Redetermination of skimmianine: a new inhibitor against the Leishmania APRT enzyme

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Acta Cryst.(2003). E59, o1503±o1505 DOI: 10.1107/S1600536803019913 H. B. Napolitanoet al. C14H13NO4

o1503

organic papers

Acta Crystallographica Section E Structure Reports Online

ISSN 1600-5368

Redetermination of skimmianine: a

new inhibitor against the Leishmania

APRT enzyme

H. B. Napolitano,a* M. Silva,a

J. Ellena,aW. C. Rocha,b

P. C. Vieira,bO. H. Thiemanna

and G. Olivaa

aInstituto de FõÂsica de SaÄo Carlos USP, Cx Postal

369, 13560-970 SaÄo Carlos SP, Brazil, and

bDepto. QuõÂmica, UFSCar, Cx Postal 676,

13565-905 SaÄo Carlos SP, Brazil

Correspondence e-mail: hamilton@if.sc.usp.br

Key indicators

Single-crystal X-ray study

T= 120 K

Mean(C±C) = 0.002 AÊ

Rfactor = 0.038

wRfactor = 0.104

Data-to-parameter ratio = 12.9

For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.

#2003 International Union of Crystallography Printed in Great Britain ± all rights reserved

The title compound (alternative names 7,8-dimethoxydictam-mine and 4,7,8-trimethoxyfuro[2,3-b]quinoline), C14H13NO4, is a natural product extracted from Adiscanthus fusci¯orus (Rutaceae). Our biochemical tests show that it has inhibitory activity against the enzyme adenine phosphoribosyl-transferase (APRT) from Leishmania, a tropical parasite causing endemic disease in poor countries. It crystallizes in the centrosymmetric space groupP21/c, with one molecule in the asymmetric unit, and has at least two CÐH O intermole-cular interactions, leading to the formation of centrosym-metric dimers.

Comment

Leishmaniasis is a disease caused by a protozoal parasite of the order Kinetoplastid. According to the World Heath Organization reports (WHO, 1998), 88 countries are affected, with 12 million infected people and approximately 350 million people at risk. The need for new drugs for the treatment of the leishmaniasis infections comes from a lack of safe drugs and the serious secondary effects observed in available chemo-therapy (McGreevy & Marsden, 1986). The purine nucleotide salvage pathway in Kinetoplastid is a potential target for the development of new drugs, owing to its dependence on that biosynthetic pathway (Berenset al., 1995). In Kinetoplastid, the phosphoribosyltransferase (PRTase) protein family is responsible for purine nucleotide salvage. Looking for new bioactive substances, potentially useful against leishmaniasis, we used the PRTase adenine phosphoribosyltransferase (APRT) fromL. tarentolaeas a model system to screen the inhibitory capacity of several small molecule compounds from Brazilian plants.

The screening was performed using the APRT inhibitory assay, either in the presence of extracts or with the puri®ed compound, and was monitored spectrophotometrically (Tuttle & Krenitsky, 1980). The title compound, (I), was isolated from A. fusci¯orusextracts and has been structurally investigated because of its inhibitory activity against APRT. Enzymatic tests of (I) at 50mg/ml show an inhibition activity of 68%. Further investigations by molecular docking and dynamic simulations will be performed to study the interactions

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organic papers

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H. B. Napolitanoet al. C14H13NO4 Acta Cryst.(2003). E59, o1503±o1505 between this compound and the APRT active site. In light of

this interest, structural characterization will give us important information with respect to the interaction mode of compound (I) with APRT, and allow the investigation of possible inhi-bition of that compound by other PRTases.

With the aim of obtaining more accurate structural data for comparison of (I) and other inhibitors against APRT enzyme, and in order to use this information in molecular docking and dynamic simulations, we undertook a structure determination at 120 K. AnORTEPview (Farrugia, 1997) of compound (I), together with the atom-labelling scheme, is shown in Fig. 1. All bond lengths and angles of this compound are close to normal values (Allenet al., 1983). The crystallographic structure of (I), measured at room temperature, has been previously published (Coxet al., 1989).

