Influence of metal complex formation on the biological activity of metronidazole: spectroscopic, DFT calculation, in vitro and in silico biological activity
-
Hennia Slaouti
,
Fayrouz Djellouli
Abstract
In the present study, the interaction between an ethanolic solution of metronidazole (C6H9N3O3), hereafter denoted as MTZ, and aqueous solutions of three transition metal ions Iron(III), Cobalt(II), and Nickel(II) was investigated. This interaction led to the formation of three monomeric complexes, C1, C2, and C3, with the respective molecular formulas [Fe(C6H9N3O3)2Cl3·H2O]·H2O, Co(C6H9N3O3)4Cl2, and Ni(C6H9N3O3)3Cl2·H2O. The chemical compositions of these complexes were confirmed by elemental (CHNS and metal) analysis, FTIR, Raman, 1H NMR, magnetic susceptibility, and electronic absorption spectroscopy. The combined results indicate that all complexes are monomeric and that metronidazole coordinates to the metal center in a monodentate manner through the imidazole nitrogen. Spectroscopic and magnetic data further support an octahedral geometry for the complexes. The biological properties of the synthesized complexes were assessed through in vitro antibacterial and antifungal assays against both aerobic and anaerobic strains. Among the tested compounds, the C2 complex exhibited notable inhibitory activity against Enterococcus faecalis and Staphylococcus aureus. Additionally, in silico molecular docking studies were performed to simulate the interactions between the complexes and selected biological targets. The docking results revealed strong binding affinities toward epidermal growth factor receptor (EGFR), a tyrosine kinase enzyme implicated in several cancer types, and dihydropteroate synthase (DHPS), an essential enzyme in the bacterial folate pathway. These findings highlight the promising antibacterial and anticancer potential of the synthesized complexes. Furthermore, the molecular structures of the complexes were optimized using density functional theory (DFT) calculations to support the experimental observations.
-
Research ethics: Not applicable.
-
Informed consent: Not applicable.
-
Author contributions: H.S: Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. F.D: Writing – original draft, Visualization, Formal analysis, Conceptualization. B.C: Writing – original draft, Visualization, Methodology, Formal analysis, Writing – review & editing. Z.S: Software, DFT calculations. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
-
Use of Large Language Models, AI and Machine Learning Tools: To improve language.
-
Conflict of interest: The authors state no conflict of interest.
-
Research funding: None declared.
-
Data availability: Available upon request.
References
1. Hernández Ceruelos, A.; Romero-Quezada, L. C.; Ruvalcaba Ledezma, J. C.; López Contreras, L. Therapeutic Uses of Metronidazole and its Side Effects: An Update. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 397.Suche in Google Scholar
2. Ingham, H. R.; Selkon, J. B.; Hale, J. H. The Antibacterial Activity of Metronidazole. J. Antimicrob. Chemother. 1975, 1, 355; https://doi.org/10.1093/jac/1.4.355.Suche in Google Scholar PubMed
3. Löfmark, S.; Edlund, C.; Nord, C. E. Metronidazole is Still the Drug of Choice for Treatment of Anaerobic Infections. Clin. Infect. Dis. 2010, 50, S16; https://doi.org/10.1086/647939.Suche in Google Scholar PubMed
