C181.394 (3)
C3—C41.381 (3)C18—C191.386 (3)
C3—H30.9300C19—C201.366 (3)
C4—C51.373 (3)C19—H190.9300
C4—H40.9300C20—C211.380 (3)
C5—C61.402 (3)C20—H200.9300
C5—H50.9300C21—C221.369 (3)
C6—C71.464 (3)C22—H220.9300
C16—O3—H3A113.5 (18)C9—C10—H10119.2
C18—O4—H4A109.5C10—C11—C12120.20 (18)
C15—N1—C1119.83 (14)C10—C11—H11119.9
C15—N1—C14122.25 (13)C12—C11—H11119.9
C1—N1—C14116.94 (13)C11—C12—C13119.9 (2)
C15—N2—H1A117.1 (14)C11—C12—H12120.1
C15—N2—H1B119.4 (16)C13—C12—H12120.1
H1A—N2—H1B122 (2)C14—C13—C12119.76 (19)
C2—C1—C6121.34 (16)C14—C13—H13120.1
C2—C1—N1119.33 (16)C12—C13—H13120.1
C6—C1—N1119.34 (15)C13—C14—C9121.46 (16)
C3—C2—C1119.73 (19)C13—C14—N1119.98 (16)
C3—C2—H2120.1C9—C14—N1118.55 (16)
C1—C2—H2120.1O1—C15—N2121.82 (16)
C2—C3—C4119.94 (19)O1—C15—N1120.53 (15)
C2—C3—H3120.0N2—C15—N1117.64 (15)
C4—C3—H3120.0O2—C16—O3123.17 (17)
C5—C4—C3120.36 (19)O2—C16—C17121.58 (16)
C5—C4—H4119.8O3—C16—C17115.25 (16)
C3—C4—H4119.8C22—C17—C18118.94 (17)
C4—C5—C6121.0 (2)C22—C17—C16121.36 (16)
C4—C5—H5119.5C18—C17—C16119.69 (17)
C6—C5—H5119.5O4—C18—C19117.91 (18)
C1—C6—C5117.66 (17)O4—C18—C17122.43 (18)
C1—C6—C7122.88 (16)C19—C18—C17119.66 (19)
C5—C6—C7119.44 (17)C20—C19—C18120.85 (19)
C8—C7—C6126.50 (18)C20—C19—H19119.6
C8—C7—H7116.8C18—C19—H19119.6
C6—C7—H7116.7C19—C20—C21119.43 (18)
C7—C8—C9127.61 (17)C19—C20—H20120.3
C7—C8—H8116.2C21—C20—H20120.3
C9—C8—H8116.2C22—C21—C20120.77 (19)
C14—C9—C10117.08 (18)C22—C21—Cl120.17 (16)
C14—C9—C8123.01 (16)C20—C21—Cl119.06 (15)
C10—C9—C8119.90 (18)C21—C22—C17120.34 (18)
C11—C10—C9121.6 (2)C21—C22—H22119.8
C11—C10—H10119.2C17—C22—H22119.8
C15—N1—C1—C278.0 (2)C8—C9—C14—C13179.12 (16)
C14—N1—C1—C2113.11 (18)C10—C9—C14—N1178.46 (15)
C15—N1—C1—C6101.90 (18)C8—C9—C14—N12.2 (2)
C14—N1—C1—C667.0 (2)C15—N1—C14—C1376.2 (2)
C6—C1—C2—C30.3 (3)C1—N1—C14—C13115.19 (18)
N1—C1—C2—C3179.52 (16)C15—N1—C14—C9102.58 (19)
C1—C2—C3—C40.4 (3)C1—N1—C14—C966.1 (2)
C2—C3—C4—C50.3 (3)C1—N1—C15—O10.9 (2)
C3—C4—C5—C60.7 (3)C14—N1—C15—O1169.25 (15)
C2—C1—C6—C51.2 (2)C1—N1—C15—N2179.91 (16)
N1—C1—C6—C5178.62 (15)C14—N1—C15—N211.6 (2)
C2—C1—C6—C7177.14 (16)O2—C16—C17—C22179.58 (19)
N1—C1—C6—C73.0 (2)O3—C16—C17—C220.4 (3)
C4—C5—C6—C11.4 (3)O2—C16—C17—C180.6 (3)
C4—C5—C6—C7177.01 (18)O3—C16—C17—C18178.59 (18)
C1—C6—C7—C833.5 (3)C22—C17—C18—O4179.2 (2)
C5—C6—C7—C8144.8 (2)C16—C17—C18—O40.2 (3)
C6—C7—C8—C90.3 (3)C22—C17—C18—C190.6 (3)
C7—C8—C9—C1433.6 (3)C16—C17—C18—C19179.6 (2)
C7—C8—C9—C10145.8 (2)O4—C18—C19—C20180.0 (2)
C14—C9—C10—C110.7 (3)C17—C18—C19—C200.2 (4)
C8—C9—C10—C11178.71 (18)C18—C19—C20—C210.9 (3)
C9—C10—C11—C121.0 (3)C19—C20—C21—C220.8 (3)
C10—C11—C12—C130.9 (3)C19—C20—C21—Cl178.99 (17)
C11—C12—C13—C140.5 (3)C20—C21—C22—C170.0 (3)
C12—C13—C14—C90.2 (3)Cl—C21—C22—C17179.79 (15)
C12—C13—C14—N1178.55 (16)C18—C17—C22—C210.7 (3)
C10—C9—C14—C130.3 (3)C16—C17—C22—C21179.70 (17)
2-Azatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,9,12,14-heptaene-2-carboxamide; 3-phenylprop-2-enoic acid (CBZTCA) top
Crystal data top
C15H12N2O·C9H8O2F(000) = 808
Mr = 384.42Dx = 1.293 Mg m3
Monoclinic, P21/cCu Kα radiation, λ = 1.54178 Å
a = 15.3440 (6) ÅCell parameters from 6596 reflections
b = 5.4552 (3) Åθ = 2.9–67.3°
c = 23.7301 (9) ŵ = 0.69 mm1
β = 96.148 (2)°T = 285 K
V = 1974.89 (15) Å3NEEDLE, colourless
