Hostname: page-component-74656f9884-6grmk Total loading time: 0 Render date: 2026-11-06T02:24:06.225Z Has data issue: false hasContentIssue false
  • English
  • Français

Crystal structure of merimepodib, C23H24N4O6

Published online by Cambridge University Press:  19 May 2022

James A. Kaduk Open the ORCID record for James A. Kaduk [Opens in a new window] ,
Stacy Gates-Rector Open the ORCID record for Stacy Gates-Rector [Opens in a new window] ,
Amy M. Gindhart Open the ORCID record for Amy M. Gindhart [Opens in a new window]  and
Thomas N. Blanton Open the ORCID record for Thomas N. Blanton [Opens in a new window]
James A. Kaduk*
Affiliation:
Illinois Institute of Technology, 3101 S. Dearborn St., Chicago, IL 60616, USA North Central College, 131 S. Loomis St., Naperville, IL 60540, USA
Stacy Gates-Rector
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
Amy M. Gindhart
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
Thomas N. Blanton
Affiliation:
ICDD, 12 Campus Blvd., Newtown Square, PA 19073-3273, USA
*
a)Author to whom correspondence should be addressed. Electronic mail: kaduk@polycrystallography.com

Abstract

The crystal structure of merimepodib has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional theory techniques. Merimepodib crystallizes in space group P212121 (#19) with a = 4.60827(3), b = 12.30400(14), c = 37.9583(4) Å, V = 2152.241(20) Å3, and Z = 4. The crystal structure is dominated by two chains of N–H⋯O hydrogen bonds along the a-axis. The solid-state conformation has a similar general shape to the minimum-energy conformation, but different orientations of several of the rings. The differences indicate that intermolecular interactions are important in determining the solid-state conformation. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).

Keywords

merimepodibVX-497powder diffractionRietveld refinementdensity functional theory

Information

Type
New Diffraction Data
Information
Powder Diffraction , Volume 37 , Issue 3 , September 2022 , pp. 143 - 149
Check for updates
Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press on behalf of International Centre for Diffraction Data

I. INTRODUCTION

Merimepodib (also known as VX-497) is an antiviral drug that inhibits the generation of inosine monophosphate, an enzyme necessary for the synthesis of nucleotide bases containing guanine. Merimepodib was originally tested as a treatment for Hepatitis C; however, its efficacy was found to be less than that of existing treatments. There have been recent studies investigating the safety and efficacy of merimepodib (ViralClear Pharmaceuticals) in combination with remdesivir, for treatment of adults with advanced COVID-19. However, the study was halted in Phase 2 when it was concluded that the combination treatment was not adequately effective (BioSig, 2020). Merimepodib has also shown some antiviral activity against other diseases, such as Zika virus, and foot and mouth disease. The systematic name (CAS Registry Number 198821-22-6) is [(3S)-oxolan-3-yl] N-[[3-[[3-methoxy-4-(1,3-oxazol-5-yl)phenyl] carbamoylamino]phenyl]methyl]carbamate. A two-dimensional molecular diagram is shown in Figure 1.

Figure 1.

The 2D molecular structure of merimepodib.

The synthesis of merimepodib has been described by Vertex Pharmaceuticals (Jain et al., Reference Jain, Almquist, Shlyakhter and Harding2001; Looker et al., Reference Looker, Littler, Blythe, Snoonian, Ansell, Jones, Nyce, Chen and Neubert2008), as well as in several patents (Armistead et al., Reference Armistead, Badia, Bemis, Bethiel, Fank, Novak, Ronkin and Saunders1997, Reference Armistead, Badia, Bemis, Bethiel, Fank, Novak, Ronkin and Saunders1998, Reference Armistead, Badia, Bemis, Bethiel, Fank, Novak, Ronkin and Saunders2000), but no diffraction data has been published.

This work was carried out as part of a project (Kaduk et al., Reference Kaduk, Crowder, Zhong, Fawcett and Suchomel2014) to determine the crystal structures of large-volume commercial pharmaceuticals and include high-quality powder diffraction data for them in the Powder Diffraction File (Gates-Rector and Blanton, Reference Gates-Rector and Blanton2019).

