research communications
Structural characterization and antimycobacterial evaluation of a benzimidazole analogue of the antituberculosis clinical drug candidate TBA-7371
aMartin-Luther-Universität Halle-Wittenberg, Institut für Pharmazie, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany, and bMax-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
*Correspondence e-mail: ruediger.seidel@pharmazie.uni-halle.de
The in vitro antimycobacterial properties of N-(2-fluoroethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo[d]imidazole-4-carboxamide (C17H18FN5O2, 1), a previously reported benzimidazole analogue of the 1,4-azaindole-based antituberculosis drug candidate TBA-7371, are reported. The was achieved using Hirshfeld atom Compound 1 crystallizes in the triclinic system (space group P) with two molecules in the (Z′ = 2). The two crystallographically distinct molecules exhibit a similar conformation with the amide groups in a Z conformation, forming an intramolecular Namide—H⋯Nbenzimidazole hydrogen bond. The most significant supramolecular feature in the solid-state is a relatively short Cbenzimidazole—H⋯Npyrimidine hydrogen bond. Antimycobacterial testing confirmed in vitro activity against Mycobacterium smegmatis, but no growth inhibtion of Mycobacterium abscessus was found.
andKeywords: benzimidazole; TBA-7371; scaffold morphing; DprE1 inhibitor; tuberculosis; crystal structure.
CCDC reference: 2216847
1. Chemical context
TBA-7371 (Fig. 1) is a 1,4-azaindole-based drug candidate for the treatment of tuberculosis, which has advanced to a Phase 2a clinical study (ClinicalTrials.gov identifier: NCT04176250). The compound is a non-covalent inhibitor of the mycobacterial enzyme decaprenylphosphoryl-β-D-ribose-2′-epimerase (DprE1), which is essential for cell-wall synthesis in Mycobacterium tuberculosis, the causative agent of tuberculosis (Shirude et al., 2013, 2014; Chikhale et al., 2018). As shown in Fig. 1, scaffold morphing, a medicinal chemistry approach to the design of new ligands for the same target with a different core, led to the identification of N-(2-fluoroethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo[d]imidazole-4-carboxamide (1) (Manjunatha et al., 2019). In 1, the 1,4-azaindole core has been replaced by a benzimidazole core, while the 6-methoxy-5-methylpyrimidine-4-yl group and the amide side chain were maintained. Compound 1 exhibits potent DprE1 inhibition and antimycobacterial activity (vide infra).
Late steps in the synthesis of 1, following the previously published route (Manjunatha et al., 2019), are sketched in Fig. 2. Benzimidazole derivative A was reacted with 4-(chloromethyl)-6-methoxy-5-methylpyrimidine to give B. It is worth mentioning that N-alkylation in part occurred at position 3 of the benzimidazole scaffold, affording side product C. Regioisomers B and C were separated by flash resulting in an approximate 3.75:1 ratio. Compound C was identified by 1H and 13C NMR spectroscopy and APCI (see Supporting Information). Hydrolysis of B followed by amide coupling with 2-fluoroethanamine gave the target compound 1. X-ray crystallography unambiguously confirmed the structure.
2. Structural commentary
Compound 1 crystallizes in the triclinic P with two crystallographically distinct molecules (Fig. 3). In both molecules, the tilt of the 6-methoxy-5-methylpyrimidin-4-yl group of the plane out of the central benzimidazole moiety renders the conformers axially chiral. The C2—N1—C11—C12 torsion angle is 101.9 (1)° in molecule 1 and 79.0 (1)° in molecule 2. The enantiomeric conformers in the chosen thus exhibit the same handedness, but the corresponding oppositely handed conformers are present in the centrosymmetric The most marked structural difference between the two unique molecules is the orientation of the 2-fluoroethyl group about the C9—C10 bond with N2—C9—C10—F1 = 68.1 (1)° for molecule 1 and −61.8 (1)° for molecule 2.
The plane of the amide group and the mean plane of the benzimidazole moiety are nearly co-planar in molecules 1 and 2. The angle between the two planes is 8.8 (1)° in molecule 1 and 7.7 (1)° in molecule 2. The amide group adopts a Z conformation in both molecules and forms an intramolecular N—H⋯H hydrogen bond to atom N3 of the benzimidazole system (Table 1), resulting in a six-membered hydrogen-bonded ring with an S(6) motif (Bernstein et al., 1995). This is in line with Etter's second hydrogen-bond rule for organic compounds, which states that intramolecular six-membered hydrogen-bonded rings form in preference to intermolecular hydrogen bonds (Etter, 1990).
3. Supramolecular features
The most significant supramolecular feature of the title compound's solid-state structure is a short C—H⋯N contact between the amidine C2—H2 group of the benzimidazole moiety in molecule 2 and N5 of the pyrimidine ring in molecule 1 (Fig. 3), which provides structural evidence for a C—H⋯N weak hydrogen bond (Table 1). The amidine C2—H2 group in molecule 1 forms a short C—H⋯O contact to the amide carbonyl group of molecule 2. The geometric parameters including a D—H⋯A angle >140° (Wood et al., 2009) are characteristic of a weak hydrogen bond (Thakuria et al., 2017). F⋯F interactions are not encountered in the but parallel arrangements between the pyrimidine ring of molecule 1 and the benzimidazole moiety of a neighbouring molecule 2 (Fig. 4) and between the benzimidazole moieties of two molecules 1 about a center of symmetry are notable features (Fig. 5). The latter and the stacking of these units with the pyrimidine rings of molecule 2 in the b*-axis direction no doubt contribute to the 040 reflection having by far the strongest intensity in the diffraction data set. A packing index of 71.9% (Kitaigorodskii, 1973), as calculated with PLATON (Spek, 2020), suggests that the solid-state structure appears to be mainly governed by close packing.
4. Database survey
A search of the Cambridge Structural Database (CSD; Groom et al., 2016) for acyclic 1-alkyl benzimidazole-4-carboxamides via WebCSD (accessed on 21 October 2022; CCDC, 2017) yielded the structure of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-1H-benzimidazole-4-carboxamide (Ziółkowska et al., 2010; CSD refcode: PUMXAX). In PUMXAX, the amide group likewise forms an intramolecular N—H⋯N hydrogen bond to N3 of the benzimidazole system with an S(6) motif, and the 2,6-difluorobenzyl group and the benzimidazole moiety adopt an orientation to one another similar to that of the 6-methoxy-5-methylpyrimidin-4-yl group and the benzimidazole system in 1.
