Crystal Structures of New Ivermectin Pseudopolymorphs
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthesis of Ivermectin Pseudopolymorphs
2.2. Single Crystal X-ray Diffraction
2.3. Modeling and Quantitative Analysis of Crystal Structures
2.4. Thermal Analysis
3. Results
3.1. Molecular Structure in the Crystal Cell
3.2. Qualitative Analysis of Intermolecular Interactions: Hirshfeld Surface and 2D Fingerprint Plots
3.3. Intermolecular Interaction Energy of IVM Ethanol Solvate I
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
- Campbell, W.; Fisher, M.; Stapley, E.; Albers-Schonberg, G.; Jacob, T. Ivermectin: A potent new antiparasitic agent. Science 1983, 221, 823–828. [Google Scholar] [CrossRef] [PubMed]
- Crump, A. Ivermectin: Enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J. Antibiot. 2017, 70, 495–505. [Google Scholar] [CrossRef] [Green Version]
- Ashour, D.S. Ivermectin: From theory to clinical application. Int. J. Antimicrob. Agents 2019, 54, 134–142. [Google Scholar] [CrossRef]
- Laing, R.; Gillan, V.; Devaney, E. Ivermectin—Old Drug, New Tricks? Trends Parasitol. 2017, 33, 463–472. [Google Scholar] [CrossRef] [Green Version]
- Perez-Garcia, L.A.; Mejias-Carpio, I.E.; Delgado-Noguera, L.A.; Manzanarez-Motezuma, J.P.; Escalona-Rodriguez, M.A.; Sordillo, E.M.; Mogollon-Rodriguez, E.A.; Hernandez-Pereira, C.E.; Marquez-Colmenarez, M.C.; Paniz-Mondolfi, A.E. Ivermectin: Repurposing a multipurpose drug for Venezuela’s humanitarian crisis. Int. J. Antimicrob. Agents 2020, 56, 106037. [Google Scholar] [CrossRef] [PubMed]
- Juarez, M.; Schcolnik-Cabrera, A.; Dueñas-Gonzalez, A. The multitargeted drug ivermectin: From an antiparasitic agent to a repositioned cancer drug. Am. J. Cancer Res. 2018, 8, 317–331. [Google Scholar]
- Laudisi, F.; Marônek, M.; Di Grazia, A.; Monteleone, G.; Stolfi, C. Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System. IJMS 2020, 21, 4957. [Google Scholar] [CrossRef]
- Mudassar, F.; Shen, H.; O’Neill, G.; Hau, E. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J. Exp. Clin. Cancer Res. 2020, 39, 208. [Google Scholar] [CrossRef] [PubMed]
- Tang, M.; Hu, X.; Wang, Y.; Yao, X.; Zhang, W.; Yu, C.; Cheng, F.; Li, J.; Fang, Q. Ivermectin, a potential anticancer drug derived from an antiparasitic drug. Pharmacol. Res. 2020, 105207. [Google Scholar] [CrossRef]
- Sahni, D.R.; Feldman, S.R.; Taylor, S.L. Ivermectin 1% (CD5024) for the treatment of rosacea. Expert Opin. Pharmacother. 2018, 19, 511–516. [Google Scholar] [CrossRef]
- McGregor, S.P.; Alinia, H.; Snyder, A.; Tuchayi, S.M.; Fleischer, A.; Feldman, S.R. A Review of the Current Modalities for the Treatment of Papulopustular Rosacea. Dermatol. Clin. 2018, 36, 135–150. [Google Scholar] [CrossRef]
- Feaster, B.; Cline, A.; Feldman, S.R.; Taylor, S. Clinical effectiveness of novel rosacea therapies. Curr. Opin. Pharmacol. 2019, 46, 14–18. [Google Scholar] [CrossRef]
- Heidary, F.; Gharebaghi, R. Ivermectin: A systematic review from antiviral effects to COVID-19 complementary regimen. J. Antibiot. 2020, 73, 593–602. [Google Scholar] [CrossRef] [PubMed]
- Jans, D.A.; Wagstaff, K.M. Ivermectin as a Broad-Spectrum Host-Directed Antiviral: The Real Deal? Cells 2020, 9, 2100. [Google Scholar] [CrossRef]
- Sen Gupta, P.S.; Rana, M.K. Ivermectin, Famotidine, and Doxycycline: A Suggested Combinatorial Therapeutic for the Treatment of COVID-19. Acs Pharmacol. Transl. Sci. 2020, 3, 1037–1038. [Google Scholar] [CrossRef]
- Rajter, J.C.; Sherman, M.S.; Fatteh, N.; Vogel, F.; Sacks, J.; Rajter, J.-J. ICON (Ivermectin in COvid Nineteen) study: Use of Ivermectin is Associated with Lower Mortality in Hospitalized Patients with COVID19; Public and Global Health. 2020. Available online: https://www.medrxiv.org/content/10.1101/2020.06.06.20124461v2 (accessed on 2 February 2021).
