Structural characterization and anti­mycobacterial evaluation of a benzimidazole analogue of the anti­tuberculosis clinical drug candidate TBA-7371

Richter, A.; Goddard, R.; Schönefeld, R.; Imming, P.; Seidel, R.W.

doi:10.1107/S2056989022010556

research communications

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 78| Part 12| December 2022| Pages 1184-1188

https://doi.org/10.1107/S2056989022010556

Open

access

Structural characterization and antimycobacterial evaluation of a benzimidazole analogue of the antituberculosis clinical drug candidate TBA-7371

Adrian Richter,^a Richard Goddard,^b Roy Schönefeld,^a Peter Imming ^a and Rüdiger W. Seidel ^a ^*

^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

Edited by L. Van Meervelt, Katholieke Universiteit Leuven, Belgium (Received 21 October 2022; accepted 1 November 2022; online 8 November 2022)

The crystal structure and 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 structure determination was achieved using Hirshfeld atom refinement. Compound 1 crystallizes in the triclinic system (space group P $[\overline{1}]$ ) with two molecules in the asymmetric unit (Z′ = 2). The two crystallographically distinct molecules exhibit a similar conformation with the amide groups in a Z conformation, forming an intramolecular N_amide—H⋯N_{benzimidazole} hydrogen bond. The most significant supramolecular feature in the solid-state is a relatively short C_{benzimidazole}—H⋯N_pyrimidine hydrogen bond. Antimycobacterial testing confirmed in vitro activity against Mycobacterium smegmatis, but no growth inhibtion of Mycobacterium abscessus was found.

Keywords: 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).

Figure 1
Scaffold morphing of 1,4-azaindole in TBA-7371 to benzimidazole in 1 (Manjunatha et al., 2019

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 chromatography, resulting in an approximate 3.75:1 ratio. Compound C was identified by ¹H and ¹³C NMR spectroscopy and APCI mass spectrometry (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.

Figure 2
Synthesis of 1, following the published procedure (Manjunatha et al., 2019

). Reagents and solvents: (a) 4-(chloromethyl)-6-methoxy-5-methylpyrimidine, Cs₂CO₃, NaI, DMF; (b) LiOH, MeOH; (c) HATU, 2-fluoroethanamine, NMP.

2. Structural commentary

Compound 1 crystallizes in the triclinic space group P $[\overline{1}]$ 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 asymmetric unit thus exhibit the same handedness, but the corresponding oppositely handed conformers are present in the centrosymmetric crystal structure. 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.

Figure 3
Asymmetric unit of 1. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented by small spheres of arbitrary radius. Dashed lines represent hydrogen bonds. The number after the underscore indicates unique molecule 1 or 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 ).

Table 1
Hydrogen-bond geometry (Å, °)

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_1^iv	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) ; (ii) ; (iii) ; (iv) .

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 crystal structure, 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.

Figure 4
Section of the crystal structure of 1, showing π–π stacking between the 6-methoxy-5-methylpyrimidin-4-yl moiety and the benzimidazole system in adjacent molecules. The distance between the centroids of the two six-membered rings (thin dashed line) is 3.6164 (11) Å. Thick dashed lines represent hydrogen bonds. Carbon-bound H atoms have been omitted for clarity. Symmetry code: (i) −x + 1, −y + 1, −z.

Figure 5
View of the triclinic unit cell of 1, showing the stacking of benzimidazole and 6-methoxy-5-methylpyrimidin moieties in an AABB fashion in the b^*-axis direction. Dashed lines represent hydrogen bonds. H atoms have been omitted for clarity, except for amide and amidine H atoms.

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 crystal structure of its non-covalent complex with M. tuberculosis DprE1 (PDB code: 4FDO; Batt et al., 2012 ), as shown in Fig. 6.

Figure 6
Structure overlay of the benzene rings of the two unique molecules of 1 (molecule 1: green; molecule 2: orange) and the benzene ring of CT319 in the crystal structure of its non-covalent complex with M. tuberculosis DprE1 (pink; PDB code: 4FDO; resolution: 2.4 Å), showing the similar conformations of the benzamide moieties.

5. Antimycobacterial evaluation

Manjunatha et al. (2019) reported an in vitro minimal inhibitory concentration (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 refinement with SHELXL2018/3 (Sheldrick, 2015b ). The final structure refinement was carried out by Hirshfeld atom refinement 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 refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₇H₁₈FN₅O₂
M_r	343.36
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	100
a, b, c (Å)	7.6940 (19), 15.013 (4), 15.281 (4)
α, β, γ (°)	71.040 (4), 77.874 (5), 87.780 (4)
V (Å³)	1631.3 (7)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.10 × 0.05 × 0.02

Data collection
Diffractometer	Bruker Kappa Mach3 APEXII
Absorption correction	Gaussian (SADABS; Krause et al., 2015 )
T_min, T_max	0.994, 0.999
No. of measured, independent and observed [I ≥ 2u(I)] reflections	58016, 8147, 6141
R_int	0.048
(sin θ/λ)_max (Å⁻¹)	0.671