A survey of crystal structures of the target enzyme DprE1 in the Protein Data Bank (PDB; Burley et al., 2019), revealed that the conformation of the benzamide part of both molecules in 1 is similar to that of CT319, which is (R)-3-nitro-N-(1-phenylethyl)-5-(trifluoromethyl)benzamide, in the of its non-covalent complex with M. tuberculosis DprE1 (PDB code: 4FDO; Batt et al., 2012), as shown in Fig. 6.
5. Antimycobacterial evaluation
Manjunatha et al. (2019) reported an in vitro minimal (MIC) of 1.56–3.12 µM for 1 against M. tuberculosis H37Rv and MIC 0.78–1.56 µM against Mycobacterium smegmatis. Potent inhibition of the M. tuberculosis DprE1 and molecular docking suggested a mode of action similar to TBA-7371. We re-evaluated the in vitro activity of 1 against M. smegmatis mc2 155, using broth microdilution assays (for the assay protocols, see supporting information and Richter et al., 2018). We determined a MIC90 of 12.5 µM in Middlebrook 7H9 medium supplemented with 10% ADS (albumin-dextrose-saline) and 0.05% polysorbate 80, and 6.25 µM in Mueller Hinton II Broth with 0.05% polysorbate 80.
The non-tuberculous Mycobacterium abscessus is an opportunistic pathogen, which can cause difficult-to-treat skin, soft tissue and pulmonary infections, in particular in patients with structural lung diseases such as cystic fibrosis (Boudehen & Kremer, 2021). Screening of antitubercular agents for activity against M. abscessus has been proposed (Ganapathy & Dick, 2022). Mechanism-based covalent DprE1 inhibitors with potent activity against M. tuberculosis and other mycobacteria like M. smegmatis form covalent adducts with the thiol group of Cys387 on the FAD substrate binding domain (Shetye et al., 2020). These compounds are usually inactive against M. abscessus, since the M. abscessus DprE1 has an alanine residue in the corresponding amino-acid position, which prevents covalent linkage. Testing of non-covalent DprE1 inhibitors against M. abscessus, however, could be a promising approach to identifying potential lead structures. Therefore, we also tested 1 against M. abscessus ATCC19977 in vitro. In both Middlebrook 7H9 medium supplemented with 10% ADS and 0.05% polysorbate 80 and Mueller Hinton II Broth with 0.05% polysorbate 80, however, no growth inhibition could be detected (MIC90 > 100 µM). While this work was in progress, the same observation was reported for the parent 1,4-azaindole TBA-7371 (Sarathy et al., 2022). It is worth noting, however, that Sarathy et al. (2022) found moderate in vitro activity against several M. abscessus strains and clinical isolates for the 3,4-dihydrocarbostyril-based non-covalent DprE1 inhibitor and Phase 2b/c clinical antituberculosis drug candidate OPC-167832.
6. Synthesis and crystallization
Compound 1 was synthesized as described by Manjunatha et al. (2019). Analytical data for A, B, C and 1 can be found in the supporting information. Crystals of 1 suitable for X-ray diffraction were grown from a solution in ethyl acetate/n-heptane (1:1) by slow evaporation of the solvents at room temperature.
7. Refinement
Initially, the structure was refined to convergence using independent atom model SHELXL2018/3 (Sheldrick, 2015b). The final structure was carried out by Hirshfeld atom with aspherical scattering factors using NoSpherA2 (Kleemiss et al., 2021; Midgley et al., 2021) partitioning in OLEX2 (Dolomanov et al., 2009) based on electron density from iterative single-determinant SCF single-point DFT calculations using ORCA (Neese et al., 2020) with a B3LYP functional (Becke, 1993; Lee et al., 1988) and a def2-TZVPP basis set. Crystal data, data collection and structure details are summarized in Table 2.
with
|
Supporting information
CCDC reference: 2216847
https://doi.org/10.1107/S2056989022010556/vm2273sup1.cif