The crystal packing of (I) does not show any strong hydrogen bonds. Nevertheless, two weak intermolecular interactions of the type CÐH O (C10ÐH10 O3i, C12Ð H12 O3ii) and two of the type CÐH N (C10ÐH10 Ni and C14ÐH14 Niii) stabilize the three-dimensional struc-ture (symmetry codes as in Table 1). The latter type links two neighbouring molecules in a centrosymmetric dimeric form, as shown in Fig. 2. The C10ÐH10 O3i interaction is respon-sible for the formation of in®nite chains along thebaxis, and C12ÐH12 O3iifor the formation of in®nite chains along the caxis. All structural details of the intermolecular contacts for compound (I) were interpreted as hydrogen bonds on geometrical grounds (Ellenaet al., 2001).

Experimental

The roots and leaves ofA. fusci¯oruswere collected from the Manaus region of the Brazilian Amazon forest in December 2000. An authenticated specimen was deposited in the herbarium of the Instituto de Pesquisas da Amazonia±INPA (code 189859). The powdered parts (roots 2.380 kg and leaves 1.040 kg) were extracted successively with hexane (10 l) and methanol (8.5 l). The crude

hexane crude extract of the root (5.0 g) was extracted by chroma-tography on a silica gel column (h= 282 cm). Fractions 6 and 7 were combined and subjected to silica gel column chromatography, using the isocratic system (hexane/ethyl acetate 7:3). Fraction 8 was collected according to TLC analysis (normal phase) and fractions 6 and 7 were combined and subjected to CCDP using hexane/ethyl acetate 7:3 as the mobile phase. 10 mg of compound (I) were obtained; this crystallized by vapour diffusion as a prismatic, light yellow solid, using 1:1 hexane/dichloromethane as solvent.

Crystal data

C14H13NO4

Mr= 259.25 Monoclinic,P21=c

a= 7.2429 (1) AÊ

b= 10.4418 (2) AÊ

c= 15.4618 (3) AÊ

= 94.353 (1)

V= 1165.99 (4) AÊ3

Z= 4

Dx= 1.477 Mg mÿ3 MoKradiation Cell parameters from 2808

re¯ections

= 3.4±27.5

= 0.11 mmÿ1

T= 120 (2) K Prism, light yellow 0.320.180.16 mm

Data collection

Nonius KappaCCD diffractometer

'and!scans

Absorption correction: none 5117 measured re¯ections 2672 independent re¯ections 2301 re¯ections with I > 2(I)

Rint= 0.013

max= 27.5

h=ÿ9!9

k=ÿ13!13

l=ÿ20!20

Re®nement

Re®nement onF2

R[F2> 2(F2)] = 0.038

wR(F2) = 0.104

S= 1.04 2672 re¯ections 207 parameters

H atoms treated by a mixture of independent and constrained re®nement

w= 1/[2(F

o2) + (0.0633P)2 + 0.2061P]

whereP= (Fo2+ 2Fc2)/3 (/)max< 0.001

max= 0.29 e AÊÿ3

min=ÿ0.22 e AÊÿ3

Figure 1

A view of the molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as spheres of arbitrary radii.

Figure 2

A view of (I), showing dimerization due to C12ÐH12 O3ii[symmetry

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Table 1

Hydrogen-bonding geometry (AÊ,).

DÐH A DÐH H A D A DÐH A

C10ÐH10 O3i 0.97 (1) 2.47 (1) 3.315 (1) 144.8 (11)

C12ÐH12A O3ii 0.99 (1) 2.54 (1) 3.159 (1) 120.3 (11)

C10ÐH10 Ni 0.97 (1) 2.53 (1) 3.290 (1) 134.9 (11)

C14ÐH14A Niii 0.99 (1) 2.69 (1) 3.403 (1) 128.0 (11)

Symmetry codes: (i) 1ÿx;yÿ1

2;12ÿz; (ii) 1ÿx;1ÿy;ÿz; (iii)x;32ÿy;zÿ12.

All of the H atoms, except those attached to the C atom C13, were found in a Fourier synthesis and subsequently re®ned freely. The H atoms attached to C13 were placed at calculated positions.