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.031, 0.072, 1.07
No. of reflections	8147
No. of parameters	595
H-atom treatment	All H-atom parameters refined
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.32
Computer programs: APEX3 (Bruker, 2017 ), SAINT (Bruker, 2004 ), SHELXT (Sheldrick, 2015a ), OLEX2.refine (Bourhis et al., 2015 ), DIAMOND (Brandenburg, 2018 ), Mercury (Macrae et al., 2020 ), enCIFer (Allen et al., 2004 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 2216847

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989022010556/vm2273sup1.cif

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

checkCIF report

Computing details top

Data collection: APEX3 (Bruker, 2017); cell refinement: 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).

N-(2-Fluoroethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1,3-benzodiazole-4-carboxamide top

Crystal data top

C₁₇H₁₈FN₅O₂	Z = 4
M_r = 343.36	F(000) = 720
Triclinic, P1	D_x = 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

Data collection top

Bruker AXS Kappa Mach3 APEX II diffractometer	8147 independent reflections
Radiation source: Incoatec IµS	6141 reflections with I ≥ 2u(I)
Incoatec Helios mirrors monochromator	R_int = 0.048
Detector resolution: 66.67 pixels mm^-1	θ_max = 28.5°, θ_min = 1.4°
φ– and ω–scans	h = −10→10
Absorption correction: gaussian (SADABS; Krause et al., 2015)	k = −20→20
T_min = 0.994, T_max = 0.999	l = −20→19
58016 measured reflections

Refinement top

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(F_o²) + (0.0302P)² + 0.1357P] where P = (F_o² + 2F_c²)/3
8147 reflections	(Δ/σ)_max = −0.001
595 parameters	Δρ_max = 0.34 e Å⁻³
0 restraints	Δρ_min = −0.32 e Å⁻³
0 constraints

Special details top

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.

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

	x	y	z	U_iso*/U_eq
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)

Atomic displacement parameters (Å²) top

	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)

Geometric parameters (Å, º) top

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)

Hydrogen-bond geometry (Å, º) top

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_1^iv	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.