contains datablocks global, I. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989022010556/vm2273Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S2056989022010556/vm2273Isup3.mol
NMR and mass spectra, antimicrobial susceptibility testing. DOI: https://doi.org/10.1107/S2056989022010556/vm2273sup4.pdf
Supporting information file. DOI: https://doi.org/10.1107/S2056989022010556/vm2273Isup5.cml
Data collection: APEX3 (Bruker, 2017); cell
SAINT (Bruker, 2004); data reduction: SAINT (Bruker, 2004); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: olex2.refine (Bourhis et al., 2015); molecular graphics: DIAMOND (Brandenburg, 2018) and Mercury (Macrae et al., 2020); software used to prepare material for publication: enCIFer (Allen et al., 2004) and publCIF (Westrip, 2010).C17H18FN5O2 | Z = 4 |
Mr = 343.36 | F(000) = 720 |
Triclinic, P1 | Dx = 1.398 Mg m−3 |
a = 7.6940 (19) Å | Mo Kα radiation, λ = 0.71073 Å |
b = 15.013 (4) Å | Cell parameters from 9963 reflections |
c = 15.281 (4) Å | θ = 2.7–28.2° |
α = 71.040 (4)° | µ = 0.10 mm−1 |
β = 77.874 (5)° | T = 100 K |
γ = 87.780 (4)° | Plate, colourless |
V = 1631.3 (7) Å3 | 0.10 × 0.05 × 0.02 mm |
Bruker AXS Kappa Mach3 APEX II diffractometer | 8147 independent reflections |
Radiation source: Incoatec IµS | 6141 reflections with I ≥ 2u(I) |
Incoatec Helios mirrors monochromator | Rint = 0.048 |
Detector resolution: 66.67 pixels mm-1 | θmax = 28.5°, θmin = 1.4° |
φ– and ω–scans | h = −10→10 |
Absorption correction: gaussian (SADABS; Krause et al., 2015) | k = −20→20 |
Tmin = 0.994, Tmax = 0.999 | l = −20→19 |
58016 measured reflections |
Refinement on F2 | Primary atom site location: dual |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.031 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.072 | All H-atom parameters refined |
S = 1.07 | w = 1/[σ2(Fo2) + (0.0302P)2 + 0.1357P] where P = (Fo2 + 2Fc2)/3 |
8147 reflections | (Δ/σ)max = −0.001 |
595 parameters | Δρmax = 0.34 e Å−3 |
0 restraints | Δρmin = −0.32 e Å−3 |
0 constraints |
Experimental. Crystal mounted on a MiTeGen loop using Perfluoropolyether PFO-XR75. |
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2sigma(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
C2_1 | 0.24678 (14) | 0.11875 (7) | 0.50249 (7) | 0.0171 (2) | |
H2_1 | 0.1399 (16) | 0.1169 (8) | 0.4698 (8) | 0.033 (3)* | |
C3A_1 | 0.40214 (12) | 0.12795 (6) | 0.60043 (7) | 0.01224 (19) | |
C4_1 | 0.46666 (13) | 0.12885 (6) | 0.67969 (7) | 0.0138 (2) | |
C5_1 | 0.64993 (14) | 0.12841 (7) | 0.67153 (8) | 0.0188 (2) | |
H5_1 | 0.7017 (16) | 0.1288 (9) | 0.7320 (9) | 0.037 (3)* | |
C6_1 | 0.76757 (14) | 0.12644 (8) | 0.58895 (8) | 0.0223 (2) | |
H6_1 | 0.9064 (17) | 0.1261 (8) | 0.5876 (9) | 0.040 (3)* | |
C7_1 | 0.70606 (13) | 0.12396 (7) | 0.51032 (8) | 0.0187 (2) | |
H7_1 | 0.7946 (16) | 0.1207 (8) | 0.4507 (9) | 0.038 (3)* | |
C7A_1 | 0.52267 (12) | 0.12461 (6) | 0.51864 (7) | 0.0131 (2) | |
C8_1 | 0.35297 (14) | 0.12221 (7) | 0.77376 (7) | 0.0175 (2) | |
C9_1 | 0.05871 (17) | 0.09121 (8) | 0.87354 (8) | 0.0265 (3) | |
H9a_1 | 0.1274 (19) | 0.0422 (11) | 0.9242 (10) | 0.057 (4)* | |
H9b_1 | −0.0673 (19) | 0.0628 (10) | 0.8694 (10) | 0.050 (4)* | |
C10_1 | 0.01296 (17) | 0.17191 (8) | 0.91114 (8) | 0.0258 (3) | |
H10a_1 | −0.0661 (19) | 0.1461 (10) | 0.9831 (11) | 0.057 (4)* | |
H10b_1 | 0.1311 (18) | 0.2145 (9) | 0.9030 (9) | 0.047 (4)* | |
C11_1 | 0.48068 (16) | 0.10678 (7) | 0.36547 (7) | 0.0188 (2) | |
H11a_1 | 0.3719 (18) | 0.0773 (9) | 0.3485 (9) | 0.044 (4)* | |
H11b_1 | 0.5883 (18) | 0.0590 (9) | 0.3682 (9) | 0.048 (4)* | |
C12_1 | 0.54232 (13) | 0.19816 (6) | 0.28726 (7) | 0.01278 (19) | |
C13_1 | 0.66938 (12) | 0.19801 (6) | 0.20828 (7) | 0.01218 (19) | |
C14_1 | 0.70948 (12) | 0.28746 (6) | 0.13868 (6) | 0.01223 (19) | |
C15_1 | 0.51185 (13) | 0.35548 (7) | 0.22720 (7) | 0.0151 (2) | |