- Gupta, D.; Sahoo, A.K.; Singh, A. Ivermectin: Potential candidate for the treatment of Covid 19. Braz. J. Infect. Dis. 2020, 24, 369–371. [Google Scholar] [CrossRef]
- Healy, A.M.; Worku, Z.A.; Kumar, D.; Madi, A.M. Pharmaceutical solvates, hydrates and amorphous forms: A special emphasis on cocrystals. Adv. Drug Deliv. Rev. 2017, 117, 25–46. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pindelska, E.; Sokal, A.; Kolodziejski, W. Pharmaceutical cocrystals, salts and polymorphs: Advanced characterization techniques. Adv. Drug Deliv. Rev. 2017, 117, 111–146. [Google Scholar] [CrossRef]
- Calvo, N.L.; Maggio, R.M.; Kaufman, T.S. Chemometrics-assisted solid-state characterization of pharmaceutically relevant materials. Polymorphic substances. J. Pharm. Biomed. Anal. 2018, 147, 518–537. [Google Scholar] [CrossRef] [PubMed]
- Springer, J.P.; Arison, B.H.; Hirshfield, J.M.; Hoogsteen, K. The absolute stereochemistry and conformation of avermectin B2a aglycone and avermectin B1a. J. Am. Chem. Soc. 1981, 103, 4221–4224. [Google Scholar] [CrossRef]
- Keates, A.C. CCDC 1904192: Experimental Crystal Structure Determination 2019. Available online: https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=1904192&DatabaseToSearch=Published (accessed on 3 February 2021).
- Jelínkova, I.; Vávra, V.; Jindrichova, M.; Obsil, T.; Zemkova, H.W.; Zemkova, H.; Stojilkovic, S.S. Identification of P2X4 receptor transmembrane residues contributing to channel gating and interaction with ivermectin. Pflug. Arch. Eur. J. Physiol. 2008, 456, 939–950. [Google Scholar] [CrossRef]
- Huang, X.; Chen, H.; Shaffer, P.L. Crystal Structures of Human GlyRα3 Bound to Ivermectin. Structure 2017, 25, 945–950.e2. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grobler, M.L.J. Genome-Wide Analysis of Wolbachia-Host Interactions. Master’s Thesis, North-West University, Potchefstroom, South Africa, 2000. [Google Scholar]
- Rolim, L.A.; dos Santos, F.C.M.; Chaves, L.L.; Gonçalves, M.L.C.M.; Freitas-Neto, J.L.; da Silva do Nascimento, A.L.; Soares-Sobrinho, J.L.; de Albuquerque, M.M.; do Carmo Alves de Lima, M.; Rolim-Neto, P.J. Preformulation study of ivermectin raw material. J. Anal. Calorim. 2015, 120, 807–816. [Google Scholar] [CrossRef]
- Starkloff, W.J.; Bucalá, V.; Palma, S.D.; Gonzalez Vidal, N.L. Design and in vitro characterization of ivermectin nanocrystals liquid formulation based on a top–down approach. Pharm. Dev. Technol. 2017, 22, 809–817. [Google Scholar] [CrossRef] [PubMed]
- Lu, M.; Xiong, D.; Sun, W.; Yu, T.; Hu, Z.; Ding, J.; Cai, Y.; Yang, S.; Pan, B. Sustained release ivermectin-loaded solid lipid dispersion for subcutaneous delivery: In vitro and in vivo evaluation. Drug Deliv. 2017, 24, 622–631. [Google Scholar] [CrossRef] [Green Version]
- Seppala, E.; Kolehmainen, E.; Osmialowski, B.; Gawinecki, R. CCDC 187337: Experimental Crystal Structure Determination 2005. Available online: https://www.ccdc.cam.ac.uk/structures/Search?Ccdcid=187337&DatabaseToSearch=Published (accessed on 3 February 2021).
- Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Cryst. A Found. Adv. 2015, 71, 3–8. [Google Scholar] [CrossRef] [Green Version]
- Sheldrick, G.M. A short history of SHELX. Acta Cryst. A Found. Cryst. 2008, 64, 112–122. [Google Scholar] [CrossRef] [Green Version]
- Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H. OLEX2: A complete structure solution, refinement and analysis program. J. Appl. Cryst. 2009, 42, 339–341. [Google Scholar] [CrossRef]
- Turner, M.J.; McKinnon, J.J.; Wolff, S.K.; Grimwood, D.J.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. CrystalExplorer17; The University of Western Australia: Perth, WA, Australia, 2017. [Google Scholar]
- McKinnon, J.J.; Jayatilaka, D.; Spackman, M.A. Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem. Commun. 2007, 3814. [Google Scholar] [CrossRef]
- Spackman, M.A.; Jayatilaka, D. Hirshfeld surface analysis. CrystEngComm 2009, 11, 19–32. [Google Scholar] [CrossRef]
- Mackenzie, C.F.; Spackman, P.R.; Jayatilaka, D.; Spackman, M.A. CrystalExplorer model energies and energy frameworks: Extension to metal coordination compounds, organic salts, solvates and open-shell systems. IUCrJ 2017, 4, 575–587. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bochevarov, A.D.; Harder, E.; Hughes, T.F.; Greenwood, J.R.; Braden, D.A.; Philipp, D.M.; Rinaldo, D.; Halls, M.D.; Zhang, J.; Friesner, R.A. Jaguar: A high-performance quantum chemistry software program with strengths in life and materials sciences. Int. J. Quantum Chem. 2013, 113, 2110–2142. [Google Scholar] [CrossRef]
- Saršūns, K.; Bērziņš, A.; Rekis, T. Solid Solutions in the Xanthone–Thioxanthone Binary System: How Well Are Similar Molecules Discriminated in the Solid State? Cryst. Growth Des. 2020, 20, 7997–8004. [Google Scholar] [CrossRef]
- Marczenko, K.M.; Mercier, H.P.A.; Schrobilgen, G.J. A Stable Crown Ether Complex with a Noble-Gas Compound. Angew. Chem. Int. Ed. 2018, 57, 12448–12452. [Google Scholar] [CrossRef] [PubMed]
- Popov, I.; Chen, T.-H.; Belyakov, S.; Daugulis, O.; Wheeler, S.E.; Miljanić, O.Š. Macrocycle Embrace: Encapsulation of Fluoroarenes by m -Phenylene Ethynylene Host. Chem. A Eur. J. 2015, 21, 2750–2754. [Google Scholar] [CrossRef] [PubMed]
- Turner, M.J.; Grabowsky, S.; Jayatilaka, D.; Spackman, M.A. Accurate and Efficient Model Energies for Exploring Intermolecular Interactions in Molecular Crystals. J. Phys. Chem. Lett. 2014, 5, 4249–4255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Parameter | I at Low Temperature | I at Room Temperature | II | III |
---|---|---|---|---|
Empirical formula | (IVM) × C2H5OH × 0.75H2O | (IVM) × C2H5OH × 0.75H2O | 2(IVM) × 0.5C5H8O2 | 2(IVM) × 0.5C5H12O |
Formula weight | 931.85 | 931.85 | 1794.59 | 1787.605 |
Temperature (K) | 173 | 293 | 160 | 160 |
Crystal size (mm3) | 0.21 × 0.11 × 0.08 | 0.17 × 0.09 × 0.06 | 0.22 × 0.16 × 0.11 | 0.21 × 0.17 × 0.12 |
