A new bioactive cocrystal of coumarin-3-carb­oxy­lic acid and thio­urea: detailed structural features and biological activity studies

Cocrystallization is a phenomenon widely used to enhance the biological and physicochemical properties of active pharmaceutical ingredients (APIs). The present study deals with the synthesis of a cocrystal of coumarin-3-carb­oxy­lic acid (2-oxochromene-3-carb­oxy­lic acid, C₁₀H₆O₄), a synthetic analogue of the naturally occurring anti­oxidant coumarin, with thio­urea (CH₄N₂S) using the neat grinding method. The purity and homogeneity of the coumarin-3-carb­oxy­lic acid–thio­urea (1/1) cocrystal was confirmed by single-crystal X-ray diffraction, FT–IR analysis and thermal stability studies based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed geometry analysis via density functional theory (DFT) demonstrated that the 1:1 cocrystal stoichiometry is sustained by N—H...O hydrogen bonding between the amine (–NH₂) groups of thio­urea and the carbonyl group of coumarin. The synthesized cocrystal exhibited potent anti­oxidant activity (IC₅₀ = 127.9 ± 5.95 µM) in a DPPH radical scavenger assay in vitro in com­parison with the standard N-acetyl-L-cysteine (IC₅₀ = 111.6 ± 2.4 µM). The promising results of the present study highlight the significance of cocrystallization as a crystal engineering tool to improve the efficacy of pharmaceutical ingredients.

Computing details

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: SHELXTL (Bruker, 2016), ORTEP-3 for Windows (Farrugia, 2012) and Mercury (Macrae et al., 2020); software used to prepare material for publication: SHELXTL (Bruker, 2016), PLATON (Spek, 2020).

2-Oxochromene-3-carboxylic acid–thiourea (1/1)

Crystal data

C10H6O4·CH4N2S	F(000) = 552
Mr = 266.27	Dx = 1.512 Mg m^−3
Monoclinic, P21/n	Cu Kα radiation, λ = 1.54178 Å
a = 11.0390 (4) Å	Cell parameters from 7384 reflections
b = 6.7554 (2) Å	θ = 4.8–68.3°
c = 15.6951 (4) Å	µ = 2.57 mm^−1
β = 91.905 (1)°	T = 293 K
V = 1169.78 (6) Å^3	Block, colourless
Z = 4	0.20 × 0.08 × 0.05 mm

Data collection

Bruker APEX-II CCD diffractometer	1837 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.054
Absorption correction: multi-scan (Blessing, 1995)	θmax = 68.3°, θmin = 4.8°
Tmin = 0.627, Tmax = 0.882	h = −13→13
14985 measured reflections	k = −8→8
2131 independent reflections	l = −18→18

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.037	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.102	w = 1/[σ^2(Fo^2) + (0.0538P)^2 + 0.4417P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max < 0.001
2131 reflections	Δρmax = 0.31 e Å^−3
184 parameters	Δρmin = −0.36 e Å^−3
0 restraints	Extinction correction: SHELXL2018 (Sheldrick, 2015b), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: dual	Extinction coefficient: 0.0070 (7)

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.

Refinement. A fine crystal of suitable size was selected and mounted on a Bruker D8 Venture Single-crystal X-ray diffraction (SC-XRD) instrument, fitted with a Photon (100) detector with CMOS technology. The crystal was irradiated with graphite-monochromated Cu Kα radiation (λ = 1.54178 Å) at 298 K. The SAINT program (Bruker, 2016) was used for data integration and reduction, while dual-space methods were employed to determine the structure (SHELXT2014/5, Sheldrick, 2015a) followed by full-matrix least-squares refinement up to the final refinement (SHELXL2018/3, Sheldrick, 2015b).