II. EXPERIMENTAL

Merimepodib was a commercial reagent, purchased from TargetMol (Lot #130804), and was used as-received. The white powder was packed into a 1.5 mm diameter Kapton capillary and rotated during the measurement at ~50 Hz. The powder pattern was measured at 295 K at beamline 11-BM (Antao et al., Reference Antao, Hassan, Wang, Lee and Toby2008; Lee et al., Reference Lee, Shu, Ramanathan, Preissner, Wang, Beno, Von Dreele, Ribaud, Kurtz, Antao, Jiao and Toby2008; Wang et al., Reference Wang, Toby, Lee, Ribaud, Antao, Kurtz, Ramanathan, Von Dreele and Beno2008) of the Advanced Photon Source at Argonne National Laboratory using a wavelength of 0.458133(2) Å from 0.5 to 50° 2θ with a step size of 0.001° and a counting time of 0.1 s per step. The high-resolution powder diffraction data were collected using 12 silicon crystal analyzers that allow for high angular resolution, high precision, and accurate peak positions. A silicon (NIST SRM 640c) and alumina (SRM 676a) standard (ratio Al2O3:Si = 2:1 by weight) were used to calibrate the instrument and refine the monochromatic wavelength used in the experiment.

The pattern could be indexed on a primitive orthorhombic unit cell with a = 4.61028(21), b = 12.31085(64), c = 37.97628(183) Å, V = 2155.40(18) Å3, and Z = 4 using DICVOL14 (Louër and Boultif, Reference Louër and Boultif2014). The space group suggested by EXPO2014 (Altomare et al., Reference Altomare, Cuocci, Giacovazzo, Moliterni, Rizzi, Corriero and Falcicchio2013) was P212121, which was confirmed by successful solution and refinement of the structure. A reduced cell search in the Cambridge Structural Database (Groom et al., Reference Groom, Bruno, Lightfoot and Ward2016) yielded 14 hits, but no structures of merimepodib derivatives. Visual inspection of the pattern showed that the sample contained a NaCl impurity. During the refinement, additional peaks were noted. These corresponded to thenardite, Na2SO4-V. The concentrations of NaCl and Na2SO4 refined to 1.2 and 1.7 wt-%, respectively. We suspect that these impurities arise from a washing step during the synthesis of the compound.

A merimepodib molecule was downloaded as Conformer3D_CID_153241.sdf from PubChem (Kim et al., Reference Kim, Chen, Cheng, Gindulyte, He, He, Li, Shoemaker, Thiessen, Yu, Zaslavsky, Zhang and Bolton2019). The file was converted to a *.mol2 file using Mercury (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020) and to a Fenske-Hall Z-matrix using OpenBabel (O'Boyle et al., Reference O'Boyle, Banck, James, Morley, Vandermeersch and Hutchison2011). The structure was solved using Monte Carlo simulated annealing (parallel tempering) techniques as implemented in FOX (Favre-Nicolin and Černý, Reference Favre-Nicolin and Černý2002).

Rietveld refinement was carried out using GSAS-II (Toby and Von Dreele, Reference Toby and Von Dreele2013). Only the 1.0–30.0° portion of the pattern was included in the refinement (d min = 0.885 Å). The region 1.49–2.03° 2θ, which contains scatter from the Kapton capillary, was excluded. All non-H bond distances and angles were subjected to restraints, based on a Mercury/Mogul Geometry Check (Bruno et al., Reference Bruno, Cole, Kessler, Luo, Motherwell, Purkis, Smith, Taylor, Cooper, Harris and Orpen2004; Sykes et al., Reference Sykes, McCabe, Allen, Battle, Bruno and Wood2011). The Mogul average and standard deviation for each quantity were used as the restraint parameters. The restraints contributed 5.5% to the final χ 2. The hydrogen atoms were included in calculated positions, which were recalculated during the refinement using Materials Studio (Dassault, 2021). The U iso of the heavy atoms were grouped by chemical similarity. The U iso for the H atoms were fixed at 1.3× the U iso of the heavy atoms to which they are attached. The peak profiles were described using the generalized microstrain model. The background was modeled using a 9-term shifted Chebyshev polynomial.

The final refinement of 142 variables using 28 508 observations and 84 restraints yielded the residuals R wp = 0.0988 and GOF = 1.61. The largest peak (2.11 Å from C22) and hole (1.83 Å from C21) in the difference Fourier map were 0.51 and −0.52(14) eÅ−3, respectively. The largest errors in the difference plot (Figure 2) are in the background and some of the impurity peaks.

Figure 2.

The Rietveld plot for the refinement of merimepodib. The blue crosses represent the observed data points and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 5× for 2θ > 11.0° and by a factor of 10× for 2θ > 15.0°.