Z = 40.21 × 0.05 × 0.04 mm
Data collection top
Bruker APEXII CCD
diffractometer
2506 reflections with I > 2σ(I)
Radiation source: CuRint = 0.067
φ and ω scansθmax = 68.2°, θmin = 2.9°
Absorption correction: multi-scan
(SADABS; Bruker, 2016)
h = 1818
Tmin = 0.868, Tmax = 0.973k = 66
25468 measured reflectionsl = 2828
3559 independent reflections
Refinement top
Refinement on F2Hydrogen site location: mixed
Least-squares matrix: fullH atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.043 w = 1/[σ2(Fo2) + (0.0522P)2 + 0.4333P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.113(Δ/σ)max < 0.001
S = 1.01Δρmax = 0.17 e Å3
3559 reflectionsΔρmin = 0.20 e Å3
319 parametersExtinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
197 restraintsExtinction coefficient: 0.0035 (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. For data collection and structure determination, suitable-sized crystals were mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the diffraction data. The SAINT (Bruker, 1998) program was utilized to reduce the collected data, followed by direct methods and Fourier transformation techniques to solve the structures. The refined structures were subjected to full-matrix least-square calculations on F2 using the SHELXL program, with non-H atoms being refined anisotropically and placed at geometrically idealized positions (Sheldrick, 2015b).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
O10.40139 (7)0.1827 (2)0.48224 (5)0.0446 (3)
N10.37041 (8)0.4543 (3)0.55005 (5)0.0373 (3)
N20.50449 (9)0.2589 (3)0.55460 (7)0.0441 (4)
H2A0.5405640.1591880.5412960.053*0.5
H2B0.5197030.3367330.5856170.053*0.5
H2C0.528 (2)0.352 (8)0.5817 (16)0.053*0.5
H2D0.531 (2)0.135 (8)0.5395 (15)0.053*0.5
C10.28236 (10)0.4877 (3)0.52383 (7)0.0382 (4)
C20.26490 (12)0.6662 (4)0.48316 (8)0.0488 (5)
H20.3097140.7680180.4736860.059*
C30.18132 (13)0.6944 (4)0.45649 (9)0.0613 (6)
H30.1693560.8156650.4292020.074*
C40.11576 (13)0.5420 (5)0.47053 (9)0.0664 (7)
H40.0595200.5577610.4519520.080*
C50.13253 (12)0.3658 (5)0.51189 (9)0.0633 (6)
H50.0875200.2630910.5206420.076*
C60.21637 (11)0.3393 (4)0.54095 (8)0.0472 (5)
C70.23114 (13)0.1734 (4)0.58898 (10)0.0638 (6)
H70.1984660.0295010.5869490.077*
C80.28683 (13)0.2058 (4)0.63585 (9)0.0637 (6)
H80.2873560.0833770.6631450.076*
C90.34635 (12)0.4092 (4)0.64907 (8)0.0503 (5)
C100.36617 (15)0.4918 (5)0.70528 (9)0.0726 (7)
H100.3426330.4103740.7345850.087*
C110.42012 (17)0.6922 (6)0.71745 (10)0.0809 (8)
H110.4308950.7473170.7546270.097*
C120.45766 (17)0.8097 (5)0.67543 (10)0.0764 (7)
H120.4944310.9430740.6840140.092*
C130.44107 (13)0.7307 (4)0.62065 (8)0.0555 (5)
H130.4670810.8098890.5920400.067*
C140.38613 (11)0.5348 (3)0.60758 (7)0.0408 (4)
C150.42488 (10)0.2930 (3)0.52711 (7)0.0347 (4)
C16A0.28984 (19)0.3835 (6)0.35628 (12)0.0500 (7)0.907 (4)
O2A0.34838 (15)0.5333 (5)0.35944 (9)0.0676 (6)0.907 (4)
O3A0.28359 (15)0.2049 (4)0.39373 (10)0.0661 (6)0.907 (4)
H3A10.3323 (15)0.222 (5)0.4251 (9)0.099*0.907 (4)
C17A0.21566 (14)0.3778 (5)0.31132 (9)0.0541 (7)0.907 (4)
H17A0.1767070.2468180.3100290.065*0.907 (4)
C18A0.20282 (16)0.5513 (5)0.27313 (10)0.0492 (7)0.907 (4)
H18A0.2431330.6791560.2755310.059*0.907 (4)
C16B0.3160 (19)0.494 (6)0.3479 (13)0.057 (5)0.093 (4)