4. Athar, F.; Husain, K.; Abid, M.; Agarwal, S. M.; Coles, S. J.; Hursthouse, M. B.; Maurya, M. R.; Azam, A. Synthesis and Anti-Amoebic Activity of Gold(I), Ruthenium(II), and Copper(II) Complexes of Metronidazole. Chem. Biodiversity 2005, 2, 1320–1330; https://doi.org/10.1002/cbdv.200590104.Suche in Google Scholar PubMed
5. Żyro, D.; Radko, L.; Śliwińska, A.; Chęcińska, L.; Kusz, J.; Korona-Głowniak, I.; Przekora, A.; Wójcik, M.; Posyniak, A.; Ochocki, J. Multifunctional Silver(I) Complexes with Metronidazole Drug Reveal Antimicrobial Properties and Antitumor Activity Against Human Hepatoma and Colorectal Adenocarcinoma Cells. Cancers 2022, 14 (4), 900; https://doi.org/10.3390/cancers14040900.Suche in Google Scholar PubMed PubMed Central
6. Mohamed, H. B.; Mekkawy, A. I.; Mahmoud, A. Z.; Fathalla, D.; Fouad, E. A. A Green Chemistry Approach for Preparation of Metronidazole-Zinc (ІІ) Complexes: In Vitro Characterization, Antimicrobial Activity and Promising Cytotoxicity. J. Drug Deliv. Sci. Technol. 2024, 95, 105616; https://doi.org/10.1016/j.jddst.2024.105616.Suche in Google Scholar
7. Gaur, A. Comparative Antimicrobial Activity of Metronidazole and it’s Metal Complexes Against Anaerobic Pathogens. Int. J. Appl. Res. 2025, 11 (8), 186–192; https://doi.org/10.22271/allresearch.2025.v11.i8c.12788.Suche in Google Scholar
8. Al-Khodir, F. A. I.; Refat, M. S. Investigation of Coordination Ability of Mn(II), Fe(III), Co(II), Ni(II), and Cu(II) with Metronidazole, the Antiprotozoal Drug, in Alkaline Media: Synthesis and Spectroscopic Studies. Russ. J. Gen. Chem. 2017, 87 (4), 873–879; https://doi.org/10.1134/S107036321704034X.Suche in Google Scholar
9. Galván-Tejada, N.; Bernès, S.; Castillo-Blum, S. E.; Nöth, H.; Vicente, R.; Barba-Behrens, N. Supramolecular Structures of Metronidazole and its Copper(II), Cobalt(II) and Zinc(II) Coordination Compounds. J. Inorg. Biochem. 2002, 91 (1), 339–348; https://doi.org/10.1016/S0162-0134(02)00468-3.Suche in Google Scholar
10. Chang, E. L.; Simmers, C.; Knight, D. A. Cobalt Complexes as Antiviral and Antibacterial Agents. Pharmaceuticals 2010, 3, 1711; https://doi.org/10.3390/ph3061711.Suche in Google Scholar PubMed PubMed Central
11. Munteanu, C. R.; Suntharalingam, K. Advances in Cobalt Complexes as Anticancer Agents. Dalton Trans. 2015, 44, 13796–13808; https://doi.org/10.1039/c5dt02101d.Suche in Google Scholar PubMed
12. Bouché, M.; Hognon, C.; Grandemange, S.; Monari, A.; Gros, P. C. Recent Advances in Iron-Complexes as Drug Candidates for Cancer Therapy: Reactivity, Mechanism of Action and Metabolites. Dalton Trans. 2020, 49 (33), 11451; https://doi.org/10.1039/D0DT02135Kï.10.1039/D0DT02135KSuche in Google Scholar
13. Sharma, B.; Shukla, S.; Rattan, R.; Fatima, M.; Goel, M.; Bhat, M.; Dutta, S.; Ranjan, R. K.; Sharma, M. Antimicrobial Agents Based on Metal Complexes: Present Situation and Future Prospects. Int. J. Biomater. 2022, 2022, 6819080; https://doi.org/10.1155/2022/6819080.Suche in Google Scholar PubMed PubMed Central
14. Hildebrandt, J.; Häfner, N.; Görls, H.; Barth, M.-C.; Dürst, M.; Runnebaum, I. B.; Weigand, W. Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues. Int. J. Mol. Sci. 2022, 23 (12), 6669; https://doi.org/10.3390/ijms23126669.Suche in Google Scholar PubMed PubMed Central
15. Li, Y.; Dong, J.; Zhao, P.; Hu, P.; Yang, D.; Gao, L.; Li, L.; Pettinari, C. Synthesis of Amino Acid Schiff Base Nickel (II) Complexes as Potential Anticancer Drugs in Vitro. Bioinorg. Chem. Appl. 2020, 2020, 8834859; https://doi.org/10.1155/2020/8834859.Suche in Google Scholar PubMed PubMed Central
