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Acta Crystallographica Section E: Crystallographic Communications logoLink to Acta Crystallographica Section E: Crystallographic Communications
. 2021 Jan 1;77(Pt 1):28–33. doi: 10.1107/S2056989020015960

Crystal structure, Hirshfeld surface analysis, DFT and mol­ecular docking investigation of 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl 2-[2-(2-oxo-1,3-oxazolidin-3-yl)eth­oxy]quinoline-4-carboxyl­ate

Younos Bouzian a, Cemile Baydere b,*, Necmi Dege b, Noureddine Hamou Ahabchane a, Joel T Mague c, Abdulmalik Abudunia d,*, Khalid Karrouchi e, El Mokhtar Essassi a
PMCID: PMC7784058  PMID: 33520278

In the crystal of the title compound, corrugated layers of mol­ecules extending along the ab plane are generated by C—H⋯O hydrogen bonds.

Keywords: crystal structure, Covid-19, DFT, Hirshfeld surface analysis, oxazolidine, quinoline, Mol­ecular docking

Abstract

In the mol­ecular structure of the title compound, C20H21N3O7, the quinoline ring system is slightly bent, with a dihedral angle between the phenyl and the pyridine rings of 3.47 (7)°. In the crystal, corrugated layers of mol­ecules extending along the ab plane are generated by C—H⋯O hydrogen bonds. The inter­molecular inter­actions were qu­anti­fied by Hirshfeld surface analysis and two-dimensional fingerprint plots. The most significant contributions to the crystal packing are from H⋯H (42.3%), H⋯O/O⋯H (34.5%) and H⋯C/ C⋯H (17.6%) contacts. Mol­ecular orbital calculations providing electron-density plots of the HOMO and LUMO as well as mol­ecular electrostatic potentials (MEP) were computed, both with the DFT/B3LYP/6–311 G++(d,p) basis set. A mol­ecular docking study between the title mol­ecule and the COVID-19 main protease (PDB ID: 6LU7) was performed, showing that it is a good agent because of its affinity and ability to adhere to the active sites of the protein.

Chemical context  

Quinoline and its derivatives have attracted the inter­est of synthetic and biological chemists because of their inter­esting chemical and pharmacological properties (Chu et al., 2019 ▸), including anti­bacterial (Bouzian et al., 2020 ▸), anti­cancer (Tang et al., 2018 ▸), anti­tubercular (Xu et al., 2017 ▸), anti-COVID19 (Gao et al., 2020 ▸), anti­malarial (Hu et al., 2017 ▸), anti­leishmanial (Palit et al., 2009 ▸) and anti-inflammatory (Pinz et al., 2016 ▸) activities. Furthermore, many studies have shown that quinoline derivatives are good corrosion inhibitors (Douche et al. 2020 ▸).graphic file with name e-77-00028-scheme1.jpg

In a continuation of our research work devoted to the syntheses and crystal structures of quinoline derivatives (Bouzian et al., 2019a ▸), we report herein the mol­ecular and crystal structures, Hirshfeld surface analysis, DFT and mol­ecular docking investigation of 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl 2-[2-(2-oxo-1,3-oxazolidin-3-yl)eth­oxy]quinoline-4-carboxyl­ate.

Structural commentary  

In the title mol­ecule (Fig. 1 ▸), the phenyl and pyridine rings of the quinoline system are slightly bent, with a dihedral angle between their mean planes of 3.47 (7)°. The oxazolidine ring (N2/O2/C12–C14) adopts an envelope conformation, with puckering parameters of Q(2) = 0.112 (2) Å and φ(2) = 115.3 (10)°. The C14 atom is at the envelope flap position, and it deviates from the least-square plane through the remaining four atoms by 0.070 (2) Å. The other oxazolidine ring (N3/O7/C18–C20) has a twisted conformation along the C20—C19 bond, with puckering parameters Q(2) = 0.1732 (18) Å and φ(2) = 299.7 (6)°. The dihedral angles between the mean planes of the oxazolidine rings and the quinoline ring systems are 38.04 (9)° for (N2/O2/C12–C14) and 57.34 (8)° for (N3/O7/C18–C20). The mol­ecular conformation is stabilized by an intra­molecular C20—H20B⋯O4 contact (Fig. 1 ▸, Table 1 ▸), producing an S(8) ring motif.

Figure 1.

Figure 1

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The mol­ecular structure of the title compound, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The intra­molecular hydrogen bond is indicated by a dashed line.

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A D—H H⋯A D⋯A D—H⋯A
C2—H2⋯O4 0.969 (19) 2.335 (18) 2.919 (2) 118.1 (13)
C20—H20B⋯O4 0.98 (2) 2.52 (2) 3.275 (2) 133.7 (15)
C11—H11A⋯O3i 1.026 (19) 2.486 (19) 3.262 (2) 131.8 (13)
C17—H17A⋯O6ii 0.98 (2) 2.53 (2) 3.219 (2) 127.0 (15)
C19—H19B⋯O3iii 0.90 (3) 2.51 (3) 3.157 (2) 129 (2)
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Symmetry codes: (i) Inline graphic; (ii) Inline graphic; (iii) Inline graphic.

Supra­molecular features  

In the crystal, C11—H11A⋯O3i and C17—H17A⋯O6ii hydrogen bonds between methyl­ene groups and carbonyl O atoms as well as C19—H19B⋯O3iii hydrogen bonds lead to the formation of corrugated layers extending parallel to (001) (Fig. 2 ▸, Table 1 ▸). Notable C—H⋯π and π–π inter­actions are not observed.

Figure 2.