H15_1 | 0.4475 (15) | 0.4202 (8) | 0.2342 (8) | 0.031 (3)* | |
C16_1 | 0.75853 (15) | 0.11175 (7) | 0.19506 (8) | 0.0172 (2) | |
H16a_1 | 0.8798 (19) | 0.1290 (10) | 0.1421 (10) | 0.054 (4)* | |
H16b_1 | 0.8024 (18) | 0.0689 (10) | 0.2556 (10) | 0.052 (4)* | |
H16c_1 | 0.677 (2) | 0.0719 (11) | 0.1756 (10) | 0.061 (4)* | |
C17_1 | 0.88043 (14) | 0.38333 (7) | −0.00710 (7) | 0.0181 (2) | |
H17a_1 | 0.9829 (17) | 0.3724 (8) | −0.0611 (9) | 0.040 (3)* | |
H17b_1 | 0.7668 (16) | 0.4161 (8) | −0.0362 (8) | 0.033 (3)* | |
H17c_1 | 0.9341 (16) | 0.4290 (9) | 0.0248 (9) | 0.037 (3)* | |
N1_1 | 0.41820 (11) | 0.11800 (5) | 0.45741 (5) | 0.01466 (17) | |
N2_1 | 0.17564 (12) | 0.11793 (6) | 0.78099 (6) | 0.0202 (2) | |
H2a_1 | 0.1293 (17) | 0.1211 (9) | 0.7235 (10) | 0.036 (4)* | |
N3_1 | 0.22925 (10) | 0.12443 (6) | 0.58814 (6) | 0.01580 (18) | |
N4_1 | 0.46198 (11) | 0.27632 (6) | 0.29767 (6) | 0.01515 (18) | |
N5_1 | 0.63354 (10) | 0.36553 (5) | 0.14786 (6) | 0.01407 (17) | |
O1_1 | 0.41907 (11) | 0.11614 (5) | 0.84196 (5) | 0.02732 (19) | |
O2_1 | 0.83091 (9) | 0.29152 (5) | 0.06084 (5) | 0.01625 (15) | |
F1_1 | −0.09275 (9) | 0.23342 (5) | 0.85713 (5) | 0.0407 (2) | |
C2_2 | 0.63497 (13) | 0.58977 (7) | 0.02129 (7) | 0.0161 (2) | |
H2_2 | 0.6202 (16) | 0.5177 (9) | 0.0635 (9) | 0.038 (3)* | |
C3A_2 | 0.71862 (12) | 0.72002 (6) | −0.08890 (7) | 0.01256 (19) | |
C4_2 | 0.79584 (12) | 0.79156 (7) | −0.17228 (7) | 0.0130 (2) | |
C5_2 | 0.75312 (13) | 0.88396 (7) | −0.17785 (7) | 0.0161 (2) | |
H5_2 | 0.8156 (16) | 0.9408 (9) | −0.2421 (9) | 0.035 (3)* | |
C6_2 | 0.63746 (14) | 0.90545 (7) | −0.10381 (7) | 0.0188 (2) | |
H6_2 | 0.6057 (16) | 0.9770 (9) | −0.1100 (8) | 0.036 (3)* | |
C7_2 | 0.55929 (14) | 0.83519 (7) | −0.02112 (7) | 0.0171 (2) | |
H7_2 | 0.4735 (16) | 0.8528 (8) | 0.0344 (8) | 0.034 (3)* | |
C7A_2 | 0.60227 (12) | 0.74284 (7) | −0.01578 (7) | 0.0140 (2) | |
C8_2 | 0.91827 (12) | 0.77332 (7) | −0.25397 (7) | 0.0138 (2) | |
C9_2 | 1.08197 (14) | 0.65409 (8) | −0.31197 (8) | 0.0188 (2) | |
H9a_2 | 1.1513 (16) | 0.5933 (9) | −0.2806 (9) | 0.039 (3)* | |
H9b_2 | 1.1762 (16) | 0.7109 (9) | −0.3576 (9) | 0.035 (3)* | |
C10_2 | 0.97648 (16) | 0.62865 (9) | −0.37364 (8) | 0.0269 (3) | |
H10a_2 | 0.8958 (17) | 0.6864 (9) | −0.4029 (9) | 0.044 (3)* | |
H10b_2 | 1.0606 (18) | 0.6044 (9) | −0.4256 (10) | 0.054 (4)* | |
C11_2 | 0.43832 (14) | 0.64282 (8) | 0.14634 (7) | 0.0192 (2) | |
H11a_2 | 0.3521 (16) | 0.5797 (9) | 0.1648 (9) | 0.039 (3)* | |
H11b_2 | 0.3542 (16) | 0.7039 (9) | 0.1409 (9) | 0.038 (3)* | |
C12_2 | 0.54170 (13) | 0.63169 (7) | 0.22336 (7) | 0.0154 (2) | |
C13_2 | 0.45344 (13) | 0.63352 (7) | 0.31175 (7) | 0.0161 (2) | |
C14_2 | 0.56317 (15) | 0.62089 (7) | 0.37788 (7) | 0.0201 (2) | |
C15_2 | 0.80399 (15) | 0.60741 (8) | 0.27110 (8) | 0.0257 (3) | |
H15_2 | 0.9430 (17) | 0.5958 (9) | 0.2557 (9) | 0.043 (3)* | |
C16_2 | 0.25762 (15) | 0.64610 (8) | 0.33854 (8) | 0.0215 (2) | |
H16a_2 | 0.2278 (19) | 0.6794 (10) | 0.3907 (11) | 0.061 (4)* | |
H16b_2 | 0.2055 (19) | 0.6939 (11) | 0.2826 (11) | 0.063 (4)* | |
H16c_2 | 0.187 (2) | 0.5814 (12) | 0.3640 (11) | 0.075 (5)* | |
C17_2 | 0.5973 (2) | 0.61725 (10) | 0.52889 (10) | 0.0379 (3) | |
H17a_2 | 0.513 (2) | 0.6183 (12) | 0.5923 (13) | 0.078 (5)* | |
H17b_2 | 0.6689 (18) | 0.5546 (10) | 0.5403 (10) | 0.053 (4)* | |
H17c_2 | 0.691 (2) | 0.6769 (12) | 0.5007 (11) | 0.063 (4)* | |
N1_2 | 0.54919 (11) | 0.65749 (6) | 0.05356 (6) | 0.01600 (18) | |
N2_2 | 0.97000 (11) | 0.68391 (6) | −0.23867 (6) | 0.01570 (18) | |
H2a_2 | 0.9130 (17) | 0.6344 (9) | −0.1783 (10) | 0.034 (3)* | |
N3_2 | 0.73649 (10) | 0.62313 (5) | −0.06356 (6) | 0.01434 (17) | |
N4_2 | 0.71695 (11) | 0.61835 (6) | 0.20201 (6) | 0.0216 (2) | |
N5_2 | 0.73631 (12) | 0.60823 (6) | 0.35843 (6) | 0.0252 (2) | |