16. Odisitse, S.; Matshwele, J. T. P.; Mazimba, O.; Demissie, T. B.; Moseki, M.; Julius, L. G.; Jongman, M.; Nareetsile, F. Nickel Mixed Ligand Complexes Against Drug Resistant Bacteria: Synthesis, Characterization, Antibacterial Activities and Molecular Docking Studies. Results Chem. 2023, 6, 101098; https://doi.org/10.1016/j.rechem.2023.101098.Suche in Google Scholar
17. Sarkar, D.; Mandal, B.; Pramanik, A.; Haldar, A.; Das, D.; Ganguly, R.; Mandal, D.; Bhattacharyya, S. Synthesis, Structure, and Mechanism of Action of a Unique Mixed-Ligand Nickel (II)-Complex of Tetra-Dentate Phenol-Based Ligand with Di-Aquo Co-Ligands with Significant Pro-Apoptotic and Anti-Metastatic Effect Against Malignant Human Cancer Cells. Inorg. Chim. Acta 2024, 569, 122136; https://doi.org/10.1016/j.ica.2024.122136.Suche in Google Scholar
18. Donaldson, J. R.; Warner, S. L.; Cates, R. G.; Gary Young, D. Assessment of Antimicrobial Activity of Fourteen Essential Oils When Using Dilution and Diffusion Methods. Pharm. Biol. 2005, 43 (8), 687–695; https://doi.org/10.1080/13880200500384932.Suche in Google Scholar
19. Ali, A. E.; Elasala, G. S.; Ibrahim, R. S. Synthesis, Characterization, Spectral, Thermal Analysis and Biological Activity Studies of Metronidazole Complexes. J. Mol. Struct. 2019, 1176, 673–684; https://doi.org/10.1016/j.molstruc.2018.08.095.Suche in Google Scholar
20. Bourouai, M. A.; Bouchoucha, A.; Si Larbi, K.; Cosnier, S.; Djebbar, S. Novel Mn(II) and Cu(II) Metal Complexes with Sulfa Drug-Derived Ligands as Potent Antimicrobial and Anticancer Agents: In Vitro Studies, ADMET Profile and Molecular Docking. Polyhedron 2024, 253, 116914; https://doi.org/10.1016/j.poly.2024.116914.Suche in Google Scholar
21. Al-Majedy, Y. K.; Al-Amiery, A. A.; Kadhum, A. A. H.; Mohamad, A. B. Antioxidant Activities of 4-Methylumbelliferone Derivatives. PLoS One 2016, 11 (5), e0156625; https://doi.org/10.1371/journal.pone.0156625.Suche in Google Scholar PubMed PubMed Central
22. Yun, M. K.; Wu, Y.; Li, Z.; Zhao, Y.; Waddell, M. B.; Ferreira, A. M.; Lee, R. E.; Bashford, D.; White, S. W. Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase. Science 2012, 335 (6072), 1110–1114; https://doi.org/10.1126/science.1214641.Suche in Google Scholar PubMed PubMed Central
23. Park, J. H.; Liu, Y.; Lemmon, M. A.; Radhakrishnan, R. Erlotinib Binds Both Inactive and Active Conformations of the EGFR Tyrosine Kinase Domain. Biochem. J. 2012, 448 (3), 417–423; https://doi.org/10.1042/BJ20121513.Suche in Google Scholar PubMed PubMed Central
24. Madhavi Sastry, G.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and Ligand Preparation: Parameters, Protocols, and Influence on Virtual Screening Enrichments. J. Comput. Aided Mol. Des. 2013, 27 (3), 221–234; https://doi.org/10.1007/s10822-013-9644-8.Suche in Google Scholar PubMed
25. Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.; Olson, A. J. AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility. J. Comput. Chem. 2009, 30 (16), 2785–2791; https://doi.org/10.1002/jcc.21256.Suche in Google Scholar PubMed PubMed Central
26. Santos-Martins, D.; Forli, S.; Ramos, M. J.; Olson, A. J. AutoDock4Zn: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins. J. Chem. Inf. Model. 2014, 54 (8), 2371–2379; https://doi.org/10.1021/ci500209e.Suche in Google Scholar PubMed PubMed Central