Data collection:COLLECT(Nonius, 1998); cell re®nement:HKL SCALEPACK(Otwinowski & Minor, 1997); data reduction:HKL DENZO (Otwinowski & Minor, 1997) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to re®ne structure:SHELXL97 (Sheldrick, 1997);

molecular graphics: ORTEP-3 for Windows (Farrugia, 1997) and

PLATON (Spek, 2002); software used to prepare material for publication:WinGXpublication routines (Farrugia, 1999).

This work was supported by CNPq and FAPESP (SaÄo Paulo), Brazil, and by the WHO.

References

Allen, F. H., Kennard, O. & Taylor, R. (1983).Acc. Chem. Res.16, 146±153. Berens, R., Krug, R. & Marr, J. J. (1995).Biochemistry and Molecular Biology

of Parasites, edited by J. J. Marr and M. MuÈller, p. 89±118. London: Academic Press Ltd.

Cox, O., Steiner, J. R., Barnes, C. L. & retamozo, H. R. (1989).Acta Cryst.C45, 1263±1265.

Ellena, J., Goeta, A. E., Howard, J. A. K. & Punte, G. (2001).J. Phys. Chem. A105, 8696±8708.

Farrugia, L. J. (1997).J. Appl. Cryst.30, 565. Farrugia, L. J. (1999).J. Appl. Cryst.32, 837±838.

McGreevy, P. B. & Marsden, P. D. (1986).Chemotheraphy of Parasitic Diseases, edited by W. C. Campbell and R. S. Rew, Vol. 1, p. 115±127. New York: Plenum Press.

Nonius (1998).COLLECT. Nonius BV, Delft, The Netherlands.

Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276,

Macromolecular Crystallography, Part A, edited by C. W. Carter Jr and R. M. Sweet, pp. 307±326. New York: Academic Press.

Sheldrick, G. M. (1997). SHELXS97 and SHELXL97. University of GoÈttingen, Germany.

Spek, A. L. (2002)PLATON.Utrecht University, Utrecht, The Netherlands. Tuttle, J. V. & Krenitsky, T. A. (1980).J. Biol. Chem.255(3), 909±916. WHO (1998). World Heath Organization. http://www.who.Int/tdr/diseases/

leish/diseaseinfo.htm

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Acta Cryst. (2003). E59, o1503–o1505

supporting information

Acta Cryst. (2003). E59, o1503–o1505 [https://doi.org/10.1107/S1600536803019913]

Redetermination of skimmianine: a new inhibitor against the Leishmania APRT

enzyme

H. B. Napolitano, M. Silva, J. Ellena, W. C. Rocha, P. C. Vieira, O. H. Thiemann and G. Oliva

(I)

Crystal data

C14H13NO4

Mr = 259.25

Monoclinic, P21/c

Hall symbol: -P 2ybc

a = 7.2429 (1) Å

b = 10.4418 (2) Å

c = 15.4618 (3) Å

β = 94.353 (1)°

V = 1165.99 (4) Å3

Z = 4

F(000) = 544

Dx = 1.477 Mg m−3

Mo radiation, λ = 0.71073 Å

Cell parameters from 2808 reflections

θ = 3.4–27.5°

µ = 0.11 mm−1

T = 120 K

Prism, light yellow 0.32 × 0.18 × 0.16 mm

Data collection

KappaCCD diffractometer

φ and ω scans

5117 measured reflections 2672 independent reflections

2301 reflections with I > 2σ(I)

Rint = 0.013

θmax = 27.5°, θmin = 3.8°

h = −9→9

k = −13→13

l = −20→20

Refinement

Refinement on F2

Least-squares matrix: full

R[F2 > 2σ(F2)] = 0.038

wR(F2) = 0.104

S = 1.04

2672 reflections 207 parameters 0 restraints

H atoms treated by a mixture of independent and constrained refinement

w = 1/[σ2(F

o2) + (0.0633P)2 + 0.2061P]

where P = (Fo2 + 2Fc2)/3

(Δ/σ)max < 0.001

Δρmax = 0.29 e Å−3

Δρmin = −0.22 e Å−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken

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Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq

N 0.33424 (12) 0.57374 (9) 0.13399 (5) 0.0194 (2)

O1 0.42550 (11) 0.43483 (8) 0.24532 (5) 0.0243 (2)

O2 0.28060 (11) 0.25320 (7) −0.03212 (5) 0.0233 (2)

O3 0.27979 (10) 0.81129 (7) 0.06424 (5) 0.02058 (19)

O4 0.13823 (11) 0.84432 (7) −0.09956 (5) 0.0245 (2)

C1 0.36749 (14) 0.45696 (11) 0.15976 (6) 0.0194 (2)

C2 0.35529 (13) 0.33930 (10) 0.11348 (7) 0.0192 (2)

C3 0.29818 (13) 0.34916 (10) 0.02597 (7) 0.0186 (2)

C4 0.25319 (13) 0.47355 (10) −0.00799 (6) 0.0177 (2)

C5 0.27531 (13) 0.58198 (10) 0.04770 (6) 0.0175 (2)

C6 0.18805 (14) 0.49268 (11) −0.09582 (7) 0.0200 (2)

C7 0.14623 (14) 0.61268 (11) −0.12728 (7) 0.0208 (2)

C8 0.17206 (14) 0.72110 (10) −0.07294 (6) 0.0186 (2)

C9 0.23761 (13) 0.70556 (10) 0.01291 (7) 0.0178 (2)

C10 0.45022 (15) 0.30320 (11) 0.25283 (8) 0.0253 (3)

C11 0.41129 (14) 0.24193 (11) 0.17749 (7) 0.0234 (2)

C12 0.32400 (16) 0.12536 (11) −0.00303 (8) 0.0261 (3)

C13 0.13052 (15) 0.85758 (11) 0.11072 (7) 0.0249 (2)

H13A 0.0434 0.9021 0.0716 0.037*

H13B 0.1777 0.9151 0.1555 0.037*

H13C 0.07 0.7867 0.1363 0.037*

C14 0.09275 (16) 0.86442 (11) −0.19021 (7) 0.0244 (2)

H6 0.1727 (18) 0.4202 (15) −0.1341 (8) 0.027 (3)*

H7 0.0956 (19) 0.6262 (15) −0.1894 (10) 0.035 (4)*

H11 0.4213 (18) 0.1499 (14) 0.1694 (9) 0.027 (3)*

H10 0.4961 (18) 0.2723 (14) 0.3098 (9) 0.027 (3)*

H12A 0.454 (2) 0.1187 (15) 0.0224 (10) 0.041*

H12B 0.307 (2) 0.0721 (16) −0.0552 (10) 0.041*

H12C 0.241 (2) 0.0970 (16) 0.0400 (10) 0.041*

H14A 0.189 (2) 0.8265 (15) −0.2252 (10) 0.041*

H14B 0.089 (2) 0.9608 (17) −0.1963 (9) 0.041*

H14C −0.032 (2) 0.8273 (15) −0.2072 (10) 0.041*

Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23

N 0.0198 (4) 0.0202 (4) 0.0179 (4) 0.0013 (3) −0.0001 (3) −0.0006 (3)

O1 0.0288 (4) 0.0239 (4) 0.0194 (4) 0.0034 (3) −0.0040 (3) 0.0025 (3)

O2 0.0292 (4) 0.0149 (4) 0.0253 (4) 0.0008 (3) −0.0002 (3) −0.0024 (3)

O3 0.0217 (4) 0.0172 (4) 0.0228 (4) −0.0003 (3) 0.0019 (3) −0.0052 (3)

O4 0.0351 (4) 0.0183 (4) 0.0198 (4) 0.0040 (3) −0.0003 (3) 0.0022 (3)

C1 0.0175 (5) 0.0227 (5) 0.0178 (5) 0.0017 (4) −0.0002 (4) 0.0017 (4)

C2 0.0155 (5) 0.0196 (5) 0.0225 (5) 0.0002 (4) 0.0017 (4) 0.0013 (4)

C3 0.0161 (4) 0.0180 (5) 0.0219 (5) −0.0007 (4) 0.0024 (4) −0.0026 (4)