Figure 2

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The crystal packing of the title compound, with C11—H11A⋯O3i, C17—H17A⋯O6ii and C19—H19B⋯O3iii inter­actions shown as black, blue and green dashed lines, respectively.

Database survey  

A search of the Cambridge Structural Database (CSD, version 5.40, update of August 2019; Groom et al., 2016 ▸) using ethyl quinoline-4-carboxyl­ate as the main skeleton revealed the presence of ten structures with different substituents on the quinoline ring. The three structures most similar to the title compound are ethyl 2-(2,4,5-tri­meth­oxy­phen­yl)quinoline-4-carboxyl­ate (OJAGUD; Shrungesh Kumar et al., 2015 ▸), ethyl 2-(3,5-di­fluoro­phen­yl)quinoline-4-carboxyl­ate (UHUHAI; Sunitha et al., 2015 ▸) and ethyl 6-chloro-2-eth­oxy­quinoline-4-carboxyl­ate (XOFGAD; Bouzian et al., 2019b ▸). In OJAGUD, the dihedral angle between the quinoline ring system (r.m.s. deviation = 0.028 Å) and the tri­meth­oxy­benzene ring is 43.38 (5)°. A short intra­molecular C—H⋯O contact closes an S(6) ring. In the crystal structure, inversion dimers linked by pairs of weak C—H⋯O inter­actions generate R 2 2(6) loops. In UHUHAI, the two rings of the quinoline system have a dihedral angle of 2.28 (8)° between their mean planes. The plane of the attached benzene ring is inclined to the plane of the quinoline system by 7.65 (7)°. There is a short intra­molecular C—H⋯O contact involving the carbonyl group. In XOFGAD, the mol­ecule is essentially planar with the mean plane of the ethyl acetate group making a dihedral angle of 5.02 (3)° with the ethyl 6-chloro-2-eth­oxy­quinoline mean plane. There is an intra­molecular C— H⋯O hydrogen bond forming an S(6) graph-set motif. Weak inter­molecular π–π inter­actions are observed in this crystal structure.

Hirshfeld surface analysis  

Hirshfeld surface analysis was used to qu­antify the inter­molecular contacts of the title compound, using Crystal Explorer (Turner et al., 2017 ▸). The Hirshfeld surface was generated with a standard (high) surface resolution and with the three-dimensional d norm surface plotted over a fixed colour scale of −0.1538 (red) to 1.1337 (blue) a.u. (Fig. 3 ▸ a). The pale-red spots symbolize short contacts and negative d norm values on the surface and correspond to the C—H⋯O inter­actions (Table 1 ▸). The shape-index map of the title mol­ecule was generated in the range −1 to 1 Å (Fig. 3 ▸ b). The convex blue regions symbolize hydrogen-donor groups and the concave red regions hydrogen-acceptor groups. The absence of adjacent red and blue triangles in the shape-index map, which generally indicate π–π inter­actions, reveals that this kind of inter­action is not present in the title compound. The curvedness map was generated in the range −4.0 to 4.0 Å (Fig. 3 ▸ c). It shows large regions of green with a relatively flat (i.e. planar) surface area while the blue regions demonstrate areas of curvature. The overall two-dimensional fingerprint plot is illustrated in Fig. 4 ▸ a, with those delineated into H⋯H, H⋯O/O⋯H, H⋯C/ C⋯H, H⋯N/N⋯H and C⋯N/N⋯C contacts associated with their relative contributions to the Hirshfeld surface given in Fig. 4 ▸ a–f, respectively. The most important inter­molecular inter­actions are H⋯H, contributing 42.3% to the overall crystal packing. H⋯O/O⋯H contacts arising from inter­molecular C—H⋯O hydrogen bonding (Table 1 ▸) make a 34.5% contribution to the Hirshfeld surface and are represented by a pair of sharp spikes in the region d e + d i ∼2.35 Å (Fig. 4 ▸ c). The pair of wings in the fingerprint plot delineated into H⋯C/ C⋯H contacts (17.6% contribution to the Hirshfeld surface) have a nearly symmetrical distribution of points, with the tips at d e + d i ∼2.54 Å. The contributions of the other contacts to the Hirshfeld surface are negligible, i.e. H⋯N/N⋯H of 2.0% and C⋯N/N⋯C of 1.2%.

Figure 3.

Figure 3

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(a) d norm mapped on the Hirshfeld surface to visualize the inter­molecular inter­actions, (b) shape-index map of the title compound and (c) curvedness map of the title compound using a range from −4 to 4 Å.

Figure 4.

Figure 4

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The full two-dimensional fingerprint plots for the title compound, showing (a) all inter­actions, and delineated into (b) H⋯H, (c) H⋯O/O⋯H, (d) H⋯C/ C⋯H, (e) H⋯N/N⋯H and (f) C⋯N/N⋯C inter­actions.

Frontier mol­ecular orbital analyses  

The energy levels for the title compound were computed on basis of density functional theory (DFT) using the standard B3LYP functional and 6–311G++ (d,p) basis-set calculations (Becke, 1993 ▸) as implemented in GAUSSIAN 09 (Frisch et al., 2009 ▸). The HOMO (highest occupied mol­ecular orbital) acts as an electron donor and the LUMO (lowest occupied mol­ecular orbital) as an electron acceptor. The energy levels, energy gaps, the ionization potential (IP), electron affinity (EA), the chemical potential (μ), the electronegativity (χ), chemical hardness (η), chemical softness (σ), and the electrophilicity index (ω) are given in Table 2 ▸. The electron transition from the HOMO to the LUMO energy level is shown in Fig. 5 ▸. If a mol­ecule has a large HOMO–LUMO energy gap, it can be considered as hard with a low polarizability and a low chemical reactivity. Based on the numerical values collated in Table 2 ▸, the title compound can be classified as a hard material with a HOMO–LUMO energy gap of 4.2907 eV.