O1_2 | 0.96957 (9) | 0.83717 (5) | −0.32943 (5) | 0.01908 (16) | |
O2_2 | 0.48417 (11) | 0.62231 (5) | 0.46393 (5) | 0.02792 (19) | |
F1_2 | 0.85963 (9) | 0.55284 (5) | −0.31786 (5) | 0.03320 (17) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C2_1 | 0.0170 (5) | 0.0220 (5) | 0.0124 (5) | 0.0007 (4) | −0.0054 (4) | −0.0044 (4) |
C3A_1 | 0.0134 (5) | 0.0129 (4) | 0.0095 (5) | 0.0004 (4) | −0.0016 (4) | −0.0029 (4) |
C4_1 | 0.0163 (5) | 0.0139 (5) | 0.0113 (5) | 0.0005 (4) | −0.0031 (4) | −0.0041 (4) |
C5_1 | 0.0171 (5) | 0.0217 (5) | 0.0184 (6) | −0.0004 (4) | −0.0067 (4) | −0.0057 (4) |
C6_1 | 0.0120 (5) | 0.0290 (6) | 0.0242 (6) | −0.0018 (4) | −0.0022 (4) | −0.0071 (5) |
C7_1 | 0.0138 (5) | 0.0211 (5) | 0.0174 (5) | −0.0009 (4) | 0.0025 (4) | −0.0045 (4) |
C7A_1 | 0.0140 (5) | 0.0130 (4) | 0.0100 (5) | −0.0002 (4) | 0.0005 (4) | −0.0024 (4) |
C8_1 | 0.0251 (6) | 0.0171 (5) | 0.0112 (5) | 0.0044 (4) | −0.0043 (4) | −0.0059 (4) |
C9_1 | 0.0330 (7) | 0.0225 (6) | 0.0184 (6) | 0.0017 (5) | 0.0070 (5) | −0.0068 (5) |
C10_1 | 0.0307 (7) | 0.0269 (6) | 0.0178 (6) | 0.0104 (5) | 0.0001 (5) | −0.0088 (5) |
C11_1 | 0.0304 (6) | 0.0133 (5) | 0.0103 (5) | −0.0028 (4) | 0.0001 (4) | −0.0030 (4) |
C12_1 | 0.0182 (5) | 0.0107 (4) | 0.0090 (5) | −0.0004 (4) | −0.0029 (4) | −0.0026 (4) |
C13_1 | 0.0141 (5) | 0.0120 (5) | 0.0104 (5) | −0.0004 (4) | −0.0017 (4) | −0.0039 (4) |
C14_1 | 0.0141 (4) | 0.0127 (5) | 0.0097 (5) | −0.0003 (4) | −0.0026 (4) | −0.0032 (4) |
C15_1 | 0.0187 (5) | 0.0126 (5) | 0.0122 (5) | 0.0021 (4) | −0.0008 (4) | −0.0031 (4) |
C16_1 | 0.0198 (5) | 0.0142 (5) | 0.0180 (6) | 0.0025 (4) | −0.0038 (5) | −0.0061 (4) |
C17_1 | 0.0174 (5) | 0.0197 (5) | 0.0137 (5) | −0.0031 (4) | 0.0004 (4) | −0.0025 (4) |
N1_1 | 0.0194 (4) | 0.0146 (4) | 0.0086 (4) | −0.0007 (3) | −0.0010 (3) | −0.0029 (3) |
N2_1 | 0.0228 (5) | 0.0221 (5) | 0.0142 (5) | 0.0016 (4) | 0.0011 (4) | −0.0071 (4) |
N3_1 | 0.0128 (4) | 0.0217 (4) | 0.0125 (4) | 0.0016 (3) | −0.0019 (3) | −0.0055 (3) |
N4_1 | 0.0195 (4) | 0.0130 (4) | 0.0116 (4) | 0.0009 (3) | −0.0005 (3) | −0.0039 (3) |
N5_1 | 0.0169 (4) | 0.0126 (4) | 0.0112 (4) | 0.0009 (3) | −0.0016 (3) | −0.0027 (3) |
O1_1 | 0.0369 (5) | 0.0343 (4) | 0.0155 (4) | 0.0107 (4) | −0.0107 (3) | −0.0123 (3) |
O2_1 | 0.0177 (3) | 0.0157 (3) | 0.0132 (3) | −0.0011 (3) | 0.0013 (3) | −0.0044 (3) |
F1_1 | 0.0328 (4) | 0.0471 (5) | 0.0366 (4) | 0.0222 (3) | −0.0055 (3) | −0.0094 (3) |
C2_2 | 0.0188 (5) | 0.0155 (5) | 0.0119 (5) | 0.0025 (4) | −0.0030 (4) | −0.0017 (4) |
C3A_2 | 0.0144 (5) | 0.0129 (5) | 0.0102 (5) | 0.0018 (4) | −0.0036 (4) | −0.0031 (4) |
C4_2 | 0.0147 (5) | 0.0132 (5) | 0.0113 (5) | 0.0015 (4) | −0.0034 (4) | −0.0038 (4) |
C5_2 | 0.0201 (5) | 0.0125 (5) | 0.0166 (5) | 0.0007 (4) | −0.0058 (4) | −0.0048 (4) |
C6_2 | 0.0226 (5) | 0.0157 (5) | 0.0211 (6) | 0.0041 (4) | −0.0074 (4) | −0.0089 (4) |
C7_2 | 0.0196 (5) | 0.0204 (5) | 0.0156 (5) | 0.0057 (4) | −0.0063 (4) | −0.0105 (4) |
C7A_2 | 0.0161 (5) | 0.0168 (5) | 0.0106 (5) | 0.0041 (4) | −0.0046 (4) | −0.0059 (4) |
C8_2 | 0.0150 (5) | 0.0150 (5) | 0.0111 (5) | −0.0010 (4) | −0.0027 (4) | −0.0035 (4) |
C9_2 | 0.0164 (5) | 0.0215 (6) | 0.0190 (5) | 0.0007 (4) | −0.0011 (4) | −0.0089 (5) |
C10_2 | 0.0316 (6) | 0.0330 (7) | 0.0236 (6) | 0.0063 (5) | −0.0092 (5) | −0.0176 (5) |
C11_2 | 0.0171 (5) | 0.0295 (6) | 0.0107 (5) | 0.0041 (5) | −0.0047 (4) | −0.0053 (4) |
C12_2 | 0.0172 (5) | 0.0181 (5) | 0.0111 (5) | 0.0019 (4) | −0.0051 (4) | −0.0035 (4) |
C13_2 | 0.0224 (5) | 0.0151 (5) | 0.0116 (5) | −0.0004 (4) | −0.0055 (4) | −0.0041 (4) |
C14_2 | 0.0316 (6) | 0.0174 (5) | 0.0135 (5) | −0.0012 (4) | −0.0111 (5) | −0.0040 (4) |
C15_2 | 0.0198 (6) | 0.0324 (6) | 0.0247 (6) | 0.0021 (5) | −0.0115 (5) | −0.0050 (5) |
C16_2 | 0.0244 (6) | 0.0236 (6) | 0.0171 (6) | 0.0016 (5) | −0.0027 (5) | −0.0085 (5) |