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C5 0.0150 (4) 0.0187 (5) 0.0188 (5) −0.0002 (4) 0.0015 (4) −0.0005 (4)

C6 0.0207 (5) 0.0205 (5) 0.0188 (5) −0.0009 (4) 0.0012 (4) −0.0031 (4)

C7 0.0220 (5) 0.0230 (5) 0.0172 (5) 0.0001 (4) 0.0006 (4) −0.0010 (4)

C8 0.0191 (5) 0.0174 (5) 0.0193 (5) 0.0012 (4) 0.0024 (4) 0.0017 (4)

C9 0.0174 (5) 0.0171 (5) 0.0191 (5) −0.0004 (4) 0.0016 (4) −0.0022 (4)

C10 0.0248 (5) 0.0241 (6) 0.0265 (6) 0.0028 (4) −0.0013 (4) 0.0063 (4)

C11 0.0214 (5) 0.0220 (5) 0.0267 (5) 0.0018 (4) 0.0002 (4) 0.0051 (4)

C12 0.0283 (6) 0.0155 (5) 0.0340 (6) 0.0004 (4) 0.0002 (5) −0.0015 (4)

C13 0.0270 (5) 0.0240 (6) 0.0240 (5) 0.0017 (4) 0.0043 (4) −0.0052 (4)

C14 0.0280 (6) 0.0250 (6) 0.0202 (5) 0.0045 (4) 0.0013 (4) 0.0050 (4)

Geometric parameters (Å, º)

N—C1 1.2996 (14) C6—C7 1.3697 (15)

N—C5 1.3723 (13) C6—H6 0.962 (15)

O1—C1 1.3769 (12) C7—C8 1.4137 (15)

O1—C10 1.3898 (14) C7—H7 1.012 (15)

O2—C3 1.3452 (12) C8—C9 1.3848 (14)

O2—C12 1.4358 (13) C10—C11 1.3401 (16)

O3—C9 1.3804 (12) C10—H10 0.973 (14)

O3—C13 1.4272 (12) C11—H11 0.973 (15)

O4—C8 1.3674 (13) C12—H12A 0.992 (16)

O4—C14 1.4306 (13) C12—H12B 0.980 (16)

C1—C2 1.4211 (15) C12—H12C 0.976 (15)

C2—C3 1.3883 (15) C13—H13A 0.96

C2—C11 1.4549 (14) C13—H13B 0.96

C3—C4 1.4293 (14) C13—H13C 0.96

C4—C6 1.4176 (14) C14—H14A 0.999 (16)

C4—C5 1.4240 (14) C14—H14B 1.011 (17)

C5—C9 1.4166 (14) C14—H14C 0.998 (16)

C1—N—C5 113.18 (9) C9—C8—C7 119.74 (10)

C1—O1—C10 105.92 (8) O3—C9—C8 120.14 (9)

C3—O2—C12 118.42 (8) O3—C9—C5 118.84 (9)

C9—O3—C13 114.67 (8) C8—C9—C5 120.86 (10)

C8—O4—C14 117.11 (8) C11—C10—O1 112.47 (10)

N—C1—O1 119.20 (10) C11—C10—H10 131.6 (9)

N—C1—C2 130.83 (10) O1—C10—H10 115.9 (9)

O1—C1—C2 109.97 (9) C10—C11—C2 106.69 (10)

C3—C2—C1 115.41 (10) C10—C11—H11 124.8 (8)

C3—C2—C11 139.63 (10) C2—C11—H11 128.5 (8)

C1—C2—C11 104.96 (9) O2—C12—H12A 111.6 (9)

O2—C3—C2 126.98 (10) O2—C12—H12B 105.0 (9)

O2—C3—C4 115.10 (9) H12A—C12—H12B 110.1 (12)

C2—C3—C4 117.91 (9) O2—C12—H12C 111.3 (10)

C6—C4—C5 118.76 (9) H12A—C12—H12C 108.8 (12)

C6—C4—C3 122.00 (9) H12B—C12—H12C 110.1 (13)