The crystal structure was optimized using VASP (Kresse and Furthmüller, Reference Kresse and Furthmüller1996) (fixed experimental unit cell) through the MedeA graphical interface (Materials Design, 2016). The calculation was carried out on 16 2.4 GHz processors (each with 4 GB RAM) of a 64-processor HP Proliant DL580 Generation 7 Linux cluster at North Central College. The calculation used the GGA-PBE functional, a plane wave cutoff energy of 400.0 eV, and a k-point spacing of 0.5 Å−1 leading to a 3 × 2 × 1 mesh, and took ~70.5 h. A single-point density functional calculation (fixed experimental cell) and population analysis were carried out using CRYSTAL17 (Dovesi et al., Reference Dovesi, Erba, Orlando, Zicovich-Wilson, Civalleri, Maschio, Rerat, Casassa, Baima, Salustro and Kirtman2018). The basis sets for the H, C, N, and O atoms in the calculation were those of Gatti et al. (Reference Gatti, Saunders and Roetti1994). The calculations were run on a 3.5 GHz PC using 8 k-points and the B3LYP functional, and took ~3.0 h.

III. RESULTS AND DISCUSSION

The root-mean-square (rms) Cartesian displacement between the Rietveld-refined and DFT-optimized structures is 0.159 Å (Figure 3), within the normal range for correct structures (van de Streek and Neumann, Reference van de Streek and Neumann2014). This discussion concentrates on the DFT-optimized structure. The asymmetric unit (with atom numbering) is illustrated in Figure 4. The best view of the crystal structure is down the short a-axis (Figure 5), but this view obscures the principal hydrogen bonds, discussed below. This view illustrates mainly van der Waals interactions.

Figure 3.

Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of merimepodib. The rms Cartesian displacement is 0.149 Å.

Figure 4.

The asymmetric unit of merimepodib, with the atom numbering. The atoms are represented by 50% probability spheroids.

Figure 5.

The crystal structure of merimepodib, viewed down the a-axis. Figure generated using Diamond (Crystal Impact, 2021)

All of the bond distances and angles fall within the normal ranges indicated by a Mercury/Mogul Geometry check (Macrae et al., Reference Macrae, Sovago, Cottrell, Galek, McCabe, Pidcock, Platings, Shields, Stevens, Towler and Wood2020). The torsion angles involving rotation about the C19–N8 and C23–N9 bonds are flagged as unusual. These torsion angles fall on the tails of bimodal 0/180° distributions of similar torsion angles. They reflect the orientation of the ends of the molecule around the central urea core and may indicate the effect of intramolecular interactions on the molecular conformation.

Quantum chemical geometry optimization of the merimepodib molecule (DFT/B3LYP/6-31G*/water) using Spartan ‘18 (Wavefunction, 2020) indicated that the observed conformation is 8.7 kcal mol−1 higher in energy than the local minimum, which has different orientations of the C14–C19 phenyl ring and the oxazole ring. A conformational analysis (MMFF force field) shows that the global minimum-energy conformation is a further 1.5 kcal mol−1 lower in energy. The minimum-energy conformation has a similar general shape (Figure 6), but different orientations of several of the rings. The differences indicate that intermolecular interactions are important in determining the solid-state conformation.

Figure 6.

Comparison of the solid-state conformation (blue) and the minimum-energy conformation (orange) of an isolated merimepodib molecule.

Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault, 2021) suggests that angle and torsion distortion terms dominate the intramolecular deformation energy. The intermolecular energy is dominated by electrostatic attractions, which in this force field analysis also include hydrogen bonds. The hydrogen bonds are better analyzed using the results of the DFT calculation.

Hydrogen bonds are prominent in the structure (Table I). The most important are N–H⋯O hydrogen bonds (Figure 7). Both urea nitrogen atoms N9 and N8 act as donors to the urea O atom O6. Both hydrogen bonds form a pattern with graph set (Etter, Reference Etter1990; Bernstein et al., Reference Bernstein, Davis, Shimoni and Chang1995; Shields et al., Reference Shields, Raithby, Allen and Motherwell2000) C1,1(4), and link the molecules along the a-axis. Similarly, the amide nitrogen atom N53 acts as a donor to the amide oxygen atom O3, also form a C1,1(4) chain along the a-axis. The energies of the N–H⋯O hydrogen bonds were calculated using the correlation of Wheatley and Kaduk (Reference Wheatley and Kaduk2019). Several inter- and intra-molecular C–H⋯O and C–H⋯N hydrogen bonds also contribute to the crystal energy.