O2B0.3816 (14)0.618 (5)0.3591 (10)0.072 (6)0.093 (4)
H2B10.4029310.5882710.3915860.107*0.093 (4)
O3B0.2963 (16)0.291 (5)0.3761 (10)0.061 (5)0.093 (4)
C17B0.2521 (12)0.556 (4)0.3001 (8)0.055 (4)0.093 (4)
H17B0.2667640.6928300.2798010.066*0.093 (4)
C18B0.1781 (13)0.454 (5)0.2805 (9)0.049 (5)0.093 (4)
H18B0.1552820.3210380.2984850.059*0.093 (4)
C190.13096 (12)0.5641 (4)0.22677 (7)0.0481 (5)
C200.13083 (13)0.7571 (4)0.18926 (9)0.0578 (5)
H200.1746430.8751930.1945580.069*
C210.06698 (14)0.7782 (4)0.14404 (9)0.0629 (6)
H210.0682380.9095150.1191550.075*
C220.00179 (14)0.6070 (4)0.13558 (8)0.0604 (6)
H220.0412910.6218840.1050800.073*
C230.00027 (14)0.4133 (4)0.17233 (9)0.0615 (6)
H230.0437700.2959040.1667200.074*
C240.06431 (13)0.3928 (4)0.21771 (8)0.0560 (5)
H240.0626160.2616640.2426040.067*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0396 (7)0.0458 (8)0.0471 (7)0.0057 (5)0.0012 (5)0.0064 (6)
N10.0280 (7)0.0439 (9)0.0394 (8)0.0043 (6)0.0016 (6)0.0006 (6)
N20.0327 (8)0.0442 (10)0.0541 (9)0.0063 (7)0.0017 (7)0.0042 (8)
C10.0288 (8)0.0433 (11)0.0421 (9)0.0047 (7)0.0024 (7)0.0074 (8)
C20.0424 (10)0.0542 (13)0.0484 (10)0.0055 (8)0.0016 (8)0.0019 (9)
C30.0509 (12)0.0700 (15)0.0594 (12)0.0165 (11)0.0106 (10)0.0014 (11)
C40.0377 (11)0.0919 (19)0.0655 (14)0.0170 (11)0.0134 (10)0.0196 (13)
C50.0323 (10)0.0813 (17)0.0764 (15)0.0056 (10)0.0059 (10)0.0186 (13)
C60.0347 (10)0.0522 (12)0.0546 (11)0.0009 (8)0.0049 (8)0.0066 (9)
C70.0458 (11)0.0597 (15)0.0883 (16)0.0081 (10)0.0178 (11)0.0111 (12)
C80.0501 (12)0.0761 (16)0.0671 (14)0.0056 (11)0.0159 (11)0.0298 (12)
C90.0406 (10)0.0664 (14)0.0442 (10)0.0163 (9)0.0054 (8)0.0091 (9)
C100.0643 (14)0.111 (2)0.0426 (12)0.0367 (14)0.0074 (10)0.0128 (13)
C110.0844 (18)0.100 (2)0.0512 (13)0.0413 (16)0.0240 (12)0.0212 (14)
C120.0869 (17)0.0678 (17)0.0667 (15)0.0146 (13)0.0276 (13)0.0133 (13)
C130.0572 (12)0.0500 (13)0.0555 (11)0.0011 (10)0.0119 (9)0.0034 (10)
C140.0361 (9)0.0467 (11)0.0383 (9)0.0116 (8)0.0016 (7)0.0012 (8)
C150.0303 (9)0.0313 (10)0.0426 (9)0.0014 (7)0.0040 (7)0.0060 (7)
C16A0.0462 (14)0.059 (2)0.0434 (16)0.0085 (12)0.0024 (12)0.0052 (12)
O2A0.0512 (16)0.0880 (18)0.0608 (13)0.0095 (11)0.0077 (11)0.0062 (12)
O3A0.0725 (13)0.0623 (14)0.0582 (14)0.0012 (10)0.0185 (10)0.0066 (9)
C17A0.0507 (13)0.0610 (16)0.0478 (12)0.0030 (11)0.0066 (10)0.0008 (10)
C18A0.0424 (15)0.0576 (18)0.0472 (12)0.0003 (11)0.0034 (11)0.0026 (11)
C16B0.049 (8)0.072 (9)0.046 (8)0.012 (7)0.005 (6)0.002 (7)
O2B0.057 (9)0.080 (11)0.073 (11)0.020 (8)0.014 (8)0.011 (9)
O3B0.059 (10)0.081 (10)0.036 (10)0.028 (8)0.026 (7)0.004 (7)
C17B0.047 (7)0.067 (8)0.049 (7)0.005 (6)0.003 (6)0.006 (6)
C18B0.040 (7)0.054 (10)0.052 (9)0.003 (7)0.001 (7)0.003 (8)
C190.0429 (10)0.0573 (13)0.0435 (10)0.0078 (9)0.0016 (8)0.0043 (9)
C200.0494 (12)0.0588 (14)0.0636 (12)0.0038 (10)0.0007 (10)0.0036 (11)
C210.0640 (13)0.0613 (15)0.0612 (13)0.0045 (11)0.0032 (10)0.0160 (11)
C220.0593 (13)0.0677 (16)0.0506 (12)0.0040 (11)0.0116 (10)0.0032 (11)
C230.0601 (13)0.0600 (15)0.0609 (13)0.0073 (10)0.0099 (10)0.0002 (11)
C240.0619 (13)0.0567 (14)0.0477 (11)0.0019 (10)0.0014 (9)0.0089 (9)
Geometric parameters (Å, º) top
O1—C151.2424 (19)C12—H120.9300
N1—C151.366 (2)C13—C141.376 (3)
N1—C141.430 (2)C13—H130.9300
N1—C11.437 (2)C16A—O2A1.211 (4)
N2—C151.335 (2)C16A—O3A1.329 (4)