Crystal system | Monoclinic | Monoclinic | Orthorhombic | Orthorhombic |
Space group | I2 | I2 | P212121 | P212121 |
a (Å) | 14.8197(7) | 14.8612(9) | 16.7127(2) | 16.7309(1) |
b (Å) | 9.1753(5) | 9.1973(6) | 24.5777(2) | 24.5805(2) |
c (Å) | 39.094(2) | 39.201(4) | 24.5908(2) | 24.5797(2) |
β (°) | 94.490(5) | 95.04(5) | 90.0 | 90.0 |
Unit cell volume (Å3) | 5299.5(5) | 5337.4(7) | 10100.9(2) | 10108.5(1) |
Molecular multiplicity | 4 | 4 | 4 | 4 |
Calculated density (g/cm3) | 1.168 | 1.161 | 1.180 | 1.175 |
Measured density (g/cm3) | 1.16 | |||
Absorption coefficient (mm−1) | 0.703 | 0.698 | 0.702 | 0.696 |
F(000) | 2023.5 | 2023.5 | 3887.2 | 3875.2 |
2θmax (°) | 156.0 | 150.0 | 155.0 | 155.0 |
Reflections collected | 29158 | 5217 | 71647 | 75795 |
Number of independent reflections | 9710 | - | 20489 | 20330 |
Reflections with I>2σ(I) | 9485 | - | 18694 | 19029 |
Number of refined parameters | 601 | - | 1143 | 1143 |
R-factors (for I>2σ(I) and for all data) | 0.0971, 0.0982 | - | 0.0981, 0.1051 | 0.0972, 0.1010 |
Symmetry | R/Å | Eele kJ/mol | Epol kJ/mol | Edis kJ/mol | Erep kJ/mol | Etot kJ/mol | Contact 1 |
---|---|---|---|---|---|---|---|
x, y, z | 9.18 | −4.4 | −1.7 | −46.8 | 23.4 | −32.3 | IVM-IVM |
−x + 1/2, y + 1/2, −z + 1/2 | 10.42 | −12.5 | −1.9 | −87.1 | 50.1 | −59.5 | IVM-IVM |
−x + 1/2, y + 1/2, −z + 1/2 | 17.43 | −3.3 | −0.4 | −18.5 | 10.4 | −13.4 | IVM-IVM |
x, y, z | 14.82 | −43.3 | −13.6 | −56.2 | 57 | −69.6 | IVM-IVM HBS |
−x, y, −z | 11.35 | −8.8 | −4.6 | −77.2 | 62.4 | −41.3 | IVM-IVM |
−x, y, −z | 14.60 | −5 | −1.4 | −8.7 | 4.1 | −11.5 | IVM-IVM |
−x, y, −z | 22.32 | 0 | −0.1 | −6.3 | 3.2 | −3.6 | IVM-IVM |
- | 2.65 | −14.5 | −3 | −40.6 | 27.9 | −35.7 | IVM-EtOH |
x, y, z | 17.43 | −1 | −4.3 | −47.9 | 29.7 | −27.7 | IVM-IVM |
- | 7.28 | −1.7 | −0.6 | −13.3 | 7.7 | −9.1 | IVM-EtOH |
- | 12.39 | 0.5 | −0.1 | −1.9 | 0.1 | −1.2 | IVM-EtOH |
−x, y, −z | 14.10 | −0.6 | −0.8 | −22 | 3.8 | −18 | IVM-IVM |
- | 13.5 | −35.4 | −7.8 | −12.2 | 37.8 | −30.5 | IVM-EtOH HB |
- | 14.9 | −1.1 | −0.1 | −2.9 | 1.6 | −2.8 | IVM-EtOH |
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Shubin, K.; Bērziņš, A.; Belyakov, S. Crystal Structures of New Ivermectin Pseudopolymorphs. Crystals 2021, 11, 172. https://doi.org/10.3390/cryst11020172
Shubin K, Bērziņš A, Belyakov S. Crystal Structures of New Ivermectin Pseudopolymorphs. Crystals. 2021; 11(2):172. https://doi.org/10.3390/cryst11020172
Chicago/Turabian StyleShubin, Kirill, Agris Bērziņš, and Sergey Belyakov. 2021. "Crystal Structures of New Ivermectin Pseudopolymorphs" Crystals 11, no. 2: 172. https://doi.org/10.3390/cryst11020172
APA StyleShubin, K., Bērziņš, A., & Belyakov, S. (2021). Crystal Structures of New Ivermectin Pseudopolymorphs. Crystals, 11(2), 172. https://doi.org/10.3390/cryst11020172