Table 2. Calculated frontier mol­ecular orbital energies (eV).

FMO Energy
E(HOMO) −6.2102
E(LUMO) −1.9195
Energy gap (ΔE) 4.2907
Ionization potential (IP) 6.2102
Electron affinity (EA) 1.9195
Chemical potential (μ) –4.0649
Electronegativity (χ) 4.0649
Chemical hardness (η) 2.1454
Chemical softness (σ) 0.2331
Electrophilicity index (ω) 3.8509
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Figure 5.

Figure 5

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Mol­ecular orbital energy levels of the title compound.

Mol­ecular electrostatic potentials  

The mol­ecular electrostatic potential (MEP) map (Fig. 6 ▸) was calculated at the B3LYP/6-311G++ (d,p) level of theory. In the MEP diagram, the mol­ecular electrostatic potential is in the range −7.122 e−2 to 7.122 e−2, and the different electrostatic potentials at the surface of the mol­ecule are represented by different colours. Electrostatic potentials increase in the order of red < yellow < green < blue, and red indicates the electron-rich region and blue indicates the electron-deficient region. As shown in Fig. 6 ▸, the carbonyl groups are surrounded by negative charges, indicating some possible nucleophilic attack sites. In addition, the positive charge regions are located on the H atoms.

Figure 6.

Figure 6

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Theoretical mol­ecular electrostatic potential surface calculated at the DFT/B3LYP/6–311 G++ (d,p) basis set level.

Mol­ecular docking study  

A mol­ecular docking study was performed to determine possible inter­molecular inter­actions between the COVID-19 main protease (PDB ID: 6LU7) and the title mol­ecule. The crystal structure of COVID-19 main protease in a complex with an inhibitor N3 was taken from the RSCB Protein Data Bank (PDB ID: 6LU7; Jin et al., 2020 ▸). The mol­ecular docking study was carried out using PyRx AutoDock Vina Wizard. The inter­molecular inter­actions between the title compound and the target protein were visualized by using the Discovery Studio 2020 Client program (Biovia, 2017 ▸). The active sites of this target protein are residues LYS102, VAL104, GLN110, THR111, ASN151, ASP153 and SER158. Grid box sizes were determined as 25 × 25 × 25 Å3 and x, y, z centers: −10.865636, 12.146782, and 68.902236. The binding affinity energy values and their r.m.s.d. (root-mean-square deviation) values for nine different poses of the ligand docked onto receptor 6LU7 are listed in Table 3 ▸. According to the affinity binding energies, the best binding was determined with −6.3 (kcal mol−1) energy and nine active hydrogen-bonding sites. The 2D and 3D visuals of the inter­molecular inter­actions for the best binding pose of the title compound docked into macromolecule 6LU7 can be seen in Fig. 7 ▸. Table 4 ▸ lists details of inter­molecular hydrogen-bonding inter­actions between the title mol­ecule and the macromolecule 6LU7. Additionally in Fig. 7 ▸, π–σ and alkyl inter­actions and their bonding distances are shown. The title mol­ecule appears to be a good agent because of its affinity and ability to adhere to the active sites of the protein.

Table 3. The list of binding affinities and r.m.s.d. values of different sites in protein (6LU7) of the title compound.

Ligand Affinity (kcal mol−1) r.m.s.d./ub r.m.s.d./Ib
6LU7_ligand −6.3 0.0 0.0
6LU7_ligand −6.1 4.8 2.164
6LU7_ligand −5.8 20.521 17.722
6LU7_ligand −5.7 20.874 18.477
6LU7_ligand −5.7 20.28 17.737
6LU7_ligand −5.6 21.789 19.301
6LU7_ligand −5.6 20.948 18.265
6LU7_ligand −5.5 21.63 19.349
6LU7_ligand −5.4 21.972 19.381
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Figure 7.

Figure 7

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Three- and two-dimensional visuals of the inter­molecular inter­actions for the best binding pose of the title compound docking with the residues of macromolecule 6LU7.

Table 4. The inter­molecular hydrogen-bonding inter­actions with the distances (Å) between the title mol­ecule and the macromolecule 6LU7.

Residue group Ligand group Distance Hydrogen bond
NH3 group in LYS102 O atom in ethyl acetate 2.55 Conventional
NH2 group in GLN110 O atom in oxazolidine 2.55 Conventional
NH group in THR111 O atom in oxazolidine 1.92 Conventional
OH group in THR111 O atom in oxazolidine 2.28 Conventional
O atom in THR111 CH2 group in 1-meth­oxy­propane 3.55 Carbon
NH2 group in ASN151 O atom in 1-meth­oxy­propane 2.71 Conventional
O atom in ASP153 CH2 group in ethyl acetate 2.79 Carbon
OH group in SER158 O atom in ethyl acetate 2.12 Conventional
OH group in SER158 O atom in oxazolidine 2.60 Conventional
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Synthesis and crystallization  

A solution of 0.8 g (4.23 mmol) of 2-oxo-1,2-di­hydro­quinoline-4-carb­oxy­lic acid in 30 ml of DMF was mixed with 1.5 g (8.46 mmol) bis­(2-chloro­eth­yl)amine hydro­chloride, 2.33 g (16,92 mmol) K2CO3 and 0.13 g (0.423 mmol) tetra-n-butyl­ammonium bromide (TBAB). The reaction mixture was stirred at 363 K for 9 h in DMF. After removal of formed salts by filtration, DMF was evaporated under reduced pressure, and the residue obtained was dissolved in di­chloro­methane. The organic phase was dried over Na2SO4 and then concentrated in vacuo. The resulting mixture was chromatographed on a silica gel column [eluent: ethyl acetate/hexane (2/8 v/v)]. Colourless single crystals of the title compound were obtained by slow evaporation of an ethanol solution.