C17_2 | 0.0664 (10) | 0.0319 (7) | 0.0231 (7) | 0.0034 (7) | −0.0245 (7) | −0.0101 (6) |
N1_2 | 0.0165 (4) | 0.0205 (4) | 0.0096 (4) | 0.0041 (3) | −0.0026 (3) | −0.0036 (3) |
N2_2 | 0.0163 (4) | 0.0163 (4) | 0.0142 (4) | 0.0008 (3) | −0.0020 (3) | −0.0053 (4) |
N3_2 | 0.0164 (4) | 0.0147 (4) | 0.0110 (4) | 0.0031 (3) | −0.0026 (3) | −0.0033 (3) |
N4_2 | 0.0181 (4) | 0.0288 (5) | 0.0173 (5) | 0.0040 (4) | −0.0067 (4) | −0.0052 (4) |
N5_2 | 0.0304 (5) | 0.0259 (5) | 0.0212 (5) | −0.0013 (4) | −0.0160 (4) | −0.0034 (4) |
O1_2 | 0.0218 (4) | 0.0182 (4) | 0.0131 (4) | −0.0015 (3) | 0.0001 (3) | −0.0015 (3) |
O2_2 | 0.0457 (5) | 0.0272 (4) | 0.0147 (4) | 0.0009 (4) | −0.0124 (4) | −0.0081 (3) |
F1_2 | 0.0271 (4) | 0.0315 (4) | 0.0516 (5) | 0.0002 (3) | −0.0106 (3) | −0.0262 (3) |
C2_1—H2_1 | 1.054 (12) | C2_2—H2_2 | 1.060 (13) |
C2_1—N1_1 | 1.3551 (13) | C2_2—N1_2 | 1.3599 (13) |
C2_1—N3_1 | 1.3175 (13) | C2_2—N3_2 | 1.3133 (13) |
C3A_1—C4_1 | 1.4063 (14) | C3A_2—C4_2 | 1.4043 (13) |
C3A_1—C7A_1 | 1.4051 (13) | C3A_2—C7A_2 | 1.4042 (13) |
C3A_1—N3_1 | 1.3871 (13) | C3A_2—N3_2 | 1.3877 (12) |
C4_1—C5_1 | 1.3892 (14) | C4_2—C5_2 | 1.3926 (14) |
C4_1—C8_1 | 1.4922 (14) | C4_2—C8_2 | 1.4929 (14) |
C5_1—H5_1 | 1.082 (13) | C5_2—H5_2 | 1.101 (12) |
C5_1—C6_1 | 1.3982 (15) | C5_2—C6_2 | 1.4029 (14) |
C6_1—H6_1 | 1.064 (13) | C6_2—H6_2 | 1.070 (12) |
C6_1—C7_1 | 1.3923 (16) | C6_2—C7_2 | 1.3910 (15) |
C7_1—H7_1 | 1.031 (12) | C7_2—H7_2 | 1.059 (12) |
C7_1—C7A_1 | 1.3898 (14) | C7_2—C7A_2 | 1.3932 (14) |
C7A_1—N1_1 | 1.3834 (13) | C7A_2—N1_2 | 1.3812 (13) |
C8_1—N2_1 | 1.3479 (14) | C8_2—N2_2 | 1.3448 (13) |
C8_1—O1_1 | 1.2289 (12) | C8_2—O1_2 | 1.2346 (11) |
C9_1—H9a_1 | 1.092 (15) | C9_2—H9a_2 | 1.064 (12) |
C9_1—H9b_1 | 1.096 (14) | C9_2—H9b_2 | 1.090 (13) |
C9_1—C10_1 | 1.5021 (16) | C9_2—C10_2 | 1.5073 (16) |
C9_1—N2_1 | 1.4475 (14) | C9_2—N2_2 | 1.4450 (13) |
C10_1—H10a_1 | 1.091 (15) | C10_2—H10a_2 | 1.078 (13) |
C10_1—H10b_1 | 1.094 (14) | C10_2—H10b_2 | 1.066 (14) |
C10_1—F1_1 | 1.3871 (13) | C10_2—F1_2 | 1.3989 (14) |
C11_1—H11a_1 | 1.076 (14) | C11_2—H11a_2 | 1.102 (13) |
C11_1—H11b_1 | 1.073 (13) | C11_2—H11b_2 | 1.092 (12) |
C11_1—C12_1 | 1.5107 (14) | C11_2—C12_2 | 1.5169 (14) |
C11_1—N1_1 | 1.4481 (13) | C11_2—N1_2 | 1.4456 (13) |
C12_1—C13_1 | 1.3849 (13) | C12_2—C13_2 | 1.3869 (14) |
C12_1—N4_1 | 1.3447 (12) | C12_2—N4_2 | 1.3422 (13) |
C13_1—C14_1 | 1.4129 (13) | C13_2—C14_2 | 1.4111 (14) |
C13_1—C16_1 | 1.4938 (14) | C13_2—C16_2 | 1.4974 (15) |
C14_1—N5_1 | 1.3244 (12) | C14_2—N5_2 | 1.3228 (14) |
C14_1—O2_1 | 1.3349 (11) | C14_2—O2_2 | 1.3344 (13) |
C15_1—H15_1 | 1.100 (11) | C15_2—H15_2 | 1.066 (13) |
C15_1—N4_1 | 1.3227 (13) | C15_2—N4_2 | 1.3289 (14) |
C15_1—N5_1 | 1.3358 (13) | C15_2—N5_2 | 1.3305 (15) |
C16_1—H16a_1 | 1.076 (14) | C16_2—H16a_2 | 1.055 (16) |
C16_1—H16b_1 | 1.055 (14) | C16_2—H16b_2 | 1.063 (16) |
C16_1—H16c_1 | 1.032 (16) | C16_2—H16c_2 | 1.047 (17) |
C17_1—H17a_1 | 1.065 (13) | C17_2—H17a_2 | 1.051 (17) |
C17_1—H17b_1 | 1.092 (12) | C17_2—H17b_2 | 1.055 (14) |
C17_1—H17c_1 | 1.096 (13) | C17_2—H17c_2 | 1.083 (16) |
C17_1—O2_1 | 1.4378 (12) | C17_2—O2_2 | 1.4341 (15) |
N2_1—H2a_1 | 1.002 (14) | N2_2—H2a_2 | 1.002 (14) |
N1_1—C2_1—H2_1 | 121.8 (6) | N1_2—C2_2—H2_2 | 121.1 (7) |
N3_1—C2_1—H2_1 | 124.5 (6) | N3_2—C2_2—H2_2 | 125.3 (7) |
N3_1—C2_1—N1_1 | 113.70 (9) | N3_2—C2_2—N1_2 | 113.60 (9) |
C7A_1—C3A_1—C4_1 | 119.54 (8) | C7A_2—C3A_2—C4_2 | 120.12 (8) |
N3_1—C3A_1—C4_1 | 130.61 (9) | N3_2—C3A_2—C4_2 | 130.02 (9) |
N3_1—C3A_1—C7A_1 | 109.75 (8) | N3_2—C3A_2—C7A_2 | 109.86 (8) |
C5_1—C4_1—C3A_1 | 117.17 (9) | C5_2—C4_2—C3A_2 | 117.23 (9) |
C8_1—C4_1—C3A_1 | 124.80 (9) | C8_2—C4_2—C3A_2 | 123.55 (8) |
C8_1—C4_1—C5_1 | 117.82 (9) | C8_2—C4_2—C5_2 | 119.22 (9) |
