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Nitroimidazoles Part 10. Synthesis, crystal structure, molecular docking, and anticancer evaluation of 4-nitroimidazole derivatives combined with piperazine moiety

  • Yaseen A. Al-Soud ORCID logo EMAIL logo , Sadeekah O. W. Saber , Amneh Shtaiwi , Sondos O. Alsawakhneh , Kafa’ A. S. Alhelal , Qusay F. A. Salman , Luay Abu-Qatouseh , Monther A. Khanfar and Raed A. Al-Qawasmeh EMAIL logo
Published/Copyright: May 20, 2022
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Zeitschrift für Naturforschung C
From the journal Zeitschrift für Naturforschung C Volume 78 Issue 3-4

Abstract

Piperazine-tagged imidazole derivatives 3a (symmetrical di-substituted piperazine) and 5–11 were synthesized through the combination of 4-nitroimidazole derivatives with piperazine moiety. The structural characterization was done by different physical and spectral techniques like NMR (1H and 13C) and mass spectrometry. The constituency of compound 3a was confirmed by X-ray structural analyses. All compounds were assessed for their antiproliferative inhibition potency against five human cancer cell lines namely MCF-7, PC3, MDA-231, A549 and Fibro dental. Compound 5 was found to be the most potent anticancer agents against MCF-7 cell line with IC50 values of (1.0 ± 0 µm) and against PC3 with IC50 value of (9.00 ± 0.028 µm). The molecular docking of compound 5 had been studied, and the results revealed that the newly designed 4-nitroimidazole combined with piperazine moiety derivatives bond to the hydrophobic pocket and polar contacts with high affinity.

Keywords: antitumor activity; imidazoles; piprazines; synthesis; X-ray structures
Corresponding authors: Yaseen A. Al-Soud, Department of Chemistry, Faculty of Science, Al al-Bayt University, Al-Mafraq, Jordan, E-mail: ; and Raed A. Al-Qawasmeh, Department of Chemistry, Pure and Applied Chemistry Group, College of Sciences, University of Sharjah, 27272 Sharjah, UAE; and Department of Chemistry, The University of Jordan, 11942 Amman, Jordan, E-mail:
Nitroimidazoles Part 9: ref. [21]

Funding source: Ministry of Higher Education, Jordan

Award Identifier / Grant number: Grant No. Bas 1/1/2017

Acknowledgements

Authors wish to thank the Scientific Research Support Fund/Ministry of Higher Education, Jordan (grant No. Bas 1/1/2017) for providing necessary facilities and funds for conducting this research. We are grateful to the Middle East University, MEU, Jordan for the academic license of the software’s used in this research article.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Ministry of Higher Education, Jordan (Grant No. Bas 1/1/2017).

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

References

1. Khabnadideh, S, Rezaci, Z, Khalafi, NA, Motazedian, MH, Eskandari, M. Synthesis of metronidazole derivatives as antigiardiasis agents. DARU J Pharm Sci 2007;15:17–20.Search in Google Scholar

2. Leitsch, D. A review on metronidazole: an old warhorse in antimicrobial chemotherapy. Parasitology 2019;146:1167–78. https://doi.org/10.1017/s0031182017002025.Search in Google Scholar PubMed

3. Stettendorf, S. Bifonazole – a synopsis of clinical trials worldwide. Dermatology 1984;169:69–76. https://doi.org/10.1159/000249642.Search in Google Scholar PubMed

4. Hage, SE, Lajoie, B, Feuillolay, C, Roques, C, Baziard, G. Synthesis, antibacterial and antifungal activities of bifonazole derivatives. Arch Pharm Chem Life Sci 2011;11:402–10. https://doi.org/10.1002/ardp.201000304.Search in Google Scholar PubMed

5. Josephy, PD, Palcic, B, Skarsgard, LD. In vitro metabolism of misonidazole. Br J Cancer 1981;43:443–50. https://doi.org/10.1038/bjc.1981.65.Search in Google Scholar PubMed PubMed Central

6. Ceruelos, AH, Romero-Quezada, LC, Ledezma, JR, Contreras, LL. Therapeutic uses of metronidazole and its side effects: an update. Eur Rev Med Pharmacol Sci 2019;23:397–401.Search in Google Scholar

7. Che, H, Tuyen, TN, Kim, HP, Park, H. 1,5-Diarylimidazoles with strong inhibitory activity against COX-2 catalyzed PGE2 production from LPS-induced RAW 264.7 cells. Bioorg Med Chem Lett 2010;20:4035–7. https://doi.org/10.1016/j.bmcl.2010.05.092.Search in Google Scholar PubMed