Refinement  

Crystal data, data collection and structure refinement details are summarized in Table 5 ▸. Hydrogen atoms were discernible from difference Fourier maps and were refined freely.

Table 5. Experimental details.

Crystal data
Chemical formula C20H21N3O7
M r 415.40
Crystal system, space group Monoclinic, P21/c
Temperature (K) 150
a, b, c (Å) 6.0686 (5), 19.2791 (15), 16.3795 (13)
β (°) 94.185 (4)
V (Å3) 1911.2 (3)
Z 4
Radiation type Cu Kα
μ (mm−1) 0.93
Crystal size (mm) 0.23 × 0.08 × 0.05
 
Data collection
Diffractometer Bruker D8 VENTURE PHOTON 100 CMOS
Absorption correction Multi-scan (SADABS; Krause et al., 2015 ▸)
No. of measured, independent and observed [I > 2σ(I)] reflections 14512, 3711, 3072
R int 0.042
(sin θ/λ)max (Å−1) 0.618
 
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S 0.038, 0.094, 1.05
No. of reflections 3711
No. of parameters 356
H-atom treatment All H-atom parameters refined
Δρmax, Δρmin (e Å−3) 0.22, −0.19
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Computer programs: APEX3 and SAINT (Bruker, 2016 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2018/1 (Sheldrick, 2015b ▸), Mercury (Macrae et al., 2020 ▸), PLATON (Spek, 2020 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989020015960/wm5588sup1.cif

e-77-00028-sup1.cif (448.1KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989020015960/wm5588Isup2.hkl

e-77-00028-Isup2.hkl (296.1KB, hkl)
Click here for additional data file. (8KB, cml)

Supporting information file. DOI: 10.1107/S2056989020015960/wm5588Isup3.cml

CCDC reference: 2048734

Additional supporting information: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Crystal data

C20H21N3O7 F(000) = 872
Mr = 415.40 Dx = 1.444 Mg m−3
Monoclinic, P21/c Cu Kα radiation, λ = 1.54178 Å
a = 6.0686 (5) Å Cell parameters from 9277 reflections
b = 19.2791 (15) Å θ = 3.6–72.3°
c = 16.3795 (13) Å µ = 0.93 mm−1
β = 94.185 (4)° T = 150 K
V = 1911.2 (3) Å3 Column, colourless
Z = 4 0.23 × 0.08 × 0.05 mm
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Data collection

Bruker D8 VENTURE PHOTON 100 CMOS diffractometer 3711 independent reflections
Radiation source: INCOATEC IµS micro–focus source 3072 reflections with I > 2σ(I)
Detector resolution: 10.4167 pixels mm-1 Rint = 0.042
ω scans θmax = 72.3°, θmin = 3.6°
Absorption correction: multi-scan (SADABS; Krause et al., 2015) h = −7→6
k = −21→23
14512 measured reflections l = −20→18
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Refinement