H5_1—C5_1—C4_1 | 118.1 (6) | H5_2—C5_2—C4_2 | 117.9 (6) |
C6_1—C5_1—C4_1 | 122.32 (10) | C6_2—C5_2—C4_2 | 121.84 (9) |
C6_1—C5_1—H5_1 | 119.6 (6) | C6_2—C5_2—H5_2 | 120.2 (6) |
H6_1—C6_1—C5_1 | 118.4 (7) | H6_2—C6_2—C5_2 | 120.5 (6) |
C7_1—C6_1—C5_1 | 121.32 (10) | C7_2—C6_2—C5_2 | 121.47 (9) |
C7_1—C6_1—H6_1 | 120.3 (7) | C7_2—C6_2—H6_2 | 118.0 (6) |
H7_1—C7_1—C6_1 | 120.2 (7) | H7_2—C7_2—C6_2 | 120.4 (6) |
C7A_1—C7_1—C6_1 | 116.21 (10) | C7A_2—C7_2—C6_2 | 116.54 (9) |
C7A_1—C7_1—H7_1 | 123.5 (7) | C7A_2—C7_2—H7_2 | 123.1 (6) |
C7_1—C7A_1—C3A_1 | 123.43 (9) | C7_2—C7A_2—C3A_2 | 122.79 (9) |
N1_1—C7A_1—C3A_1 | 105.24 (8) | N1_2—C7A_2—C3A_2 | 105.16 (8) |
N1_1—C7A_1—C7_1 | 131.26 (9) | N1_2—C7A_2—C7_2 | 132.05 (9) |
N2_1—C8_1—C4_1 | 116.58 (9) | N2_2—C8_2—C4_2 | 115.46 (8) |
O1_1—C8_1—C4_1 | 121.17 (9) | O1_2—C8_2—C4_2 | 121.45 (8) |
O1_1—C8_1—N2_1 | 122.15 (10) | O1_2—C8_2—N2_2 | 123.08 (9) |
H9b_1—C9_1—H9a_1 | 114.0 (11) | H9b_2—C9_2—H9a_2 | 110.2 (9) |
C10_1—C9_1—H9a_1 | 105.0 (8) | C10_2—C9_2—H9a_2 | 107.5 (7) |
C10_1—C9_1—H9b_1 | 106.5 (7) | C10_2—C9_2—H9b_2 | 107.5 (6) |
N2_1—C9_1—H9a_1 | 108.6 (7) | N2_2—C9_2—H9a_2 | 109.5 (7) |
N2_1—C9_1—H9b_1 | 109.1 (7) | N2_2—C9_2—H9b_2 | 109.8 (6) |
N2_1—C9_1—C10_1 | 113.74 (10) | N2_2—C9_2—C10_2 | 112.27 (9) |
H10a_1—C10_1—C9_1 | 109.9 (7) | H10a_2—C10_2—C9_2 | 110.4 (7) |
H10b_1—C10_1—C9_1 | 111.7 (7) | H10b_2—C10_2—C9_2 | 111.2 (7) |
H10b_1—C10_1—H10a_1 | 114.6 (10) | H10b_2—C10_2—H10a_2 | 113.6 (10) |
F1_1—C10_1—C9_1 | 109.35 (10) | F1_2—C10_2—C9_2 | 108.97 (9) |
F1_1—C10_1—H10a_1 | 106.5 (7) | F1_2—C10_2—H10a_2 | 106.7 (7) |
F1_1—C10_1—H10b_1 | 104.4 (7) | F1_2—C10_2—H10b_2 | 105.6 (7) |
H11b_1—C11_1—H11a_1 | 109.0 (10) | H11b_2—C11_2—H11a_2 | 108.4 (9) |
C12_1—C11_1—H11a_1 | 108.2 (7) | C12_2—C11_2—H11a_2 | 109.4 (6) |
C12_1—C11_1—H11b_1 | 108.6 (7) | C12_2—C11_2—H11b_2 | 109.5 (7) |
N1_1—C11_1—H11a_1 | 107.6 (7) | N1_2—C11_2—H11a_2 | 108.5 (6) |
N1_1—C11_1—H11b_1 | 109.8 (7) | N1_2—C11_2—H11b_2 | 106.9 (6) |
N1_1—C11_1—C12_1 | 113.63 (8) | N1_2—C11_2—C12_2 | 113.96 (8) |
C13_1—C12_1—C11_1 | 120.19 (8) | C13_2—C12_2—C11_2 | 119.79 (9) |
N4_1—C12_1—C11_1 | 116.34 (8) | N4_2—C12_2—C11_2 | 117.08 (9) |
N4_1—C12_1—C13_1 | 123.40 (8) | N4_2—C12_2—C13_2 | 123.11 (9) |
C14_1—C13_1—C12_1 | 114.47 (8) | C14_2—C13_2—C12_2 | 114.56 (9) |
C16_1—C13_1—C12_1 | 124.13 (9) | C16_2—C13_2—C12_2 | 124.46 (9) |
C16_1—C13_1—C14_1 | 121.40 (9) | C16_2—C13_2—C14_2 | 120.97 (9) |
N5_1—C14_1—C13_1 | 123.18 (9) | N5_2—C14_2—C13_2 | 123.50 (10) |
O2_1—C14_1—C13_1 | 117.08 (8) | O2_2—C14_2—C13_2 | 116.73 (10) |
O2_1—C14_1—N5_1 | 119.74 (8) | O2_2—C14_2—N5_2 | 119.77 (9) |
N4_1—C15_1—H15_1 | 117.2 (6) | N4_2—C15_2—H15_2 | 117.0 (7) |
N5_1—C15_1—H15_1 | 116.0 (6) | N5_2—C15_2—H15_2 | 115.9 (7) |
N5_1—C15_1—N4_1 | 126.82 (9) | N5_2—C15_2—N4_2 | 127.12 (10) |
H16a_1—C16_1—C13_1 | 111.8 (7) | H16a_2—C16_2—C13_2 | 111.5 (8) |
H16b_1—C16_1—C13_1 | 113.0 (7) | H16b_2—C16_2—C13_2 | 113.1 (8) |
H16b_1—C16_1—H16a_1 | 102.7 (10) | H16b_2—C16_2—H16a_2 | 101.5 (11) |
H16c_1—C16_1—C13_1 | 111.6 (8) | H16c_2—C16_2—C13_2 | 111.4 (9) |
H16c_1—C16_1—H16a_1 | 108.3 (11) | H16c_2—C16_2—H16a_2 | 108.5 (12) |
H16c_1—C16_1—H16b_1 | 109.1 (11) | H16c_2—C16_2—H16b_2 | 110.3 (12) |
H17b_1—C17_1—H17a_1 | 110.8 (9) | H17b_2—C17_2—H17a_2 | 110.4 (12) |
H17c_1—C17_1—H17a_1 | 108.6 (9) | H17c_2—C17_2—H17a_2 | 111.0 (12) |
H17c_1—C17_1—H17b_1 | 109.7 (9) | H17c_2—C17_2—H17b_2 | 108.9 (11) |
O2_1—C17_1—H17a_1 | 105.9 (6) | O2_2—C17_2—H17a_2 | 106.2 (9) |
O2_1—C17_1—H17b_1 | 110.8 (6) | O2_2—C17_2—H17b_2 | 110.5 (7) |
O2_1—C17_1—H17c_1 | 111.0 (6) | O2_2—C17_2—H17c_2 | 109.9 (8) |
C7A_1—N1_1—C2_1 | 106.63 (8) | C7A_2—N1_2—C2_2 | 106.66 (8) |
C11_1—N1_1—C2_1 | 126.92 (9) | C11_2—N1_2—C2_2 | 126.10 (9) |
C11_1—N1_1—C7A_1 | 126.35 (8) | C11_2—N1_2—C7A_2 | 126.98 (9) |