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N—C5—C9 117.59 (9) O3—C13—H13B 109.5

N—C5—C4 123.40 (10) H13A—C13—H13B 109.5

C9—C5—C4 119.01 (9) O3—C13—H13C 109.5

C7—C6—C4 121.18 (10) H13A—C13—H13C 109.5

C7—C6—H6 119.3 (8) H13B—C13—H13C 109.5

C4—C6—H6 119.5 (8) O4—C14—H14A 110.7 (9)

C6—C7—C8 120.38 (9) O4—C14—H14B 103.9 (8)

C6—C7—H7 121.3 (9) H14A—C14—H14B 111.1 (12)

C8—C7—H7 118.3 (9) O4—C14—H14C 109.7 (9)

O4—C8—C9 116.07 (9) H14A—C14—H14C 111.1 (12)

O4—C8—C7 124.19 (9) H14B—C14—H14C 110.1 (12)

C5—N—C1—O1 −179.22 (8) C6—C7—C8—O4 178.33 (9)

C5—N—C1—C2 1.00 (16) C6—C7—C8—C9 −0.90 (15)

C10—O1—C1—N −179.69 (9) C13—O3—C9—C8 91.14 (11)

C10—O1—C1—C2 0.13 (11) C13—O3—C9—C5 −93.42 (11)

N—C1—C2—C3 −0.10 (17) O4—C8—C9—O3 −5.38 (14)

O1—C1—C2—C3 −179.89 (8) C7—C8—C9—O3 173.90 (8)

N—C1—C2—C11 179.60 (11) O4—C8—C9—C5 179.27 (8)

O1—C1—C2—C11 −0.19 (11) C7—C8—C9—C5 −1.45 (15)

C12—O2—C3—C2 0.09 (15) N—C5—C9—O3 6.65 (14)

C12—O2—C3—C4 179.76 (8) C4—C5—C9—O3 −172.47 (8)

C1—C2—C3—O2 178.01 (9) N—C5—C9—C8 −177.94 (8)

C11—C2—C3—O2 −1.6 (2) C4—C5—C9—C8 2.94 (15)

C1—C2—C3—C4 −1.65 (14) C1—O1—C10—C11 −0.02 (12)

C11—C2—C3—C4 178.79 (11) O1—C10—C11—C2 −0.10 (12)

O2—C3—C4—C6 2.33 (14) C3—C2—C11—C10 179.76 (13)

C2—C3—C4—C6 −177.97 (9) C1—C2—C11—C10 0.17 (11)

O2—C3—C4—C5 −177.27 (8) N—O1—O2—O3 2.22 (3)

C2—C3—C4—C5 2.43 (14) O1—O2—O3—O4 −173.67 (3)

C1—N—C5—C9 −179.19 (8) O2—O3—O4—C1 4.96 (3)

C1—N—C5—C4 −0.11 (14) O3—O4—C1—C2 −172.58 (8)

C6—C4—C5—N 178.82 (9) O4—C1—C2—C3 0.54 (10)

C3—C4—C5—N −1.57 (15) C1—C2—C3—C4 −1.65 (14)

C6—C4—C5—C9 −2.11 (14) C2—C3—C4—C5 2.43 (14)

C3—C4—C5—C9 177.50 (8) C3—C4—C5—C6 179.61 (15)

C5—C4—C6—C7 −0.18 (15) C4—C5—C6—C7 179.85 (13)

C3—C4—C6—C7 −179.77 (9) C5—C6—C7—C8 1.61 (10)

C4—C6—C7—C8 1.70 (16) C6—C7—C8—C9 −0.90 (15)

C14—O4—C8—C9 172.41 (9) C7—C8—C9—C10 −1.95 (16)

C14—O4—C8—C7 −6.84 (14) C8—C9—C10—C11 3.84 (12)

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A

C10—H10···O3i 0.97 (1) 2.47 (1) 3.315 (1) 144.8 (11)

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C10—H10···Ni 0.97 (1) 2.53 (1) 3.290 (1) 134.9 (11)

C14—H14A···Niii 0.99 (1) 2.69 (1) 3.403 (1) 128.0 (11)

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