Refinement on F2 Hydrogen site location: difference Fourier map
Least-squares matrix: full All H-atom parameters refined
R[F2 > 2σ(F2)] = 0.038 w = 1/[σ2(Fo2) + (0.0346P)2 + 0.6581P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.094 (Δ/σ)max < 0.001
S = 1.05 Δρmax = 0.22 e Å−3
3711 reflections Δρmin = −0.19 e Å−3
356 parameters Extinction correction: SHELXL-2018/3 (Sheldrick 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
0 restraints Extinction coefficient: 0.0026 (2)
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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.
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Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq
O1 0.37759 (18) 0.21379 (5) 0.57549 (6) 0.0312 (3)
O2 0.7629 (2) 0.08767 (7) 0.44369 (8) 0.0493 (3)
O3 0.7633 (2) 0.07204 (8) 0.57987 (8) 0.0506 (3)
O4 1.1362 (2) 0.34395 (7) 0.75827 (7) 0.0530 (4)
O5 1.07647 (17) 0.32859 (5) 0.62287 (6) 0.0297 (2)
O6 0.68920 (19) 0.45136 (7) 0.59441 (7) 0.0426 (3)
O7 0.76696 (19) 0.50976 (7) 0.71190 (7) 0.0410 (3)
N1 0.4550 (2) 0.18848 (6) 0.71212 (8) 0.0307 (3)
N2 0.4425 (2) 0.08645 (7) 0.49889 (8) 0.0292 (3)
N3 1.0450 (2) 0.48184 (6) 0.63804 (8) 0.0284 (3)
C1 0.7992 (3) 0.23409 (7) 0.78094 (9) 0.0275 (3)
C2 0.9438 (3) 0.23392 (9) 0.85269 (10) 0.0355 (4)
C3 0.8913 (3) 0.19732 (9) 0.92045 (10) 0.0410 (4)
C4 0.6930 (3) 0.16004 (9) 0.92016 (10) 0.0409 (4)
C5 0.5501 (3) 0.15931 (9) 0.85188 (10) 0.0367 (4)
C6 0.6007 (3) 0.19519 (8) 0.78029 (9) 0.0295 (3)
C7 0.5068 (2) 0.21938 (7) 0.64584 (9) 0.0273 (3)
C8 0.6967 (3) 0.26216 (7) 0.63962 (9) 0.0270 (3)
C9 0.8405 (3) 0.27009 (7) 0.70638 (9) 0.0263 (3)
C10 0.2011 (3) 0.16344 (8) 0.57237 (10) 0.0316 (3)
C11 0.2925 (3) 0.09066 (8) 0.56362 (10) 0.0296 (3)
C12 0.6613 (3) 0.08141 (8) 0.51449 (10) 0.0343 (4)
C13 0.5965 (4) 0.09582 (12) 0.37669 (12) 0.0521 (5)
C14 0.3811 (4) 0.10463 (13) 0.41522 (11) 0.0503 (5)
C15 1.0341 (3) 0.31748 (8) 0.70093 (9) 0.0296 (3)
C16 1.2533 (3) 0.37628 (8) 0.60659 (10) 0.0307 (3)
C17 1.1579 (3) 0.44476 (8) 0.57658 (10) 0.0305 (3)
C18 0.8247 (2) 0.47778 (8) 0.64262 (9) 0.0293 (3)
C19 0.9624 (4) 0.54073 (12) 0.75294 (14) 0.0536 (5)
C20 1.1552 (3) 0.50923 (9) 0.71305 (11) 0.0368 (4)
H2 1.087 (3) 0.2562 (10) 0.8534 (10) 0.035 (5)*
H3 0.995 (4) 0.1973 (11) 0.9668 (13) 0.051 (6)*
H4 0.662 (3) 0.1323 (10) 0.9671 (12) 0.044 (5)*
H5 0.409 (3) 0.1320 (10) 0.8502 (12) 0.047 (5)*
H8 0.718 (3) 0.2863 (9) 0.5880 (11) 0.031 (4)*
H10A 0.104 (3) 0.1775 (9) 0.5222 (11) 0.033 (4)*
H10B 0.116 (3) 0.1663 (9) 0.6224 (11) 0.034 (4)*
H11A 0.158 (3) 0.0587 (9) 0.5522 (11) 0.037 (5)*
H11B 0.378 (3) 0.0759 (9) 0.6148 (11) 0.034 (5)*
H13A 0.593 (5) 0.0502 (15) 0.3426 (16) 0.084 (8)*
H13B 0.637 (5) 0.1344 (15) 0.3451 (17) 0.087 (9)*