N2—H2A0.8600C16A—C17A1.475 (3)
N2—H2B0.8600O3A—H3A11.001 (17)
N2—H2C0.87 (4)C17A—C18A1.310 (3)
N2—H2D0.89 (4)C17A—H17A0.9300
C1—C21.377 (2)C18A—C191.474 (3)
C1—C61.391 (2)C18A—H18A0.9300
C2—C31.377 (2)C16B—O2B1.218 (18)
C2—H20.9300C16B—O3B1.346 (18)
C3—C41.374 (3)C16B—C17B1.458 (17)
C3—H30.9300O2B—H2B10.8200
C4—C51.378 (3)C17B—C18B1.303 (17)
C4—H40.9300C17B—H17B0.9300
C5—C61.400 (3)C18B—C191.520 (16)
C5—H50.9300C18B—H18B0.9300
C6—C71.454 (3)C19—C201.378 (3)
C7—C81.340 (3)C19—C241.385 (3)
C7—H70.9300C20—C211.378 (3)
C8—C91.450 (3)C20—H200.9300
C8—H80.9300C21—C221.367 (3)
C9—C141.393 (3)C21—H210.9300
C9—C101.410 (3)C22—C231.372 (3)
C10—C111.383 (4)C22—H220.9300
C10—H100.9300C23—C241.382 (3)
C11—C121.364 (4)C23—H230.9300
C11—H110.9300C24—H240.9300
C12—C131.367 (3)
C15—N1—C14122.03 (13)C12—C13—C14120.4 (2)
C15—N1—C1119.74 (13)C12—C13—H13119.8
C14—N1—C1115.41 (12)C14—C13—H13119.8
C15—N2—H2A120.0C13—C14—C9121.81 (18)
C15—N2—H2B120.0C13—C14—N1119.37 (17)
H2A—N2—H2B120.0C9—C14—N1118.81 (17)
C15—N2—H2C124 (3)O1—C15—N2121.19 (16)
H2A—N2—H2C114.3O1—C15—N1121.31 (14)
H2B—N2—H2C12.3N2—C15—N1117.50 (15)
C15—N2—H2D110 (2)O2A—C16A—O3A124.0 (3)
H2A—N2—H2D12.9O2A—C16A—C17A124.7 (3)
H2B—N2—H2D128.9O3A—C16A—C17A111.3 (3)
H2C—N2—H2D125 (4)C16A—O3A—H3A1109.2 (17)
C2—C1—C6121.56 (16)C18A—C17A—C16A122.2 (3)
C2—C1—N1119.76 (15)C18A—C17A—H17A118.9
C6—C1—N1118.67 (15)C16A—C17A—H17A118.9
C3—C2—C1120.20 (19)C17A—C18A—C19126.6 (2)
C3—C2—H2119.9C17A—C18A—H18A116.7
C1—C2—H2119.9C19—C18A—H18A116.7
C4—C3—C2119.4 (2)O2B—C16B—O3B125 (2)
C4—C3—H3120.3O2B—C16B—C17B121 (2)
C2—C3—H3120.3O3B—C16B—C17B114.1 (19)
C3—C4—C5120.61 (19)C16B—O2B—H2B1109.5
C3—C4—H4119.7C18B—C17B—C16B131.9 (19)
C5—C4—H4119.7C18B—C17B—H17B114.0
C4—C5—C6121.0 (2)C16B—C17B—H17B114.0
C4—C5—H5119.5C17B—C18B—C19116.7 (18)
C6—C5—H5119.5C17B—C18B—H18B121.6
C1—C6—C5117.07 (18)C19—C18B—H18B121.6
C1—C6—C7122.28 (16)C20—C19—C24117.71 (17)
C5—C6—C7120.55 (18)C20—C19—C18A117.9 (2)
C8—C7—C6126.9 (2)C24—C19—C18A124.4 (2)
C8—C7—H7116.5C20—C19—C18B144.1 (9)
C6—C7—H7116.5C24—C19—C18B98.1 (9)
C7—C8—C9127.71 (19)C21—C20—C19121.2 (2)
C7—C8—H8116.1C21—C20—H20119.4
C9—C8—H8116.1C19—C20—H20119.4
C14—C9—C10116.4 (2)C22—C21—C20120.3 (2)
C14—C9—C8122.49 (18)C22—C21—H21119.8
C10—C9—C8121.1 (2)C20—C21—H21119.8
C11—C10—C9120.9 (2)C21—C22—C23119.65 (19)
C11—C10—H10119.5C21—C22—H22120.2
C9—C10—H10119.5C23—C22—H22120.2
C12—C11—C10120.6 (2)C22—C23—C24119.9 (2)
C12—C11—H11119.7C22—C23—H23120.1
C10—C11—H11119.7C24—C23—H23120.1
C11—C12—C13119.8 (3)C23—C24—C19121.20 (19)
C11—C12—H12120.1C23—C24—H24119.4
C13—C12—H12120.1C19—C24—H24119.4
C15—N1—C1—C290.9 (2)C8—C9—C14—N12.5 (3)
C14—N1—C1—C2107.77 (18)C15—N1—C14—C1385.6 (2)
C15—N1—C1—C689.91 (19)C1—N1—C14—C13113.47 (18)
C14—N1—C1—C671.4 (2)C15—N1—C14—C993.25 (19)
C6—C1—C2—C32.9 (3)C1—N1—C14—C967.6 (2)
N1—C1—C2—C3177.90 (16)C14—N1—C15—O1163.73 (16)
C1—C2—C3—C40.4 (3)C1—N1—C15—O13.6 (2)
C2—C3—C4—C51.6 (3)C14—N1—C15—N216.5 (2)
C3—C4—C5—C60.6 (3)C1—N1—C15—N2176.63 (15)
C2—C1—C6—C54.9 (3)O2A—C16A—C17A—C18A6.3 (4)
N1—C1—C6—C5175.88 (16)O3A—C16A—C17A—C18A172.6 (2)
C2—C1—C6—C7171.42 (19)C16A—C17A—C18A—C19179.7 (2)
N1—C1—C6—C77.8 (3)O2B—C16B—C17B—C18B179 (4)
C4—C5—C6—C13.8 (3)O3B—C16B—C17B—C18B2 (6)
C4—C5—C6—C7172.7 (2)C16B—C17B—C18B—C19177 (3)