Figure 7.

The N–H⋯O hydrogen bond chains in merimepodib.

TABLE I.

Hydrogen bonds (CRYSTAL17) in merimepodib

a Intramolecular.

The volume enclosed by the Hirshfeld surface (Figure 8; Hirshfeld, Reference Hirshfeld1977; Turner et al., Reference Turner, McKinnon, Wolff, Grimwood, Spackman, Jayatilaka and Spackman2017) is 528.29 Å3, 98.18% of 1/4 the unit cell volume. The packing density is thus fairly typical. The only significant-close contacts (red in Figure 8) involve the hydrogen bonds. The volume/non-hydrogen atom is smaller than normal, at 16.3 Å3.

Figure 8.

The Hirshfeld surface of merimepodib. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of the radii are white.

The Bravais–Friedel–Donnay–Harker (Bravais, Reference Bravais1866; Friedel, Reference Friedel1907; Donnay and Harker, Reference Donnay and Harker1937) morphology suggests that we might expect needle-like morphology for merimepodib, with 〈100〉 as the long axis, consistent with the anisotropy of the lattice parameters. A second-order spherical harmonic model was included in the refinement. The texture index was 1.036(1), indicating that preferred orientation was slight for this phase. Both the NaCl and Na2SO4 impurities exhibited significant preferred orientation (perhaps a reflection of granularity of these minor phases). The powder pattern of merimepodib from this synchrotron dataset has been submitted to ICDD for inclusion in the Powder Diffraction File.

IV. DEPOSITED DATA

The Crystallographic Information Framework (CIF) files containing the results of the Rietveld refinement (including the raw data) and the DFT geometry optimization were deposited with the ICDD. The data can be requested at .

ACKNOWLEDGEMENTS

The use of the Advanced Photon Source at Argonne National Laboratory was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. This work was partially supported by the International Centre for Diffraction Data. We thank Lynn Ribaud and Saul Lapidus for their assistance in the data collection.

CONFLICTS OF INTEREST

The authors have no conflicts of interest to declare.