27. Milella, L.; Milazzo, S.; De Leo, M.; Vera Saltos, M. B.; Faraone, I.; Tuccinardi, T.; Lapillo, M.; De Tommasi, N.; Braca, A. a-Glucosidase and a-Amylase Inhibitors from Arcytophyllum Thymifolium. J. Nat. Prod. 2016, 79, 2104; https://doi.org/10.1021/acs.jnatprod.6b00484.Suche in Google Scholar PubMed
28. Poli, G.; Gelain, A.; Porta, F.; Asai, A.; Martinelli, A.; Tuccinardi, T. Identification of a New STAT3 Dimerization Inhibitor Through a Pharmacophore-Based Virtual Screening Approach. J. Enzyme Inhib. Med. Chem. 2016, 31 (6), 1011–1017; https://doi.org/10.3109/14756366.2015.1079184.Suche in Google Scholar PubMed
29. Fathima, S. S. A.; Meeran, M. M. S.; Nagarajan, E. R. Synthesis, Characterization and Biological Evaluation of Novel 2,2′-((1,2-Diphenylethane-1,2-Diylidene)bis(azanylylidene))bis(pyridin-3-ol)and Metal Complexes: Molecular Docking and in Silico ADMET Profile. Struct. Chem. 2020, 31 (2), 521–539; https://doi.org/10.1007/s11224-019-01425-7.Suche in Google Scholar
30. Trivedi, M. K.; Patil, S.; Shettiga, H.; Bairwa, K.; Jana, S. Spectroscopic Characterization of Biofield Treated Metronidazole and Tinidazole. Med. Chem. 2015, 5 (7), 340–344; https://doi.org/10.4172/2161-0444.1000283.Suche in Google Scholar
31. Salem, A. A.; Mossa, H. A.; Barsoum, B. N. Application of Nuclear Magnetic Resonance Spectroscopy for Quantitative Analysis of Miconazole, Metronidazole and Sulfamethoxazole in Pharmaceutical and Urine Samples. J. Pharm. Biomed. Anal. 2006, 41 (2), 654–661; https://doi.org/10.1016/j.jpba.2005.12.009.Suche in Google Scholar PubMed
32. Bourouai, M. A.; Si Larbi, K.; Bouchoucha, A.; Terrachet-Bouaziz, S.; Djebbar, S. New Ni(II) and Pd(II) Complexes Bearing Derived Sulfa Drug Ligands: Synthesis, Characterization, DFT Calculations, and In Silico and In Vitro Biological Activity Studies. BioMetals 2022, 36, 153; https://doi.org/10.1007/s10534-022-00469-3.Suche in Google Scholar PubMed
33. Allab, Y.; Chikhi, S.; Zaater, S.; Brahimi, M.; Djebbar, S. Impact of the Functionalized Tetrazole Ring on the Electrochemical Behavior and Biological Activities of Novel Nickel (II) Complexes with a Series of Tetrazole Derivatives. Inorg. Chim. Acta 2020, 504, 119436; https://doi.org/10.1016/j.ica.2020.119436.Suche in Google Scholar
34. Sevgi, F.; Bagkesici, U.; Kursunlu, A. N.; Guler, E. Fe (III), Co(II), Ni(II), Cu(II) and Zn(II) Complexes of Schiff Bases Based-on Glycine and Phenylalanine: Synthesis, Magnetic/Thermal Properties and Antimicrobial Activity. J. Mol. Struct. 2018, 1154, 256–260; https://doi.org/10.1016/j.molstruc.2017.10.052.Suche in Google Scholar
35. Estrada, A.; Wright, D. L.; Anderson, A. C. Antibacterial Antifolates: From Development Through Resistance to the Next Generation. Cold Spring Harbor Perspect. Med. 2016, 6 (8), a028324; https://doi.org/10.1101/cshperspect.a028324.Suche in Google Scholar PubMed PubMed Central
36. Wee, P.; Wang, Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017, 9, 52; https://doi.org/10.3390/cancers9050052.Suche in Google Scholar PubMed PubMed Central
37. Shyam Sunder, S.; Sharma, U. C.; Pokharel, S. Adverse Effects of Tyrosine Kinase Inhibitors in Cancer Therapy: Pathophysiology, Mechanisms and Clinical Management. Signal Transduction Targeted Ther. 2023, 8, 262; https://doi.org/10.1038/s41392-023-01469-6.Suche in Google Scholar PubMed PubMed Central
© 2025 IUPAC & De Gruyter