C1—C6—C7—C831.7 (3)C17A—C18A—C19—C20177.3 (2)
C5—C6—C7—C8144.5 (2)C17A—C18A—C19—C241.5 (4)
C6—C7—C8—C91.5 (4)C17B—C18B—C19—C208 (4)
C7—C8—C9—C1432.7 (3)C17B—C18B—C19—C24174 (2)
C7—C8—C9—C10146.6 (2)C24—C19—C20—C210.4 (3)
C14—C9—C10—C112.0 (3)C18A—C19—C20—C21178.4 (2)
C8—C9—C10—C11177.30 (19)C18B—C19—C20—C21178.0 (19)
C9—C10—C11—C122.1 (3)C19—C20—C21—C220.2 (3)
C10—C11—C12—C130.8 (4)C20—C21—C22—C230.1 (3)
C11—C12—C13—C140.6 (3)C21—C22—C23—C240.3 (3)
C12—C13—C14—C90.6 (3)C22—C23—C24—C190.5 (3)
C12—C13—C14—N1179.46 (17)C20—C19—C24—C230.6 (3)
C10—C9—C14—C130.7 (3)C18A—C19—C24—C23178.2 (2)
C8—C9—C14—C13178.63 (18)C18B—C19—C24—C23179.1 (11)
C10—C9—C14—N1178.18 (16)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2A···O1i0.862.172.987 (2)160
N2—H2C···O2Aaii0.87 (4)2.32 (4)3.091 (3)148 (3)
N2—H2C···O2Bbii0.87 (4)1.87 (4)2.63 (2)145 (4)
N2—H2C···O2Aaii0.87 (4)2.32 (4)3.091 (3)148 (3)
N2—H2C···O2Bbii0.87 (4)1.87 (4)2.63 (2)145 (4)
N2—H2A···O1i0.862.172.987 (2)160
C13—H13···N2iii0.932.693.469 (3)142
O3Aa—H3A1a···O11.00 (2)1.64 (2)2.623 (2)165 (3)
O2Bb—H2B1b···N2ii0.821.992.63 (2)135
Symmetry codes: (i) x+1, y, z+1; (ii) x+1, y+1, z+1; (iii) x, y+1, z.
2-Azatricyclo[9.4.0.03,8]pentadeca-1(11),3,5,7,9,12,14-heptaene-2-carboxamide; pyridine-3-carboxamide (CBZNA) top
Crystal data top
C15H12N2O·C6H6N2OF(000) = 752
Mr = 358.39Dx = 1.328 Mg m3
Monoclinic, P21/nCu Kα radiation, λ = 1.54178 Å
a = 5.1236 (1) ÅCell parameters from 7391 reflections
b = 17.7396 (5) Åθ = 3.4–68.2°
c = 19.7236 (6) ŵ = 0.71 mm1
β = 91.090 (2)°T = 285 K
V = 1792.37 (8) Å3Needle, colourless
Z = 40.43 × 0.06 × 0.05 mm
Data collection top
Bruker APEXII CCD
diffractometer
2538 reflections with I > 2σ(I)
Radiation source: CuRint = 0.070
φ and ω scansθmax = 68.2°, θmin = 3.4°
Absorption correction: multi-scan
(SADABS; Bruker, 2016)
h = 65
Tmin = 0.749, Tmax = 0.965k = 2121
24350 measured reflectionsl = 2323
3284 independent reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.040 w = 1/[σ2(Fo2) + (0.0489P)2 + 0.3659P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.107(Δ/σ)max = 0.001
S = 1.05Δρmax = 0.20 e Å3
3284 reflectionsΔρmin = 0.15 e Å3
254 parametersExtinction correction: SHELXL2018 (Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
0 restraintsExtinction coefficient: 0.0104 (6)
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. For data collection and structure determination, suitable-sized crystals were mounted on a Bruker APEXII CCD X-ray diffractometer. The mounted crystal was irradiated with Cu Kα radiations (λ = 1.54178 Å) to collect the diffraction data. The SAINT (Bruker, 1998) program was utilized to reduce the collected data, followed by direct methods and Fourier transformation techniques to solve the structures. The refined structures were subjected to full-matrix least-square calculations on F2 using the SHELXL program, with non-H atoms being refined anisotropically and placed at geometrically idealized positions (Sheldrick, 2015b).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
O10.1862 (2)0.42226 (7)0.96461 (5)0.0430 (3)
O20.6747 (2)0.44075 (10)0.79846 (7)0.0688 (5)
N10.4204 (2)0.35826 (7)1.04406 (6)0.0349 (3)
N20.2242 (3)0.47186 (8)1.06930 (7)0.0422 (3)
H2A0.1307770.5103521.0581870.051*
H2B0.2866740.4677521.1099090.051*