8. Almansa, C, Alfón, J, de Arriba, AF, Cavalcanti, FL, Escamilla, I, Gómez, LA, et al.. Synthesis and structure−activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles. J Med Chem 2003;46:3463–75. https://doi.org/10.1021/jm030765s.Search in Google Scholar PubMed

9. Ren, JS, Nichols, C, Bird, LE, Fujiwara, T, Sugimoto, H, Stuart, DI, et al.. Binding of the second generation non-nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding. J Biol Chem 2000;275:14316–20. https://doi.org/10.1074/jbc.275.19.14316.Search in Google Scholar PubMed

10. Mearin, F, Guarner, F, Verdú, E. Probióticos y aparato digestivo. Evidencias actuales. Gastroenterol Hepatol 2009;32:1–14. https://doi.org/10.1016/s0210-5705(09)71003-9.Search in Google Scholar PubMed

11. Kitbunnadaj, R, Zuiderveld, OP, Christophe, B, Hulscher, S, Menge, WM, Gelens, E, et al.. Identification of 4-(1H-Imidazol-4(5)-ylmethyl)pyridine (Immethridine) as a novel, potent, and highly selective histamine H3 receptor agonist. J Med Chem 2004;47:2414–7. https://doi.org/10.1021/jm049932u.Search in Google Scholar PubMed

12. Varaschin, RK, Rosenberg, MJ, Hamilton, DA, Savage, DD. Differential effects of the histamine H3 receptor agonist Methimepip on dentate granule cell excitability, paired-pulse plasticity and long-term potentiation in prenatal alcohol-exposed rats. Alcohol Clin Exp Res 2014;38:1902–11. https://doi.org/10.1111/acer.12430.Search in Google Scholar PubMed PubMed Central

13. Senn‐Bilfinger, J, Sturm, E. The development of a new proton-pump inhibitor: the case history of Pantoprazole. In: Fischer, J, Ganellin, CR, editors. Analogue-based drug discovery. Weinheim: Wiley-VCH; 2006:115–36 pp. chapter 6.10.1002/3527608001.ch6Search in Google Scholar

14. Al-Masoudi, NA, Al-Soud, YA, Kalogerakis, A, Pannecouque, C, De Clercq, E. Nitroimidazoles, part 2. Chem Biodivers 2006;3:515–26. https://doi.org/10.1002/cbdv.200690055.Search in Google Scholar PubMed

15. Al-Masoudi, NA, Al-Soud, YA, Clercq, ED, Pannecouque, C. Nitroimidazoles part 6. Synthesis, structure and in vitro anti-HIV activity of new 5-substituted piperazinyl-4-nitroimidazole derivatives. Antiviral Chem Chemother 2007;18:191–200. https://doi.org/10.1177/095632020701800403.Search in Google Scholar PubMed

16. Al-Soud, YA, Al-Masoudi, NA, Hassan, H, Clercq, ED, Pannecouque, C. Nitroimidazoles. V. Synthesis and anti-HIV evaluation of new 5-substituted piperazinyl-4-nitroimidazole derivatives. Acta Pharm 2007;57:379–93. https://doi.org/10.2478/v10007-007-0031-7.Search in Google Scholar PubMed

17. Al-Soud, YA, Al-Sa’doni, H, Amajaour, HA, Al-Masoudi, NA. Nitroimidazoles, part 3. Synthesis and anti-HIV activity of new N-alkyl-4-nitroimidazoles bearing benzothiazole and benzoxazole backbones. Z Naturforsch 2007;62b:523–8. https://doi.org/10.1515/znb-2007-0406.Search in Google Scholar

18. Al‐Soud, YA, Al‐Masoudi, NA, Clercq, ED, Paneccoque, C. Nitroimidazoles, part 4: synthesis and anti-HIV activity of new 5-alkylsulfanyl and 5-(4′-arylsulfonyl)piperazinyl-4-nitroimidazole derivatives. Heteroat Chem 2007;18:333–40.10.1002/hc.20301Search in Google Scholar

19. Al-Soud, YA, Al-Masoudi, NA, Al-Suod, HH, Pannecouque, C. Nitroimidazoles part 8. Synthesis and anti-HIV activity of new 4-nitroimidazole derivatives using the Suzuki cross-coupling reaction. Z Naturforsch 2012;67b:925–34. https://doi.org/10.5560/znb.2012-0185.Search in Google Scholar