H14A 0.267 (5) 0.0739 (14) 0.3906 (16) 0.075 (8)*
H14B 0.331 (5) 0.1581 (17) 0.4123 (17) 0.099 (10)*
H16A 1.355 (3) 0.3820 (9) 0.6562 (11) 0.031 (4)*
H16B 1.332 (3) 0.3535 (9) 0.5624 (11) 0.035 (5)*
H17A 1.281 (3) 0.4738 (10) 0.5615 (12) 0.044 (5)*
H17B 1.047 (3) 0.4375 (9) 0.5297 (11) 0.029 (4)*
H19A 0.942 (5) 0.5932 (16) 0.7433 (17) 0.092 (9)*
H19B 0.962 (4) 0.5331 (13) 0.8072 (17) 0.073 (8)*
H20A 1.268 (4) 0.5440 (13) 0.6998 (15) 0.068 (7)*
H20B 1.224 (3) 0.4711 (11) 0.7450 (12) 0.048 (5)*
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Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
O1 0.0313 (6) 0.0295 (5) 0.0318 (6) −0.0034 (4) −0.0036 (4) 0.0011 (4)
O2 0.0420 (7) 0.0586 (8) 0.0491 (7) −0.0029 (6) 0.0164 (6) −0.0012 (6)
O3 0.0275 (6) 0.0764 (10) 0.0462 (7) 0.0044 (6) −0.0090 (5) −0.0006 (7)
O4 0.0718 (9) 0.0576 (8) 0.0280 (6) −0.0357 (7) −0.0071 (6) 0.0048 (6)
O5 0.0317 (6) 0.0320 (5) 0.0259 (5) −0.0065 (4) 0.0062 (4) 0.0000 (4)
O6 0.0255 (6) 0.0581 (8) 0.0438 (7) −0.0046 (5) −0.0020 (5) −0.0064 (6)
O7 0.0361 (7) 0.0504 (7) 0.0372 (6) 0.0060 (5) 0.0066 (5) −0.0059 (5)
N1 0.0342 (7) 0.0287 (6) 0.0296 (7) −0.0023 (5) 0.0055 (5) −0.0018 (5)
N2 0.0276 (7) 0.0309 (7) 0.0284 (6) 0.0029 (5) −0.0026 (5) 0.0007 (5)
N3 0.0232 (6) 0.0301 (6) 0.0316 (7) −0.0013 (5) −0.0009 (5) −0.0002 (5)
C1 0.0368 (8) 0.0227 (7) 0.0233 (7) −0.0003 (6) 0.0048 (6) −0.0011 (5)
C2 0.0455 (10) 0.0336 (8) 0.0269 (8) −0.0060 (7) 0.0000 (7) 0.0012 (6)
C3 0.0607 (12) 0.0382 (9) 0.0234 (8) −0.0038 (8) −0.0020 (7) 0.0022 (7)
C4 0.0638 (12) 0.0347 (8) 0.0252 (8) −0.0061 (8) 0.0103 (8) 0.0022 (7)
C5 0.0480 (10) 0.0327 (8) 0.0307 (8) −0.0067 (7) 0.0118 (7) −0.0007 (6)
C6 0.0370 (9) 0.0257 (7) 0.0266 (7) 0.0001 (6) 0.0071 (6) −0.0018 (6)
C7 0.0288 (8) 0.0244 (7) 0.0284 (7) 0.0020 (6) 0.0005 (6) −0.0017 (6)
C8 0.0315 (8) 0.0245 (7) 0.0251 (7) 0.0019 (6) 0.0035 (6) 0.0012 (6)
C9 0.0326 (8) 0.0218 (7) 0.0250 (7) −0.0002 (6) 0.0047 (6) −0.0004 (5)
C10 0.0252 (8) 0.0298 (8) 0.0389 (9) −0.0008 (6) −0.0021 (7) −0.0017 (7)
C11 0.0261 (8) 0.0292 (8) 0.0331 (8) −0.0003 (6) −0.0001 (6) 0.0016 (6)
C12 0.0285 (8) 0.0347 (8) 0.0399 (9) −0.0005 (6) 0.0029 (7) −0.0017 (7)
C13 0.0700 (14) 0.0514 (12) 0.0361 (10) −0.0016 (10) 0.0106 (9) 0.0036 (9)
C14 0.0582 (13) 0.0632 (13) 0.0283 (9) 0.0099 (10) −0.0041 (8) 0.0066 (8)
C15 0.0362 (9) 0.0264 (7) 0.0262 (7) −0.0026 (6) 0.0029 (6) 0.0010 (6)
C16 0.0258 (8) 0.0319 (8) 0.0351 (8) −0.0035 (6) 0.0071 (6) 0.0039 (6)
C17 0.0263 (8) 0.0339 (8) 0.0321 (8) −0.0012 (6) 0.0062 (6) 0.0055 (6)
C18 0.0249 (8) 0.0328 (8) 0.0303 (8) 0.0008 (6) 0.0026 (6) 0.0033 (6)
C19 0.0502 (12) 0.0574 (13) 0.0509 (12) 0.0130 (10) −0.0111 (9) −0.0218 (10)
C20 0.0340 (9) 0.0346 (9) 0.0406 (9) −0.0054 (7) −0.0059 (7) −0.0023 (7)
Open in a new tab