C9_1—N2_1—C8_1 | 119.57 (10) | C9_2—N2_2—C8_2 | 122.13 (9) |
H2a_1—N2_1—C8_1 | 118.7 (8) | H2a_2—N2_2—C8_2 | 118.6 (7) |
H2a_1—N2_1—C9_1 | 120.7 (8) | H2a_2—N2_2—C9_2 | 118.4 (7) |
C3A_1—N3_1—C2_1 | 104.67 (8) | C3A_2—N3_2—C2_2 | 104.70 (8) |
C15_1—N4_1—C12_1 | 115.96 (8) | C15_2—N4_2—C12_2 | 115.91 (9) |
C15_1—N5_1—C14_1 | 116.15 (8) | C15_2—N5_2—C14_2 | 115.79 (9) |
C17_1—O2_1—C14_1 | 117.07 (8) | C17_2—O2_2—C14_2 | 116.88 (10) |
C2_1—N1_1—C7A_1—C3A_1 | 0.69 (8) | C2_2—N1_2—C7A_2—C3A_2 | 1.07 (8) |
C2_1—N1_1—C7A_1—C7_1 | 177.71 (8) | C2_2—N1_2—C7A_2—C7_2 | −179.36 (8) |
C2_1—N1_1—C11_1—C12_1 | 101.85 (10) | C2_2—N1_2—C11_2—C12_2 | 78.97 (10) |
C2_1—N3_1—C3A_1—C4_1 | −175.83 (7) | C2_2—N3_2—C3A_2—C4_2 | −179.62 (7) |
C2_1—N3_1—C3A_1—C7A_1 | 0.29 (8) | C2_2—N3_2—C3A_2—C7A_2 | −0.08 (8) |
C3A_1—C4_1—C5_1—C6_1 | −0.47 (11) | C3A_2—C4_2—C5_2—C6_2 | −0.20 (11) |
C3A_1—C4_1—C8_1—N2_1 | −2.07 (10) | C3A_2—C4_2—C8_2—N2_2 | −8.31 (10) |
C3A_1—C4_1—C8_1—O1_1 | 174.32 (10) | C3A_2—C4_2—C8_2—O1_2 | 172.85 (9) |
C3A_1—C7A_1—C7_1—C6_1 | 0.27 (11) | C3A_2—C7A_2—C7_2—C6_2 | 0.26 (11) |
C3A_1—C7A_1—N1_1—C11_1 | −175.96 (7) | C3A_2—C7A_2—N1_2—C11_2 | 175.46 (7) |
C4_1—C5_1—C6_1—C7_1 | −0.58 (12) | C4_2—C5_2—C6_2—C7_2 | −0.19 (12) |
C4_1—C8_1—N2_1—C9_1 | 166.74 (9) | C4_2—C8_2—N2_2—C9_2 | 177.21 (8) |
C5_1—C6_1—C7_1—C7A_1 | 0.67 (12) | C5_2—C6_2—C7_2—C7A_2 | 0.16 (11) |
C6_1—C7_1—C7A_1—N1_1 | −176.29 (8) | C6_2—C7_2—C7A_2—N1_2 | −179.25 (8) |
C7_1—C7A_1—N1_1—C11_1 | 1.06 (13) | C7_2—C7A_2—N1_2—C11_2 | −4.97 (14) |
C7A_1—N1_1—C11_1—C12_1 | −82.17 (10) | C7A_2—N1_2—C11_2—C12_2 | −94.36 (10) |
C8_1—N2_1—C9_1—C10_1 | 84.98 (10) | C8_2—N2_2—C9_2—C10_2 | −84.96 (10) |
C11_1—C12_1—C13_1—C14_1 | 177.37 (9) | C11_2—C12_2—C13_2—C14_2 | 178.99 (10) |
C11_1—C12_1—C13_1—C16_1 | −2.24 (12) | C11_2—C12_2—C13_2—C16_2 | −0.06 (12) |
C11_1—C12_1—N4_1—C15_1 | −177.50 (9) | C11_2—C12_2—N4_2—C15_2 | −179.04 (10) |
C12_1—C13_1—C14_1—N5_1 | 0.49 (10) | C12_2—C13_2—C14_2—N5_2 | −0.01 (11) |
C12_1—C13_1—C14_1—O2_1 | −179.87 (8) | C12_2—C13_2—C14_2—O2_2 | 179.87 (9) |
C12_1—N4_1—C15_1—N5_1 | −0.46 (10) | C12_2—N4_2—C15_2—N5_2 | 0.03 (11) |
C13_1—C14_1—N5_1—C15_1 | −1.16 (11) | C13_2—C14_2—N5_2—C15_2 | −0.37 (12) |
C13_1—C14_1—O2_1—C17_1 | −175.94 (9) | C13_2—C14_2—O2_2—C17_2 | −175.04 (10) |
C14_1—N5_1—C15_1—N4_1 | 1.18 (10) | C14_2—N5_2—C15_2—N4_2 | 0.38 (11) |
D—H···A | D—H | H···A | D···A | D—H···A |
C2_1—H2_1···O1_2i | 1.054 (12) | 2.353 (12) | 3.2907 (14) | 147.5 (9) |
C7_1—H7_1···O1_2ii | 1.031 (12) | 2.245 (13) | 3.2211 (14) | 157.4 (10) |
N2_1—H2a_1···N3_1 | 1.002 (14) | 2.035 (14) | 2.8581 (14) | 137.9 (10) |
C2_2—H2_2···N5_1 | 1.060 (13) | 2.240 (13) | 3.2922 (15) | 171.4 (9) |
C7_2—H7_2···O1_1iii | 1.059 (12) | 2.394 (12) | 3.0915 (14) | 122.3 (8) |
C11_2—H11b_2···F1_1iv | 1.092 (12) | 2.186 (12) | 3.1839 (13) | 150.7 (10) |
C16_2—H16c_2···F1_2i | 1.047 (17) | 2.403 (17) | 3.2827 (15) | 140.9 (12) |
N2_2—H2a_2···N3_2 | 1.002 (14) | 1.942 (14) | 2.7823 (13) | 139.6 (10) |
Symmetry codes: (i) −x+1, −y+1, −z; (ii) −x+2, −y+1, −z; (iii) −x+1, −y+1, −z+1; (iv) −x, −y+1, −z+1. |
Acknowledgements
We are grateful to Professor Christian W. Lehmann for providing access to the X-ray diffraction facility at the Max-Planck-Institut für Kohlenforschung (Mülheim an der Ruhr, Germany) and Dr Nadine Taudte and Dr Jens-Ulrich Rahfeld for providing and maintaining the biosafety level 2 facility.
Funding information
This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) − 432291016, and supported by a financial grant from Mukoviszidose Institut gGmbH (Bonn, Germany), the research and development arm of the German Cystic Fibrosis Association Mukoviszidose e.V. We acknowledge the financial support within the funding programme Open Access Publishing by the DFG.
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