20. Al-Qawasmeh, RA, Young, AH, Huesca, M, Lee, Y. 2,4,5-Trisubstituted imidazoles and their use as anti-microbial agents. USP 7884120 B2, 2011.Search in Google Scholar

21. Al-Soud, YA, Al-Ahmad, AH, Abu-Qatouseh, L, Shtaiwi, A, Alhelal, KAS, Al-Suod, HH, et al.. Nitroimidazoles part 9. Synthesis, molecular docking, and anticancer evaluations of piperazine-tagged imidazole derivatives. Z Naturforsch 2021;76b:293–302. https://doi.org/10.1515/znb-2020-0200.Search in Google Scholar

22. Al-Soud, YA, Alhelal, KAS, Saeed, BA, Abu-Qatouseh, L, Al-Suod, HH, Al-Ahmad, AH, et al.. Synthesis, anticancer activity and molecular docking studies of new 4-nitroimidazole derivatives. Arkivoc 2021:296–309. part viii. https://doi.org/10.24820/ark.5550190.p011.479.Search in Google Scholar

23. Abdel-Jalil, RJ, Al-Qawasmeh, RA, Voelter, W, Heeg, P, El-Abadelah, MM, Sabri, SS. Synthesis and properties of some 2,3-disubstituted 6-fluoro-7-(4-methyl-1-piperazinyl)quinoxalines. J Heterocycl Chem 2000;37:1273–5. https://doi.org/10.1002/jhet.5570370541.Search in Google Scholar

24. Zheng, H, Weiner, LM, Bar-Am, O, Epsztejn, S, Cabantchik, ZI, Warshawsky, A, et al.. Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Bioorg Med Chem 2005;13:773–83. https://doi.org/10.1016/j.bmc.2004.10.037.Search in Google Scholar PubMed

25. Najafi, M, Shayesteh, MRH, Mortezaee, K, Farhood, B, Haghi-Aminjan, H. The role of melatonin on doxorubicin-induced cardiotoxicity: a systematic review. Life Sci 2020;241:117173. https://doi.org/10.1016/j.lfs.2019.117173.Search in Google Scholar PubMed

26. Guo, J, Xu, B, Han, Q, Zhou, H, Xia, Y, Gong, C, et al.. Ferroptosis: a novel anti-tumor action for Cisplatin. Cancer Res Treat 2018;50:445–60. https://doi.org/10.4143/crt.2016.572.Search in Google Scholar PubMed PubMed Central

27. Noble, ME, Endicott, JA, Johnson, LN. Protein kinase inhibitors: insights into drug design from structure. Science 2004;303:1800–5. https://doi.org/10.1126/science.1095920.Search in Google Scholar PubMed

28. Pardo, OE, Castellano, L, Munro, CE, Hu, Y, Mauri, F, Krell, J, et al.. MiR-515-5p controls cancer cell migration through MARK 4 regulation. EMBO Rep 2016;17:570–84. https://doi.org/10.15252/embr.201540970.Search in Google Scholar PubMed PubMed Central

29. Rovina, D, Fontana, L, Monti, L, Novielli, C, Panini, N, Maria Sirchia, S, et al.. Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) plays a role in cell cycle progression and cytoskeletal dynamics. Eur J Cell Biol 2014;93:355–65.10.1016/j.ejcb.2014.07.004Search in Google Scholar PubMed

30. Heidary, A, Emad, AS, Siyuan, S, Liliana, A. MARK4 inhibits Hippo signaling to promote proliferation and migration of breast cancer cells. EMBO Rep 2017;18:420–36. https://doi.org/10.15252/embr.201642455.Search in Google Scholar PubMed PubMed Central

31. Kemphues, K. PARsing embryonic polarity. Cell 2000;101:345–8. https://doi.org/10.1016/s0092-8674(00)80844-2.Search in Google Scholar PubMed

32. Marx, A, Nugoor, C, Panneerselvam, S, Mandelkow, E. Structure and function of polarity-inducing kinase family MARK/Par-1 within the branch of AMPK/Snf1-related kinases. Faseb J 2010;24:1637–48. https://doi.org/10.1096/fj.09-148064.Search in Google Scholar PubMed

33. Morris, GM, Huey, R, Lindstrom, W, Sanner, MF, Belew, RK, Goodsell, DS, et al.. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–91. https://doi.org/10.1002/jcc.21256.Search in Google Scholar PubMed PubMed Central

34. Dennington, R, Keith, T, Millam, J. GaussView, version 5. Shawnee Mission, KS: Semichem Inc.; 2009.Search in Google Scholar