An extinction correction has been applied, which shows coefficient value to be 0.0068 (7). X-Ray structures were obtained by using the ORTEP program (Farrugia, 2012). Interactions were analysed with the help of PLATON (Spek, 2009). MERCURY (Macrae et al., 2020) was used to plot the crystal packing diagram, and generate molecular graphics of the interactions.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.52560 (5)	0.12316 (7)	0.22997 (3)	0.0425 (2)
O1	0.23789 (11)	0.76206 (18)	0.57140 (7)	0.0329 (3)
O2	0.32849 (13)	0.4796 (2)	0.59563 (8)	0.0414 (4)
O3	0.42709 (12)	0.2827 (2)	0.45638 (8)	0.0381 (3)
O4	0.38776 (17)	0.4288 (3)	0.33155 (9)	0.0553 (5)
N1	0.54529 (16)	−0.0809 (3)	0.37445 (10)	0.0364 (4)
N2	0.6478 (2)	−0.2027 (3)	0.26301 (12)	0.0552 (6)
C1	0.38209 (16)	0.4166 (3)	0.41498 (11)	0.0318 (4)
C2	0.31493 (16)	0.5869 (3)	0.45029 (11)	0.0288 (4)
C3	0.27019 (16)	0.7320 (3)	0.39856 (11)	0.0306 (4)
H3	0.279613	0.721317	0.340076	0.037*
C4	0.20913 (16)	0.9007 (3)	0.43099 (11)	0.0294 (4)
C5	0.16299 (18)	1.0564 (3)	0.38025 (13)	0.0368 (4)
H5	0.169816	1.051573	0.321381	0.044*
C6	0.10799 (18)	1.2152 (3)	0.41703 (14)	0.0408 (5)
H6	0.077090	1.317480	0.383123	0.049*
C7	0.09836 (18)	1.2235 (3)	0.50517 (14)	0.0399 (5)
H7	0.061458	1.332351	0.529651	0.048*
C8	0.14259 (17)	1.0730 (3)	0.55682 (13)	0.0365 (4)
H8	0.136115	1.079119	0.615686	0.044*
C9	0.19660 (16)	0.9135 (3)	0.51880 (11)	0.0294 (4)
C10	0.29784 (15)	0.5981 (3)	0.54205 (11)	0.0289 (4)
C11	0.57597 (16)	−0.0651 (3)	0.29395 (11)	0.0313 (4)
H1A	0.506 (2)	0.014 (4)	0.3975 (14)	0.040 (6)*
H1B	0.571 (2)	−0.178 (4)	0.4077 (15)	0.050 (7)*
H2A	0.677 (2)	−0.302 (4)	0.2940 (19)	0.070 (8)*
H4A	0.427 (3)	0.340 (4)	0.3099 (18)	0.070 (9)*
H2B	0.672 (3)	−0.190 (4)	0.210 (2)	0.076 (9)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0654 (4)	0.0365 (3)	0.0260 (3)	0.0120 (2)	0.0069 (2)	0.00480 (18)
O1	0.0424 (7)	0.0335 (7)	0.0230 (6)	0.0026 (5)	0.0036 (5)	0.0006 (5)
O2	0.0566 (9)	0.0394 (8)	0.0282 (7)	0.0044 (6)	0.0023 (6)	0.0085 (6)
O3	0.0450 (8)	0.0377 (7)	0.0319 (7)	0.0093 (6)	0.0034 (6)	0.0041 (6)
O4	0.0813 (12)	0.0587 (10)	0.0266 (7)	0.0364 (9)	0.0095 (7)	0.0036 (7)
N1	0.0448 (10)	0.0371 (9)	0.0278 (8)	0.0047 (8)	0.0079 (7)	0.0066 (7)
N2	0.0774 (14)	0.0577 (12)	0.0313 (10)	0.0305 (11)	0.0144 (9)	0.0107 (9)
C1	0.0334 (9)	0.0351 (10)	0.0272 (9)	−0.0007 (8)	0.0026 (7)	0.0010 (7)
C2	0.0278 (9)	0.0316 (9)	0.0271 (9)	−0.0022 (7)	0.0015 (7)	0.0002 (7)
C3	0.0323 (10)	0.0353 (10)	0.0240 (8)	−0.0030 (7)	0.0007 (7)	0.0007 (7)
C4	0.0297 (9)	0.0295 (9)	0.0287 (9)	−0.0031 (7)	−0.0019 (7)	−0.0002 (7)
C5	0.0424 (11)	0.0348 (10)	0.0330 (9)	−0.0029 (8)	−0.0043 (8)	0.0040 (8)
C6	0.0409 (11)	0.0298 (10)	0.0510 (12)	0.0008 (8)	−0.0082 (9)	0.0043 (9)
C7	0.0363 (10)	0.0318 (10)	0.0516 (12)	0.0000 (8)	−0.0006 (9)	−0.0075 (9)
C8	0.0370 (10)	0.0371 (10)	0.0355 (10)	−0.0021 (8)	0.0020 (8)	−0.0074 (8)
C9	0.0283 (9)	0.0296 (9)	0.0300 (9)	−0.0052 (7)	−0.0012 (7)	−0.0004 (7)
C10	0.0300 (9)	0.0298 (9)	0.0271 (9)	−0.0050 (7)	0.0019 (7)	0.0021 (7)
C11	0.0332 (9)	0.0341 (9)	0.0267 (9)	−0.0014 (8)	0.0018 (7)	0.0012 (7)

Geometric parameters (Å, º)