N30.2544 (3)0.41713 (9)0.81963 (7)0.0526 (4)
H3A0.2858760.4107580.8622270.063*
H3B0.0976270.4126920.8037640.063*
N40.4948 (3)0.50177 (10)0.59960 (9)0.0636 (5)
C10.4645 (3)0.29815 (9)0.99719 (8)0.0378 (4)
C20.6552 (4)0.30634 (12)0.94927 (9)0.0520 (5)
H20.7493470.3509790.9461620.062*
C60.3118 (3)0.23352 (9)1.00050 (8)0.0438 (4)
C70.1186 (4)0.22180 (10)1.05276 (10)0.0511 (5)
H70.0294860.1945801.0399640.061*
C80.1302 (3)0.24575 (10)1.11695 (10)0.0486 (4)
H80.0088660.2323261.1440760.058*
C90.3359 (3)0.29050 (9)1.14929 (8)0.0396 (4)
C100.3932 (4)0.28115 (12)1.21833 (9)0.0551 (5)
H100.2948710.2474861.2434310.066*
C110.5913 (4)0.32056 (13)1.24990 (9)0.0595 (5)
H110.6275830.3127361.2957380.071*
C120.7367 (4)0.37161 (12)1.21404 (10)0.0546 (5)
H120.8709950.3982171.2355470.065*
C130.6823 (3)0.38310 (10)1.14620 (9)0.0439 (4)
H130.7801100.4176091.1218820.053*
C140.4831 (3)0.34357 (9)1.11406 (8)0.0343 (4)
C150.2723 (3)0.41856 (9)1.02357 (7)0.0320 (3)
C160.4473 (3)0.43376 (11)0.77845 (8)0.0439 (4)
C180.5341 (3)0.48934 (11)0.66573 (9)0.0520 (5)
H180.6768690.5125680.6867350.062*
C190.2914 (4)0.46768 (12)0.57056 (10)0.0562 (5)
H190.2621490.4745760.5242910.067*
C200.1230 (4)0.42305 (12)0.60506 (10)0.0575 (5)
H200.0190670.4009860.5827440.069*
C210.1656 (3)0.41096 (11)0.67333 (9)0.0475 (4)
H210.0527000.3806290.6976570.057*
C170.3775 (3)0.44437 (9)0.70518 (8)0.0369 (4)
C30.704 (11)0.246 (3)0.905 (3)0.068 (3)0.5
H30.8437870.2464770.8755470.081*0.5
C40.515 (3)0.1771 (10)0.9081 (10)0.055 (2)0.5
H40.5310190.1379190.8771640.066*0.5
C50.332 (7)0.174 (3)0.954 (3)0.058 (3)0.5
H50.2173010.1334850.9551990.070*0.5
C3A0.689 (10)0.254 (3)0.901 (3)0.068 (3)0.5
H3A10.8029490.2643670.8661030.081*0.5
C4A0.579 (3)0.1937 (10)0.9008 (10)0.055 (2)0.5
H4A0.6214500.1565010.8696330.066*0.5
C5A0.377 (7)0.181 (3)0.950 (3)0.058 (3)0.5
H5A0.2865420.1353500.9486840.070*0.5
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0483 (6)0.0515 (7)0.0289 (6)0.0110 (5)0.0023 (5)0.0027 (5)
O20.0379 (6)0.1245 (13)0.0438 (8)0.0005 (7)0.0053 (5)0.0027 (8)
N10.0434 (7)0.0351 (7)0.0260 (7)0.0026 (5)0.0017 (5)0.0008 (5)
N20.0510 (8)0.0406 (8)0.0349 (8)0.0102 (6)0.0050 (6)0.0018 (6)
N30.0430 (7)0.0855 (12)0.0295 (8)0.0001 (7)0.0013 (6)0.0030 (7)
N40.0708 (11)0.0732 (12)0.0470 (10)0.0060 (9)0.0068 (8)0.0158 (9)
C10.0422 (8)0.0432 (9)0.0276 (8)0.0093 (7)0.0075 (6)0.0020 (7)
C20.0536 (10)0.0706 (13)0.0319 (9)0.0060 (9)0.0013 (7)0.0035 (9)
C60.0541 (9)0.0399 (9)0.0369 (9)0.0083 (7)0.0144 (7)0.0026 (7)
C70.0546 (10)0.0426 (10)0.0556 (12)0.0109 (8)0.0097 (8)0.0027 (9)
C80.0471 (9)0.0474 (11)0.0515 (11)0.0046 (8)0.0061 (8)0.0082 (9)
C90.0447 (8)0.0414 (9)0.0328 (9)0.0075 (7)0.0041 (7)0.0030 (7)
C100.0674 (12)0.0635 (13)0.0347 (10)0.0044 (9)0.0054 (8)0.0091 (9)
C110.0713 (12)0.0784 (15)0.0286 (10)0.0129 (11)0.0056 (9)0.0024 (9)
C120.0497 (10)0.0718 (14)0.0417 (10)0.0070 (9)0.0118 (8)0.0128 (10)
C130.0406 (8)0.0529 (11)0.0379 (9)0.0003 (7)0.0013 (7)0.0037 (8)
C140.0366 (7)0.0380 (9)0.0283 (8)0.0076 (6)0.0001 (6)0.0011 (6)
C150.0299 (7)0.0371 (9)0.0290 (8)0.0020 (6)0.0018 (6)0.0042 (6)
C160.0377 (8)0.0597 (11)0.0342 (9)0.0029 (7)0.0001 (7)0.0043 (8)
C180.0494 (10)0.0611 (12)0.0454 (11)0.0093 (8)0.0016 (8)0.0022 (9)
C190.0646 (11)0.0695 (14)0.0346 (10)0.0123 (10)0.0001 (8)0.0040 (9)