Geometric parameters (Å, º)

O1—C7 1.3499 (18) C4—H4 0.97 (2)
O1—C10 1.4437 (19) C5—C6 1.414 (2)
O2—C12 1.358 (2) C5—H5 1.00 (2)
O2—C13 1.445 (3) C7—C8 1.427 (2)
O3—C12 1.211 (2) C8—C9 1.357 (2)
O4—C15 1.2006 (19) C8—H8 0.982 (18)
O5—C15 1.3396 (18) C9—C15 1.496 (2)
O5—C16 1.4526 (18) C10—C11 1.519 (2)
O6—C18 1.2100 (19) C10—H10A 1.013 (18)
O7—C18 1.3596 (19) C10—H10B 1.001 (19)
O7—C19 1.449 (2) C11—H11A 1.026 (19)
N1—C7 1.2969 (19) C11—H11B 0.994 (19)
N1—C6 1.379 (2) C13—C14 1.502 (3)
N2—C12 1.338 (2) C13—H13A 1.04 (3)
N2—C14 1.437 (2) C13—H13B 0.95 (3)
N2—C11 1.449 (2) C14—H14A 0.98 (3)
N3—C18 1.347 (2) C14—H14B 1.08 (3)
N3—C17 1.447 (2) C16—C17 1.509 (2)
N3—C20 1.455 (2) C16—H16A 0.992 (18)
C1—C2 1.415 (2) C16—H16B 0.997 (18)
C1—C6 1.418 (2) C17—H17A 0.98 (2)
C1—C9 1.443 (2) C17—H17B 0.992 (18)
C2—C3 1.372 (2) C19—C20 1.509 (3)
C2—H2 0.969 (19) C19—H19A 1.03 (3)
C3—C4 1.401 (3) C19—H19B 0.90 (3)
C3—H3 0.95 (2) C20—H20A 0.99 (3)
C4—C5 1.364 (3) C20—H20B 0.98 (2)
C7—O1—C10 117.84 (12) C10—C11—H11B 110.9 (11)
C12—O2—C13 108.82 (14) H11A—C11—H11B 109.8 (15)
C15—O5—C16 118.18 (12) O3—C12—N2 128.04 (16)
C18—O7—C19 108.80 (13) O3—C12—O2 122.28 (15)
C7—N1—C6 117.04 (13) N2—C12—O2 109.68 (14)
C12—N2—C14 112.61 (15) O2—C13—C14 105.94 (15)
C12—N2—C11 122.16 (13) O2—C13—H13A 107.6 (15)
C14—N2—C11 123.44 (14) C14—C13—H13A 109.5 (16)
C18—N3—C17 122.17 (13) O2—C13—H13B 107.9 (17)
C18—N3—C20 111.80 (13) C14—C13—H13B 114.0 (18)
C17—N3—C20 123.69 (13) H13A—C13—H13B 112 (2)
C2—C1—C6 118.71 (14) N2—C14—C13 101.55 (16)
C2—C1—C9 124.65 (14) N2—C14—H14A 111.9 (15)
C6—C1—C9 116.63 (14) C13—C14—H14A 111.7 (16)
C3—C2—C1 120.43 (16) N2—C14—H14B 109.2 (15)
C3—C2—H2 118.6 (11) C13—C14—H14B 110.1 (16)
C1—C2—H2 120.8 (10) H14A—C14—H14B 112 (2)
C2—C3—C4 120.73 (17) O4—C15—O5 123.69 (14)
C2—C3—H3 117.8 (13) O4—C15—C9 125.14 (14)
C4—C3—H3 121.5 (13) O5—C15—C9 111.15 (13)
C5—C4—C3 120.16 (15) O5—C16—C17 110.03 (13)
C5—C4—H4 119.7 (12) O5—C16—H16A 110.2 (10)
C3—C4—H4 120.0 (12) C17—C16—H16A 111.8 (10)
C4—C5—C6 120.75 (16) O5—C16—H16B 104.6 (11)
C4—C5—H5 121.2 (11) C17—C16—H16B 110.0 (10)
C6—C5—H5 118.0 (11) H16A—C16—H16B 109.9 (15)
N1—C6—C5 117.43 (15) N3—C17—C16 113.29 (13)
N1—C6—C1 123.35 (13) N3—C17—H17A 107.6 (12)
C5—C6—C1 119.20 (15) C16—C17—H17A 107.4 (12)
N1—C7—O1 121.12 (14) N3—C17—H17B 106.3 (10)
N1—C7—C8 124.86 (14) C16—C17—H17B 110.5 (10)
O1—C7—C8 114.01 (13) H17A—C17—H17B 111.9 (15)
C9—C8—C7 118.89 (14) O6—C18—N3 128.17 (15)
C9—C8—H8 121.5 (10) O6—C18—O7 122.10 (14)
C7—C8—H8 119.6 (10) N3—C18—O7 109.72 (13)
C8—C9—C1 119.10 (14) O7—C19—C20 105.53 (14)
C8—C9—C15 118.85 (13) O7—C19—H19A 104.5 (16)
C1—C9—C15 122.03 (13) C20—C19—H19A 114.5 (17)
O1—C10—C11 110.45 (12) O7—C19—H19B 109.2 (17)
O1—C10—H10A 103.6 (10) C20—C19—H19B 114.8 (17)
C11—C10—H10A 111.5 (10) H19A—C19—H19B 108 (2)
O1—C10—H10B 111.0 (10) N3—C20—C19 100.86 (14)
C11—C10—H10B 110.0 (10) N3—C20—H20A 110.0 (14)
H10A—C10—H10B 110.3 (14) C19—C20—H20A 113.2 (14)
N2—C11—C10 111.95 (13) N3—C20—H20B 109.4 (12)
N2—C11—H11A 111.4 (10) C19—C20—H20B 112.7 (12)
C10—C11—H11A 106.3 (10) H20A—C20—H20B 110.3 (18)
N2—C11—H11B 106.5 (11)
C6—C1—C2—C3 −0.7 (2) C11—N2—C12—O3 8.8 (3)
C9—C1—C2—C3 −179.17 (16) C14—N2—C12—O2 −6.6 (2)
C1—C2—C3—C4 −0.6 (3) C11—N2—C12—O2 −171.89 (13)
C2—C3—C4—C5 0.5 (3) C13—O2—C12—O3 177.93 (17)
C3—C4—C5—C6 0.8 (3) C13—O2—C12—N2 −1.40 (19)
C7—N1—C6—C5 −177.44 (14) C12—O2—C13—C14 8.3 (2)
C7—N1—C6—C1 0.5 (2) C12—N2—C14—C13 11.2 (2)
C4—C5—C6—N1 175.98 (15) C11—N2—C14—C13 176.20 (15)
C4—C5—C6—C1 −2.1 (2) O2—C13—C14—N2 −11.2 (2)
C2—C1—C6—N1 −175.98 (14) C16—O5—C15—O4 −1.1 (2)
C9—C1—C6—N1 2.7 (2) C16—O5—C15—C9 177.08 (12)
C2—C1—C6—C5 2.0 (2) C8—C9—C15—O4 158.27 (17)
C9—C1—C6—C5 −179.41 (13) C1—C9—C15—O4 −20.1 (2)
C6—N1—C7—O1 177.84 (13) C8—C9—C15—O5 −19.91 (19)
C6—N1—C7—C8 −3.2 (2) C1—C9—C15—O5 161.75 (13)
C10—O1—C7—N1 −10.2 (2) C15—O5—C16—C17 −103.49 (15)
C10—O1—C7—C8 170.70 (13) C18—N3—C17—C16 −95.85 (17)
N1—C7—C8—C9 2.4 (2) C20—N3—C17—C16 65.35 (19)
O1—C7—C8—C9 −178.56 (13) O5—C16—C17—N3 66.50 (17)
C7—C8—C9—C1 1.1 (2) C17—N3—C18—O6 −9.0 (3)
C7—C8—C9—C15 −177.26 (13) C20—N3—C18—O6 −172.23 (16)
C2—C1—C9—C8 175.18 (15) C17—N3—C18—O7 171.83 (13)
C6—C1—C9—C8 −3.4 (2) C20—N3—C18—O7 8.61 (18)
C2—C1—C9—C15 −6.5 (2) C19—O7—C18—O6 −175.41 (17)
C6—C1—C9—C15 174.97 (13) C19—O7—C18—N3 3.81 (19)
C7—O1—C10—C11 −75.87 (16) C18—O7—C19—C20 −13.9 (2)
C12—N2—C11—C10 105.84 (17) C18—N3—C20—C19 −16.32 (19)
C14—N2—C11—C10 −57.8 (2) C17—N3—C20—C19 −179.25 (16)
O1—C10—C11—N2 −48.92 (18) O7—C19—C20—N3 17.5 (2)
C14—N2—C12—O3 174.08 (19)
Open in a new tab

Hydrogen-bond geometry (Å, º)

D—H···A D—H H···A D···A D—H···A
C2—H2···O4 0.969 (19) 2.335 (18) 2.919 (2) 118.1 (13)
C20—H20B···O4 0.98 (2) 2.52 (2) 3.275 (2) 133.7 (15)
C11—H11A···O3i 1.026 (19) 2.486 (19) 3.262 (2) 131.8 (13)
C17—H17A···O6ii 0.98 (2) 2.53 (2) 3.219 (2) 127.0 (15)
C19—H19B···O3iii 0.90 (3) 2.51 (3) 3.157 (2) 129 (2)
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Symmetry codes: (i) x−1, y, z; (ii) x+1, y, z; (iii) −x+2, y+1/2, −z+3/2.