S1—C11	1.7024 (18)	C2—C3	1.356 (3)
O1—C10	1.377 (2)	C2—C10	1.461 (2)
O1—C9	1.383 (2)	C3—C4	1.426 (2)
O2—C10	1.201 (2)	C3—H3	0.9300
O3—C1	1.211 (2)	C4—C9	1.392 (2)
O4—C1	1.316 (2)	C4—C5	1.405 (3)
O4—H4A	0.82 (3)	C5—C6	1.370 (3)
N1—C11	1.323 (2)	C5—H5	0.9300
N1—H1A	0.86 (2)	C6—C7	1.392 (3)
N1—H1B	0.88 (3)	C6—H6	0.9300
N2—C11	1.325 (3)	C7—C8	1.379 (3)
N2—H2A	0.88 (3)	C7—H7	0.9300
N2—H2B	0.89 (3)	C8—C9	1.377 (3)
C1—C2	1.486 (2)	C8—H8	0.9300
C10—O1—C9	123.23 (13)	C6—C5—H5	119.8
C1—O4—H4A	114 (2)	C4—C5—H5	119.8
C11—N1—H1A	119.4 (14)	C5—C6—C7	119.99 (18)
C11—N1—H1B	122.7 (15)	C5—C6—H6	120.0
H1A—N1—H1B	118 (2)	C7—C6—H6	120.0
C11—N2—H2A	122.8 (18)	C8—C7—C6	121.14 (18)
C11—N2—H2B	118.4 (19)	C8—C7—H7	119.4
H2A—N2—H2B	119 (3)	C6—C7—H7	119.4
O3—C1—O4	123.29 (17)	C9—C8—C7	118.16 (18)
O3—C1—C2	125.39 (16)	C9—C8—H8	120.9
O4—C1—C2	111.31 (16)	C7—C8—H8	120.9
C3—C2—C10	119.77 (16)	C8—C9—O1	117.34 (16)
C3—C2—C1	120.86 (16)	C8—C9—C4	122.44 (17)
C10—C2—C1	119.37 (15)	O1—C9—C4	120.21 (16)
C2—C3—C4	122.08 (16)	O2—C10—O1	115.39 (15)
C2—C3—H3	119.0	O2—C10—C2	127.80 (17)
C4—C3—H3	119.0	O1—C10—C2	116.80 (15)
C9—C4—C5	117.93 (17)	N1—C11—N2	117.97 (18)
C9—C4—C3	117.83 (16)	N1—C11—S1	122.29 (15)
C5—C4—C3	124.23 (17)	N2—C11—S1	119.73 (14)
C6—C5—C4	120.33 (18)
O3—C1—C2—C3	178.48 (18)	C7—C8—C9—C4	0.8 (3)
O4—C1—C2—C3	−1.2 (3)	C10—O1—C9—C8	−177.31 (16)
O3—C1—C2—C10	−1.1 (3)	C10—O1—C9—C4	3.3 (2)
O4—C1—C2—C10	179.26 (17)	C5—C4—C9—C8	−0.9 (3)
C10—C2—C3—C4	1.8 (3)	C3—C4—C9—C8	177.91 (17)
C1—C2—C3—C4	−177.74 (16)	C5—C4—C9—O1	178.47 (15)
C2—C3—C4—C9	0.2 (3)	C3—C4—C9—O1	−2.8 (2)
C2—C3—C4—C5	178.91 (17)	C9—O1—C10—O2	179.72 (15)
C9—C4—C5—C6	0.2 (3)	C9—O1—C10—C2	−1.2 (2)
C3—C4—C5—C6	−178.46 (18)	C3—C2—C10—O2	177.57 (18)
C4—C5—C6—C7	0.4 (3)	C1—C2—C10—O2	−2.9 (3)
C5—C6—C7—C8	−0.5 (3)	C3—C2—C10—O1	−1.4 (2)
C6—C7—C8—C9	−0.1 (3)	C1—C2—C10—O1	178.22 (15)
C7—C8—C9—O1	−178.55 (16)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C8—H8···S1^i	0.93	2.98	3.6742 (19)	132
N1—H1A···O3	0.86 (2)	2.23 (3)	3.082 (2)	172 (2)
N1—H1B···O2^ii	0.88 (3)	2.32 (3)	3.062 (2)	142 (2)
N1—H1B···O3^ii	0.88 (3)	2.25 (2)	2.991 (2)	142 (2)
N2—H2A···O2^ii	0.88 (3)	2.11 (3)	2.907 (2)	150 (3)
N2—H2B···O1^iii	0.89 (3)	2.37 (3)	3.224 (2)	162 (3)
O4—H4A···S1	0.82 (3)	2.23 (3)	3.0466 (16)	170 (3)

Symmetry codes: (i) x−1/2, −y+3/2, z+1/2; (ii) −x+1, −y, −z+1; (iii) x+1/2, −y+1/2, z−1/2.