References

Altomare, A., Cuocci, C., Giacovazzo, C., Moliterni, A., Rizzi, R., Corriero, N., and Falcicchio, A. (2013). “EXPO2013: a kit of tools for phasing crystal structures from powder data,” J. Appl. Crystallogr. 46, 1231–1235.CrossRefGoogle Scholar
Antao, S. M., Hassan, I., Wang, J., Lee, P. L., and Toby, B. H. (2008). “State-of-the-art high-resolution powder X-ray diffraction (HRPXRD) illustrated with Rietveld refinement of quartz, sodalite, tremolite, and meionite,” Can. Mineral. 46, 1501–1509.CrossRefGoogle Scholar
Armistead, D. M., Badia, M. C., Bemis, G. W., Bethiel, R. S., Fank, C. A., Novak, P. M., Ronkin, S. M., and Saunders, J. O. (1997). “Urea derivatives as inhibitors of IMPDH enzyme,” International Patent Application WO 97/40028.Google Scholar
Armistead, D. M., Badia, M. C., Bemis, G. W., Bethiel, R. S., Fank, C. A., Novak, P. M., Ronkin, S. M., and Saunders, J. O. (1998). “Inhibitors of IMPDH enzyme,” US Patent 5,807,876.Google Scholar
Armistead, D. M., Badia, M. C., Bemis, G. W., Bethiel, R. S., Fank, C. A., Novak, P. M., Ronkin, S. M., and Saunders, J. O. (2000). “Inhibitors of IMPDH enzyme,” US Patent 6,054,472.Google Scholar
Bernstein, J., Davis, R. E., Shimoni, L., and Chang, N. L. (1995). “Patterns in hydrogen bonding: functionality and graph set analysis in crystals,” Angew. Chem., Int. Ed. Engl. 34(15), 1555–1573.CrossRefGoogle Scholar
BioSig (2020). https://ir.biosig.com/press-releases/detail/234/viralclear-halts-its-phase-2-hospitalized-covid-19-trial (accessed January 20, 2020).Google Scholar
Bravais, A. (1866). Etudes Cristallographiques (Gauthier Villars, Paris).Google Scholar
Bruno, I. J., Cole, J. C., Kessler, M., Luo, J., Motherwell, W. D. S., Purkis, L. H., Smith, B. R., Taylor, R., Cooper, R. I., Harris, S. E., and Orpen, A. G. (2004). “Retrieval of crystallographically-derived molecular geometry information,” J. Chem. Inf. Comput. Sci. 44, 2133–2144.CrossRefGoogle ScholarPubMed
Crystal Impact - Dr. H. Putz & Dr. K. Brandenburg (2021). Diamond - Crystal and Molecular Structure Visualization (Kreuzherrenstr. 102, 53227 Bonn, Germany). Available at: https://www.crystalimpact.de/diamond.Google Scholar
Dassault Systèmes (2021). Materials Studio 2021 (BIOVIA, San Diego, CA).Google Scholar
Donnay, J. D. H., and Harker, D. (1937). “A new law of crystal morphology extending the law of Bravais,” Am. Mineral. 22, 446–447.Google Scholar
Dovesi, R., Erba, A., Orlando, R., Zicovich-Wilson, C. M., Civalleri, B., Maschio, L., Rerat, M., Casassa, S., Baima, J., Salustro, S., and Kirtman, B. (2018). “Quantum-mechanical condensed matter simulations with CRYSTAL,” Wiley Interdiscip. Rev.: Comput. Mol. Sci. 8, e1360.Google Scholar
Etter, M. C. (1990). “Encoding and decoding hydrogen-bond patterns of organic compounds,” Acc. Chem. Res. 23(4), 120–126.CrossRefGoogle Scholar
Favre-Nicolin, V., and Černý, R. (2002). “FOX, “free objects for crystallography: a modular approach to ab initio structure determination from powder diffraction,” J. Appl. Crystallogr. 35, 734–743.CrossRefGoogle Scholar
Friedel, G. (1907). “Etudes sur la loi de bravais,” Bull. Soc. Fr. Mineral. 30, 326–455.Google Scholar
Gates-Rector, S., and Blanton, T. (2019). “The Powder Diffraction File: a quality materials characterization database,” Powder Diffr. 39(4), 352–360.CrossRefGoogle Scholar
Gatti, C., Saunders, V. R., and Roetti, C. (1994). “Crystal-field effects on the topological properties of the electron-density in molecular crystals - the case of urea,” J. Chem. Phys. 101, 10686–10696.CrossRefGoogle Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P., and Ward, S. C. (2016). “The Cambridge Structural Database,” Acta Crystallogr. Sect. B: Struct. Sci., Cryst. Eng. Mater. 72, 171–179.CrossRefGoogle ScholarPubMed
Hirshfeld, F. L. (1977). “Bonded-atom fragments for describing molecular charge densities,” Theor. Chim. Acta 44, 129–138.CrossRefGoogle Scholar
Jain, J., Almquist, S. J., Shlyakhter, D., and Harding, M. W. (2001). “VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent,” J. Pharm. Sci. 90, 625–637.3.0.CO;2-1>CrossRefGoogle ScholarPubMed
Kaduk, J. A., Crowder, C. E., Zhong, K., Fawcett, T. G., and Suchomel, M. R. (2014). “Crystal structure of atomoxetine hydrochloride (strattera), C17H22NOCl,” Powder Diffr. 29(3), 269–273.CrossRefGoogle Scholar
Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S., Li, Q., Shoemaker, B. A., Thiessen, P. A., Yu, B., Zaslavsky, L., Zhang, J., and Bolton, E. E. (2019). “PubChem 2019 update: improved access to chemical data,” Nucleic Acids Res. 47(D1), D1102–D1109. doi:10.1093/nar/gky1033.CrossRefGoogle ScholarPubMed
Kresse, G., and Furthmüller, J. (1996). “Efficiency of ab-initio total energy calculations for metals and semiconductors using a plane-wave basis set,” Comput. Mater. Sci. 6, 15–50.CrossRefGoogle Scholar
Lee, P. L., Shu, D., Ramanathan, M., Preissner, C., Wang, J., Beno, M. A., Von Dreele, R. B., Ribaud, L., Kurtz, C., Antao, S. M., Jiao, X., and Toby, B. H. (2008). “A twelve-analyzer detector system for high-resolution powder diffraction,” J. Synchrotron Radiat. 15(5), 427–432.CrossRefGoogle ScholarPubMed
Looker, A. R., Littler, B. J., Blythe, T. A., Snoonian, J. R., Ansell, G. K., Jones, A. D., Nyce, P., Chen, M., and Neubert, B. J. (2008). “Development and manufacture of the inosine monophosphate dehydrogenase inhibitor merimepodib, VX-497,” Org. Process Res. Dev. 12, 666–673.CrossRefGoogle Scholar
Louër, D., and Boultif, A. (2014). “Some further considerations in powder diffraction pattern indexing with the dichotomy method,” Powder Diffr. 29, S7–S12.CrossRefGoogle 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., and Wood, P. A. (2020). “Mercury 4.0: from visualization to design and prediction,” J. Appl. Crystallogr. 53, 226–235.CrossRefGoogle ScholarPubMed
Materials Design (2016). MedeA 2.20.4 (Materials Design Inc., Angel Fire, NM).Google Scholar
O'Boyle, N., Banck, M., James, C. A., Morley, C., Vandermeersch, T., and Hutchison, G. R. (2011). “Open Babel: an open chemical toolbox,” J. Cheminformatics 3, 33. doi:10.1186/1758-2946-3-33.CrossRefGoogle ScholarPubMed
Shields, G. P., Raithby, P. R., Allen, F. H., and Motherwell, W. S. (2000). “The assignment and validation of metal oxidation states in the Cambridge Structural Database,” Acta Crystallogr. Sect. B: Struct. Sci., Cryst. Eng. Mater. 56(3), 455–465.CrossRefGoogle ScholarPubMed
Sykes, R. A., McCabe, P., Allen, F. H., Battle, G. M., Bruno, I. J., and Wood, P. A. (2011). “New software for statistical analysis of Cambridge Structural Database data,” J. Appl. Crystallogr. 44, 882–886.CrossRefGoogle Scholar
Toby, B. H., and Von Dreele, R. B. (2013). “GSAS II: the genesis of a modern open source all purpose crystallography software package,” J. Appl. Crystallogr. 46, 544–549.CrossRefGoogle Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D., and Spackman, M. A. (2017). CrystalExplorer17 (University of Western Australia). Available at: http://hirshfeldsurface.net.Google Scholar
van de Streek, J., and Neumann, M. A. (2014). “Validation of molecular crystal structures from powder diffraction data with dispersion-corrected density functional theory (DFT-D),” Acta Crystallogr. Sect. B: Struct. Sci., Cryst. Eng. Mater. 70(6), 1020–1032.CrossRefGoogle Scholar
Wang, J., Toby, B. H., Lee, P. L., Ribaud, L., Antao, S. M., Kurtz, C., Ramanathan, M., Von Dreele, R. B., and Beno, M. A. (2008). “A dedicated powder diffraction beamline at the advanced photon source: commissioning and early operational results,” Rev. Sci. Instrum. 79, 085105.CrossRefGoogle ScholarPubMed
Wavefunction, Inc. (2020). Spartan ‘18 Version 1.4.5 (Wavefunction Inc., 18401 Von Karman Ave., Suite 370, Irvine, CA 92612).Google Scholar
Wheatley, A. M., and Kaduk, J. A. (2019). “Crystal structures of ammonium citrates,” Powder Diffr. 34, 35–43.CrossRefGoogle Scholar
Figure 0