35. Stewart, JJ. Optimization of parameters for semiempirical methods II. Applications. J Comput Chem 1989;10:221–64. https://doi.org/10.1002/jcc.540100209.Search in Google Scholar

36. Frisch, M, Trucks, G, Schlegel, H, Scuseria, G, Robb, M, Cheeseman, J, et al.. Gaussian 03, revision C. 02. Wallingford, CT: Gaussian, Inc.; 2004:26 p.Search in Google Scholar

37. Morris, GM, Goodsell, DS, Halliday, RS, Huey, R, Hart, WE, Belew, RK, et al.. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem 1998;19:1639–62. https://doi.org/10.1002/(sici)1096-987x(19981115)19:14<1639::aid-jcc10>3.0.co;2-b.10.1002/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-BSearch in Google Scholar

38. BIOVIA discovery studio. Discovery studio modeling environment. San Diego, USA: Dassault Systȇmes; 2020.Search in Google Scholar

39. Pettersen, EF, Goddard, TD, Huang, CC, Couch, GS, Greenblatt, DM, Meng, EC, et al.. UCSF Chimera? a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605–12. https://doi.org/10.1002/jcc.20084.Search in Google Scholar

40. Dolomanov, OV, Bourhis, LJ, Gildea, RJ, Howard, JAK, Puschmann, HJ. OLEX2: a complete structure solution, refinement and analysis program. Appl Cryst 2009;42:339–41. https://doi.org/10.1107/s0021889808042726.Search in Google Scholar

41. Sheldrick, GM. SHELXT-integrated space-group and crystal-structure determination. Acta Crystallogr A 2015;71:3–8. https://doi.org/10.1107/s2053273314026370.Search in Google Scholar

42. Sheldrick, GM. Crystal structure refinement with SHELXL. Acta Crystallogr C 2015;71:3–8. https://doi.org/10.1107/S2053229614024218.Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2022-0023).

Received: 2022-02-03
Accepted: 2022-04-30
Published Online: 2022-05-20
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Organic chemistry and medicinal applications
  4. Research Articles
  5. Nitroimidazoles Part 10. Synthesis, crystal structure, molecular docking, and anticancer evaluation of 4-nitroimidazole derivatives combined with piperazine moiety
  6. Antibacterial, antioxidant, and cytotoxic activities of Syzygium aromaticum (L.) Merr. & Perry essential oil with identification of its chemical constituents
  7. Design, synthesis and antimicrobial assessments of aminoacetylenic-piperazine nitroimidazole hybrid compounds
  8. Design, synthesis, and molecular docking study of novel cinnoline derivatives as potential inhibitors of tubulin polymerization
  9. Thiophene ring-opening reactions VI. Attempted cyclization towards [fused]-tricyclic system involving a thiolate anion and suitably located electrophilic carbon
  10. Thermodynamic control synthesis of spiro[oxindole-3,3′-pyrrolines] via 1,4-dipolar cycloaddition utilizing imidazo[1,5-a]quinoline
  11. Bioactive secondary metabolites from Trichoderma viride MM21: structure elucidation, molecular docking and biological activity
  12. 8-Amino-7-(aryl/hetaryl)fluoroquinolones. An emerging set of synthetic antibacterial agents
https://doi.org/10.1515/znc-2022-0023
Keywords for this article
antitumor activity; imidazoles; piprazines; synthesis; X-ray structures

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Organic chemistry and medicinal applications
  4. Research Articles
  5. Nitroimidazoles Part 10. Synthesis, crystal structure, molecular docking, and anticancer evaluation of 4-nitroimidazole derivatives combined with piperazine moiety
  6. Antibacterial, antioxidant, and cytotoxic activities of Syzygium aromaticum (L.) Merr. & Perry essential oil with identification of its chemical constituents
  7. Design, synthesis and antimicrobial assessments of aminoacetylenic-piperazine nitroimidazole hybrid compounds
  8. Design, synthesis, and molecular docking study of novel cinnoline derivatives as potential inhibitors of tubulin polymerization
  9. Thiophene ring-opening reactions VI. Attempted cyclization towards [fused]-tricyclic system involving a thiolate anion and suitably located electrophilic carbon
  10. Thermodynamic control synthesis of spiro[oxindole-3,3′-pyrrolines] via 1,4-dipolar cycloaddition utilizing imidazo[1,5-a]quinoline
  11. Bioactive secondary metabolites from Trichoderma viride MM21: structure elucidation, molecular docking and biological activity
  12. 8-Amino-7-(aryl/hetaryl)fluoroquinolones. An emerging set of synthetic antibacterial agents
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