References

Allen, F. H., Johnson, O., Shields, G. P., Smith, B. R. & Towler, M. (2004). J. Appl. Cryst. 37, 335–338. Web of Science CrossRef CAS IUCr Journals Google Scholar
Batt, S. M., Jabeen, T., Bhowruth, V., Quill, L., Lund, P. A., Eggeling, L., Alderwick, L. J., Fütterer, K. & Besra, G. S. (2012). Proc. Natl Acad. Sci. USA, 109, 11354–11359. Web of Science CrossRef CAS PubMed Google Scholar
Becke, A. D. (1993). J. Chem. Phys. 98, 5648–5652. CrossRef CAS Web of Science Google Scholar
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555–1573. CrossRef CAS Web of Science Google Scholar
Boudehen, Y. M. & Kremer, L. (2021). Trends Microbiol. 29, 951–952. Web of Science CrossRef CAS PubMed Google Scholar
Bourhis, L. J., Dolomanov, O. V., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2015). Acta Cryst. A71, 59–75. Web of Science CrossRef IUCr Journals Google Scholar
Brandenburg, K. (2018). DIAMOND. Crystal Impact GbR, Bonn, Germany. Google Scholar
Bruker (2004). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Bruker (2017). APEX3. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Burley, S. K., Berman, H. M., Bhikadiya, C., Bi, C., Chen, L., DiCostanzo, L., Christie, C., Dalenberg, K., Duarte, J. M., Dutta, S., Feng, Z., Ghosh, S., Goodsell, D. S., Green, R. K., Guranović, V., Guzenko, D., Hudson, B. P., Kalro, T., Liang, Y., Lowe, R., Namkoong, H., Peisach, E., Periskova, I., Prlić, A., Randle, C., Rose, A., Rose, P., Sala, R., Sekharan, M., Shao, C., Tan, L., Tao, Y.-P., Valasatava, Y., Voigt, M., Westbrook, J., Woo, J., Yang, H., Young, J., Zhuravleva, M. & Zardecki, C. (2019). Nucleic Acids Res. 47, D464–D474. Web of Science CrossRef CAS PubMed Google Scholar
CCDC (2017). CSD web interface – intuitive, cross-platform, web-based access to CSD data. Cambridge Crystallographic Data Centre, Cambridge, England. Google Scholar
Chikhale, R. V., Barmade, M. A., Murumkar, P. R. & Yadav, M. R. (2018). J. Med. Chem. 61, 8563–8593. Web of Science CrossRef CAS PubMed Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Etter, M. C. (1990). Acc. Chem. Res. 23, 120–126. CrossRef CAS Web of Science Google Scholar
Ganapathy, U. S. & Dick, T. (2022). Molecules, 27, 6948. Web of Science CrossRef PubMed Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Kitaigorodskii, A. I. (1973). Molecular crystals and molecules. London: Academic Press. Google Scholar
Kleemiss, F., Dolomanov, O. V., Bodensteiner, M., Peyerimhoff, N., Midgley, M., Bourhis, L. J., Genoni, A., Malaspina, L. A., Jayatilaka, D., Spencer, J. L., White, F., Grundkötter-Stock, B., Steinhauer, S., Lentz, D., Puschmann, H. & Grabowsky, S. (2021). Chem. Sci. 12, 1675–1692. Web of Science CSD CrossRef CAS Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Lee, C., Yang, W. & Parr, R. G. (1988). Phys. Rev. B, 37, 785–789. CrossRef CAS Web of Science Google Scholar
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. Web of Science CrossRef CAS IUCr Journals Google Scholar
Manjunatha, M. R., Radha Shandil, R., Panda, M., Sadler, C., Ambady, A., Panduga, V., Kumar, N., Mahadevaswamy, J., Sreenivasaiah, M., Narayan, A., Guptha, S., Sharma, S., Sambandamurthy, V. K., Ramachandran, V., Mallya, M., Cooper, C., Mdluli, K., Butler, S., Tommasi, R., Iyer, P. S., Narayanan, S., Chatterji, M. & Shirude, P. S. (2019). ACS Med. Chem. Lett. 10, 1480–1485. Web of Science PubMed Google Scholar
Midgley, L., Bourhis, L. J., Dolomanov, O. V., Grabowsky, S., Kleemiss, F., Puschmann, H. & Peyerimhoff, N. (2021). Acta Cryst. A77, 519–533. Web of Science CrossRef IUCr Journals Google Scholar
Neese, F., Wennmohs, F., Becker, U. & Riplinger, C. (2020). J. Chem. Phys. 152, 224108. Web of Science CrossRef PubMed Google Scholar
Richter, A., Strauch, A., Chao, J., Ko, M. & Av-Gay, Y. (2018). Antimicrob. Agents Chemother. 62, e00828–18. Web of Science CrossRef CAS PubMed Google Scholar
Sarathy, J. P., Zimmerman, M. D., Gengenbacher, M., Dartois, V. & Thomas Dick, T. (2022). bioRxiv 2022.09.14.508059; doi: 10.1101/2022.09.14.508059. Google Scholar
Sheldrick, G. M. (2015a). Acta Cryst. A71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Sheldrick, G. M. (2015b). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Shetye, G. S., Franzblau, S. G. & Cho, S. (2020). Transl. Res. 220, 68–97. Web of Science CrossRef CAS PubMed Google Scholar
Shirude, P. S., Shandil, R., Sadler, C., Naik, M., Hosagrahara, V., Hameed, S., Shinde, V., Bathula, C., Humnabadkar, V., Kumar, N., Reddy, J., Panduga, V., Sharma, S., Ambady, A., Hegde, N., Whiteaker, J., McLaughlin, R. E., Gardner, H., Madhavapeddi, P., Ramachandran, V., Kaur, P., Narayan, A., Guptha, S., Awasthy, D., Narayan, C., Mahadevaswamy, J., Vishwas, K. G., Ahuja, V., Srivastava, A., Prabhakar, K. R., Bharath, S., Kale, R., Ramaiah, M., Choudhury, N. R., Sambandamurthy, V. K., Solapure, S., Iyer, P. S., Narayanan, S. & Chatterji, M. (2013). J. Med. Chem. 56, 9701–9708. Web of Science CrossRef CAS PubMed Google Scholar
Shirude, P. S., Shandil, R. K., Manjunatha, M. R., Sadler, C., Panda, M., Panduga, V., Reddy, J., Saralaya, R., Nanduri, R., Ambady, A., Ravishankar, S., Sambandamurthy, V. K., Humnabadkar, V., Jena, L. K., Suresh, R. S., Srivastava, A., Prabhakar, K. R., Whiteaker, J., McLaughlin, R. E., Sharma, S., Cooper, C. B., Mdluli, K., Butler, S., Iyer, P. S., Narayanan, S. & Chatterji, M. (2014). J. Med. Chem. 57, 5728–5737. Web of Science CrossRef CAS PubMed Google Scholar
Spek, A. L. (2020). Acta Cryst. E76, 1–11. Web of Science CrossRef IUCr Journals Google Scholar
Thakuria, R., Sarma, B. & Nangia, A. (2017). Hydrogen Bonding in Molecular Crystals. In Comprehensive Supramolecular Chemistry II, vol. 7, edited by J. L. Atwood, pp. 25–48. Oxford: Elsevier. Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
Wood, P. A., Allen, F. H. & Pidcock, E. (2009). CrystEngComm, 11, 1563–1571. Web of Science CrossRef CAS Google Scholar
Ziółkowska, N. E., Michejda, C. J. & Bujacz, G. D. (2010). J. Mol. Struct. 966, 53–58. Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.