Figure 1. The 2D molecular structure of merimepodib.

Figure 1

Figure 2. The Rietveld plot for the refinement of merimepodib. The blue crosses represent the observed data points and the green line is the calculated pattern. The cyan curve is the normalized error plot. The vertical scale has been multiplied by a factor of 5× for 2θ > 11.0° and by a factor of 10× for 2θ > 15.0°.

Figure 2

Figure 3. Comparison of the Rietveld-refined (red) and VASP-optimized (blue) structures of merimepodib. The rms Cartesian displacement is 0.149 Å.

Figure 3

Figure 4. The asymmetric unit of merimepodib, with the atom numbering. The atoms are represented by 50% probability spheroids.

Figure 4

Figure 5. The crystal structure of merimepodib, viewed down the a-axis. Figure generated using Diamond (Crystal Impact, 2021)

Figure 5

Figure 6. Comparison of the solid-state conformation (blue) and the minimum-energy conformation (orange) of an isolated merimepodib molecule.

Figure 6

Figure 7. The N–H⋯O hydrogen bond chains in merimepodib.

Figure 7

TABLE I. Hydrogen bonds (CRYSTAL17) in merimepodib

Figure 8

Figure 8. The Hirshfeld surface of merimepodib. Intermolecular contacts longer than the sums of the van der Waals radii are colored blue, and contacts shorter than the sums of the radii are colored red. Contacts equal to the sums of the radii are white.