C200.0548 (10)0.0762 (15)0.0412 (11)0.0033 (10)0.0080 (8)0.0108 (10)
C210.0486 (9)0.0568 (11)0.0373 (10)0.0091 (8)0.0022 (7)0.0043 (8)
C170.0355 (7)0.0421 (9)0.0332 (8)0.0037 (6)0.0031 (6)0.0043 (7)
C30.068 (4)0.097 (8)0.038 (5)0.027 (4)0.001 (3)0.015 (4)
C40.068 (7)0.057 (7)0.040 (4)0.013 (4)0.002 (4)0.016 (4)
C50.080 (10)0.041 (6)0.052 (4)0.005 (6)0.020 (7)0.011 (4)
C3A0.068 (4)0.097 (8)0.038 (5)0.027 (4)0.001 (3)0.015 (4)
C4A0.068 (7)0.057 (7)0.040 (4)0.013 (4)0.002 (4)0.016 (4)
C5A0.080 (10)0.041 (6)0.052 (4)0.005 (6)0.020 (7)0.011 (4)
Geometric parameters (Å, º) top
O1—C151.2376 (18)C10—C111.372 (3)
O2—C161.2294 (19)C10—H100.9300
N1—C151.3683 (19)C11—C121.377 (3)
N1—C11.432 (2)C11—H110.9300
N1—C141.4354 (19)C12—C131.377 (3)
N2—C151.333 (2)C12—H120.9300
N2—H2A0.8600C13—C141.382 (2)
N2—H2B0.8600C13—H130.9300
N3—C161.324 (2)C16—C171.494 (2)
N3—H3A0.8600C18—C171.382 (2)
N3—H3B0.8600C18—H180.9300
N4—C191.325 (3)C19—C201.363 (3)
N4—C181.334 (2)C19—H190.9300
C1—C21.380 (2)C20—C211.377 (3)
C1—C61.390 (2)C20—H200.9300
C2—C3A1.35 (6)C21—C171.378 (2)
C2—C31.41 (6)C21—H210.9300
C2—H20.9300C3—C41.56 (6)
C6—C51.40 (5)C3—H30.9300
C6—C5A1.41 (5)C4—C51.31 (4)
C6—C71.458 (3)C4—H40.9300
C7—C81.336 (3)C5—H50.9300
C7—H70.9300C3A—C4A1.21 (6)
C8—C91.457 (2)C3A—H3A10.9300
C8—H80.9300C4A—C5A1.45 (4)
C9—C101.397 (2)C4A—H4A0.9300
C9—C141.399 (2)C5A—H5A0.9300
C15—N1—C1119.00 (12)C13—C14—C9120.92 (15)
C15—N1—C14122.59 (12)C13—C14—N1119.92 (14)
C1—N1—C14116.79 (12)C9—C14—N1119.14 (13)
C15—N2—H2A120.0O1—C15—N2122.09 (14)
C15—N2—H2B120.0O1—C15—N1120.31 (14)
H2A—N2—H2B120.0N2—C15—N1117.60 (13)
C16—N3—H3A120.0O2—C16—N3122.65 (16)
C16—N3—H3B120.0O2—C16—C17120.37 (15)
H3A—N3—H3B120.0N3—C16—C17116.98 (14)
C19—N4—C18116.74 (17)N4—C18—C17124.57 (17)
C2—C1—C6121.68 (16)N4—C18—H18117.7
C2—C1—N1119.09 (16)C17—C18—H18117.7
C6—C1—N1119.22 (15)N4—C19—C20123.31 (18)
C3A—C2—C1121 (3)N4—C19—H19118.3
C1—C2—C3119 (2)C20—C19—H19118.3
C1—C2—H2120.7C19—C20—C21119.28 (17)
C3—C2—H2120.7C19—C20—H20120.4
C1—C6—C5122.7 (15)C21—C20—H20120.4
C1—C6—C5A112.0 (14)C20—C21—C17119.19 (17)
C1—C6—C7122.76 (15)C20—C21—H21120.4
C5—C6—C7114.5 (15)C17—C21—H21120.4
C5A—C6—C7125.2 (15)C21—C17—C18116.90 (16)
C8—C7—C6127.32 (16)C21—C17—C16123.97 (16)
C8—C7—H7116.3C18—C17—C16119.12 (15)
C6—C7—H7116.3C2—C3—C4117 (4)
C7—C8—C9127.38 (16)C2—C3—H3121.6
C7—C8—H8116.3C4—C3—H3121.6
C9—C8—H8116.3C5—C4—C3121 (3)
C10—C9—C14117.30 (16)C5—C4—H4119.6
C10—C9—C8119.92 (16)C3—C4—H4119.6
C14—C9—C8122.78 (15)C4—C5—C6119 (3)
C11—C10—C9121.43 (18)C4—C5—H5120.6
C11—C10—H10119.3C6—C5—H5120.6
C9—C10—H10119.3C4A—C3A—C2123 (5)
C10—C11—C12120.33 (17)C4A—C3A—H3A1118.4
C10—C11—H11119.8C2—C3A—H3A1118.4
C12—C11—H11119.8C3A—C4A—C5A118 (4)
C11—C12—C13119.68 (18)C3A—C4A—H4A120.8
C11—C12—H12120.2C5A—C4A—H4A120.8
C13—C12—H12120.2C6—C5A—C4A123 (3)
C12—C13—C14120.31 (18)C6—C5A—H5A118.3
C12—C13—H13119.8C4A—C5A—H5A118.3
C14—C13—H13119.8
C15—N1—C1—C280.65 (18)C15—N1—C14—C1379.81 (19)
C14—N1—C1—C2113.45 (16)C1—N1—C14—C13114.83 (16)
C15—N1—C1—C698.48 (17)C15—N1—C14—C998.52 (17)
C14—N1—C1—C667.43 (18)C1—N1—C14—C966.83 (18)
C6—C1—C2—C3A4 (2)C1—N1—C15—O12.7 (2)
N1—C1—C2—C3A175 (2)C14—N1—C15—O1167.76 (14)
C6—C1—C2—C33 (2)C1—N1—C15—N2176.82 (14)
N1—C1—C2—C3177 (2)C14—N1—C15—N211.8 (2)
C2—C1—C6—C53 (3)C19—N4—C18—C170.5 (3)