Funding Statement

This work was funded by National Science Foundation grant 1228232. Tulane University grant .

References

  1. Becke, A. D. (1993). J. Chem. Phys. 98, 5648–5652.
  2. Biovia (2017). Discovery studio visualizer. Vol. 936. Biovia, San Diego, CA, USA.
  3. Bouzian, Y., Faizi, M. S. H., Mague, J. T., Otmani, B. E., Dege, N., Karrouchi, K. & Essassi, E. M. (2019a). Acta Cryst. E75, 980–983. [DOI] [PMC free article] [PubMed]
  4. Bouzian, Y., Karrouchi, K., Anouar, E. H., Bouhfid, R., Arshad, S. & Essassi, E. M. (2019b). Acta Cryst. E75, 912–916. [DOI] [PMC free article] [PubMed]
  5. Bouzian, Y., Karrouchi, K., Sert, Y., Lai, C.-H., Mahi, L., Ahabchane, N. H., Talbaoui, A., Mague, J. T. & Essassi, E. M. (2020). J. Mol. Struct. 1209, 127940.
  6. Bruker (2016). APEX3 and SAINT. Bruker AXS, Inc., Madison, Wisconsin, USA.
  7. Chu, X. M., Wang, C., Liu, W., Liang, L. L., Gong, K. K., Zhao, C. Y. & Sun, K. L. (2019). Eur. J. Med. Chem. 161, 101–117. [DOI] [PubMed]
  8. Douche, D., Elmsellem, H., Anouar, E. H., Guo, L., Hafez, B., Tüzün, B., El Louzi, A., Bougrin, K., Karrouchi, K. & Himmi, B. (2020). J. Mol. Liq. 308, 113042.
  9. Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., Cheeseman, J. R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G. A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H. P., Izmaylov, A. F., Bloino, J., Zheng, G., Sonnenberg, J. L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A. Jr, Peralta, J. E., Ogliaro, F., Bearpark, M., Heyd, J. J., Brothers, E., Kudin, K. N., Staroverov, V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, J. M., Klene, M., Knox, J. E., Cross, J. B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, O., Foresman, J. B., Ortiz, J. V., Cioslowski, J. & Fox, D. J. (2009). GAUSSIAN09. Rev. A.02. Gaussian Inc., Wallingford, CT, USA.
  10. Gao, J., Tian, Z. & Yang, X. (2020). Biosci. Trends, 14, 72-73. [DOI] [PubMed]
  11. Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. [DOI] [PMC free article] [PubMed]
  12. Hu, Y. Q., Gao, C., Zhang, S., Xu, L., Xu, Z., Feng, L. S., Wu, X. & Zhao, F. (2017). Eur. J. Med. Chem. 139, 22–47. [DOI] [PubMed]
  13. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L. W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z. & Yang, H. (2020). Nature, 582, 289–293. [DOI] [PubMed]
  14. Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. [DOI] [PMC free article] [PubMed]
  15. Macrae, C. F., Sovago, I., Cottrell, S. J., Galek, P. T. A., McCabe, P., Pidcock, E., Platings, M., Shields, G. P., Stevens, J. S., Towler, M. & Wood, P. A. (2020). J. Appl. Cryst. 53, 226–235. [DOI] [PMC free article] [PubMed]
  16. Palit, P., Paira, P., Hazra, A., Banerjee, S., Gupta, A. D., Dastidar, S. G. & Mondal, N. B. (2009). Eur. J. Med. Chem. 44, 845–853. [DOI] [PubMed]
  17. Pinz, M., Reis, A. S., Duarte, V., da Rocha, M. J., Goldani, B. S., Alves, D., Savegnago, L., Luchese, C. & Wilhelm, E. A. (2016). Eur. J. Pharmacol. 780, 122–128. [DOI] [PubMed]
  18. Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8.
  19. Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8.
  20. Shrungesh Kumar, T. O., Naveen, S., Kumara, M. N., Mahadevan, K. M. & Lokanath, N. K. (2015). Acta Cryst. E71, o514–o515. [DOI] [PMC free article] [PubMed]
  21. Spek, A. L. (2020). Acta Cryst. E76, 1–11. [DOI] [PMC free article] [PubMed]
  22. Sunitha, V. M., Naveen, S., Manjunath, H. R., Benaka Prasad, S. B., Manivannan, V. & Lokanath, N. K. (2015). Acta Cryst. E71, o341–o342. [DOI] [PMC free article] [PubMed]
  23. Tang, Q. D., Duan, Y. L., Xiong, H. H., Chen, T., Xiao, Z., Wang, L. X., Xiao, Y. Y., Huang, S. M., Xiong, Y., Zhu, W., Gong, P. & Zheng, P. (2018). Eur. J. Med. Chem. 158, 201–213. [DOI] [PubMed]
  24. Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. University of Western Australia. http://hirshfeldsurface.net.
  25. Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.
  26. Xu, Z., Gao, C., Ren, Q. C., Song, X. F., Feng, L. S. & Lv, Z. S. (2017). Eur. J. Med. Chem. 139, 429–440. [DOI] [PubMed]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) I. DOI: 10.1107/S2056989020015960/wm5588sup1.cif

e-77-00028-sup1.cif (448.1KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989020015960/wm5588Isup2.hkl

e-77-00028-Isup2.hkl (296.1KB, hkl)
Click here for additional data file. (8KB, cml)

Supporting information file. DOI: 10.1107/S2056989020015960/wm5588Isup3.cml

CCDC reference: 2048734

Additional supporting information: crystallographic information; 3D view; checkCIF report

Articles from Acta Crystallographica Section E: Crystallographic Communications are provided here courtesy of International Union of Crystallography

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