N1—C1—C6—C5176 (3)C18—N4—C19—C201.4 (3)
C2—C1—C6—C5A0 (2)N4—C19—C20—C211.2 (3)
N1—C1—C6—C5A179 (2)C19—C20—C21—C170.0 (3)
C2—C1—C6—C7176.72 (16)C20—C21—C17—C180.8 (3)
N1—C1—C6—C74.2 (2)C20—C21—C17—C16178.34 (17)
C1—C6—C7—C833.0 (3)N4—C18—C17—C210.6 (3)
C5—C6—C7—C8147 (2)N4—C18—C17—C16178.58 (18)
C5A—C6—C7—C8143 (3)O2—C16—C17—C21153.62 (19)
C6—C7—C8—C91.4 (3)N3—C16—C17—C2126.7 (3)
C7—C8—C9—C10148.59 (19)O2—C16—C17—C1825.5 (3)
C7—C8—C9—C1431.3 (3)N3—C16—C17—C18154.25 (17)
C14—C9—C10—C112.1 (3)C1—C2—C3—C47 (4)
C8—C9—C10—C11177.82 (18)C2—C3—C4—C56 (5)
C9—C10—C11—C121.1 (3)C3—C4—C5—C61 (6)
C10—C11—C12—C130.1 (3)C1—C6—C5—C45 (5)
C11—C12—C13—C140.1 (3)C7—C6—C5—C4175 (3)
C12—C13—C14—C91.0 (2)C1—C2—C3A—C4A8 (5)
C12—C13—C14—N1177.31 (15)C2—C3A—C4A—C5A7 (6)
C10—C9—C14—C132.0 (2)C1—C6—C5A—C4A1 (5)
C8—C9—C14—C13177.86 (16)C7—C6—C5A—C4A177 (3)
C10—C9—C14—N1176.29 (15)C3A—C4A—C5A—C63 (6)
C8—C9—C14—N13.8 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2A···O1i0.862.062.8888 (17)162
N2—H2B···O2ii0.862.433.0698 (19)131
N3—H3A···O10.862.102.8887 (18)152
N3—H3B···O2iii0.862.223.0204 (18)154
C2—H2a···O1iv0.932.593.419 (2)149
C13—H13···N2iv0.932.703.556 (2)154
Symmetry codes: (i) x, y+1, z+2; (ii) x+1, y+1, z+2; (iii) x1, y, z; (iv) x+1, y, z.
Quantitative contribution of intermolecular interactions for APIs PYZ (1) and CBZ (2), and cocrystals PYZ:HMA (3), CBZ:5-SA (4), CBZ:TCA (5) and CBZ:NA (6) top
Quantitative contributions of intermolecular interactions (%)
SampleH···HO···HH···NH···CC···NC···OO···NH···ClC···ClC···C
PYZ (1)30.918.526.77.76.13.91.25.5
CBZ (2)52.111.71.332.60.81.5
PYZ:HMA (3)30.926.417.912.14.64.51.42
CBZ:5-SA (4)38.217.531.51.6162.71.5
CBZ:TCA (5)45.817.61.530.81.11.30.9
CBZ:NA (6)44.913.4433.11.51.21.9
Summary of the melting endotherms and thermal stabilities for APIs PYZ (1) and CBZ (2), co-formers HMA (7), 5-SA (8), TCA (9) and NA (10), and cocrystals PYZ:HMA (3), CBZ:5-SA (4), CBZ:TCA (5) and CBZ:NA (6). top
SampleMelting endotherm (°C)Thermal stability temperature (°C)Weight loss (%)
PYZ190.9141.11.4
PYZ:HMA156.4142.71.5
CBZ186.2218.27.4
CBZ:5-SA178.8169.83.1
CBZ:TCA139.8154.92.9
CBZ:NA156.9177.73.4
HMA187.3176.20.8
5-SA172.0148.42.6
TCA131.2148.71.8
NA125.9170.42.8
Biological activities for APIs PYZ (1) and CBZ (2), co-formers HMA (7), 5-SA (8), TCA (9) and NA (10), and cocrystals PYZ:HMA (3), CBZ:5-SA (4), CBZ:TCA (5) and CBZ:NA (6) top
SampleCytotoxicity against BJ cell line (CC50±SEM µM)Antileishmanial activity Leishmania tropica (IC50±SEM µM)Urease inhibition (IC50±SEM µM)Larvicidal activity Aedes Aegypti (% mortality
Pyrazinamide (PYZ, 1)Noncytotoxicn.a.10.35±1.0180
Homophthalic acid (HMA, 7)Noncytotoxicn.a.15.36±0.74n.a.
PYZ:HMA (3)Noncytotoxic111.98±0.9917.32±0.89100
Carbamazepine (CBZ, 2)Noncytotoxic73.20±1.557.3±0.6n.a.
5-Chlorosalicylic acid (5-SA, 8)Noncytotoxic36.2±1.02614.9±1.3n.a.
CBZ:5-SA (4)Noncytotoxicn.a.13.6±1.4n.a.
trans-Cinnamic acid (TCA, 9)Noncytotoxicn.a.6.8±1.3n.a.
CBZ:TCA (5)Noncytotoxic111.90±1.449.8±1.3n.a.
Nicotinamide (NA, 10)Noncytotoxicn.a.9.3±1.6n.a.
CBZ:NA (6)Noncytotoxicn.a.12.3±0.8n.a.
Standard0.9±0.14a169.55±0.20b20.34±0.43c100d
Notes: (a) doxorubicin; (b) miltefosine; (c) acetohydroxamc acid; (d) permethrin.
 

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