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Heteroleptic Transition Metal Complexes of Eflornithine Hydrochloride Monohydrate: Synthesis, Characterization, in silico and in vitro Biological Studies

Year 2022, Volume: 9 Issue: 4, 1309 - 1322, 30.11.2022
https://doi.org/10.18596/jotcsa.1142442

Abstract

Incessant development of resistance to drugs by microorganisms remains a major setback associated with the currently available antibiotics, thereby making imperative a continuous search for alternative candidates with improved efficacy. Previous studies have shown enhanced antimicrobial activity of some bioactive molecules upon coordination with metal ions. Thus, in this study, Cu(II), Co(II), and Ni(II) complexes of eflornithine hydrochloride monohydrate (EHM) were synthesized and probed for bactericidal activity via in vitro and in silico. The characterization results such as CHN analysis, FTIR, UV-visible magnetic susceptibility and Electrospray Ionization Mass Spectrometry (ESI-MS) reveal that EHM coordinates as a bidentate ligand to each central metal ion in the molar ratio 1:2 through O and N in the COO- and NH2 group respectively, and also suggest octahedral geometry in each complex. The physicochemical and pharmacokinetics parameters predicted in silico support the bio-applicability and safety of the complexes. From the in vitro antibacterial study, the complexes demonstrate improved activity against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa with an average minimum inhibitory concentration (MIC) of 0.01 mg/L similar to ciprofloxacin, compared to EHM whose MIC >1.00 mg/L. Although, not all the complexes satisfy Lipinski’s drugability rule of 5 due to their molecular weight, however, coordination with metal ions improves the biological activities of EHM and the complexes demonstrate potential for further transformation into antibiotic therapeutics.

Thanks

The authors gratefully acknowledge the financial support from the World Bank Science and Technology Education Post-Basic Project (STEP-B) TETFUND, Department of Chemistry University of Ilorin, Nigeria and also Tetfund Nigeria for PhD scholarship awarded to YOA.

References

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  • 12. Boechat N, Kover WB, Bastos MM, Romeiro NC, Silva ASC, Santos FC, et al. Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3- trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors. Med Chem Res. 2007;15(9):492–510.
  • 13. Osunniran WA, Obaleye JA, Tella AC, Amolegbe SA. Synthesis, characterization and in vitro antibacterial studies of novel transition metal (II) complexes of 2,5-diamino-2-(difluoromethyl)pentanoic acid hydrochloride hydrate. Orbital. 2018;10(5):367–80.
  • 14. Obaleye JA, Tella AC, Osunniran WA, Simon N, Omojasola PF. Synthesis, Characterization, Crystal Structure and Antimicrobial Evaluation of a Novel -M-X-M-X- Type Infinite Chain 1D Cu(II) Complex with Eflornithine Hydrochloride Hydrate as Ligand. J Inorg Organomet Polym Mater. 2014;24(5):827–35.
  • 15. Osunniran WA, Obaleye JA, Ayipo YO. Six Coordinate Transition Metal ( II ) Complexes of Mixed Ligands of. Jordan J Chem. 2018;13(3):149–57.
  • 16. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(October 2016):1–13.
  • 17. Okasha RM, Al Shaikh NE, Aljohani FS, Naqvi A, Ismail EH. Design of novel oligomeric mixed ligand complexes: Preparation, biological applications and the first example of their nanosized scale. Int J Mol Sci. 2019;20(3).
  • 18. Ayipo YO, Obaleye JA, Badeggi UM. Novel Metal Complexes of Mixed Piperaquine-Acetaminophen and Piperaquine-Acetylsalicylic acid : Synthesis , Characterization and Antimicrobial Activities. J Turkish Chem Soc A. 2017;4(1):313–26.
  • 19. Limbago B. M100-S11, Performance standards for antimicrobial susceptibility testing. Clin Microbiol Newsl. 2019;23(6):49.
  • 20. WikiBook. Test for Anions [Internet]. WikiBook. 2020. Available from: https://en.wikibooks.org/wiki/Inorganic_Chemistry/Qualitative_Analysis/Tests_for_anions#The_brown_ring_test
  • 21. Gichumbi JM, Friedrich HB, Omondi B. Application of arene ruthenium(II) complexes with pyridine-2-carboxaldimine ligands in the transfer hydrogenation of ketones. J Mol Catal A Chem [Internet]. 2016;416:29–38. Available from: http://dx.doi.org/10.1016/j.molcata.2016.02.012
  • 22. Otero V, Sanches D, Montagner C, Vilarigues M, Carlyle L, Lopes JA, et al. Characterisation of metal carboxylates by Raman and infrared spectroscopy in works of art. J Raman Spectrosc. 2014;45(11–12):1197–206.
  • 23. Modec B, Podjed N, Lah N. Beyond the simple copper(II) coordination chemistry with quinaldinate and secondary amines. Molecules. 2020;25(7).
  • 24. Karthik P, Shaheer ARM, Vinu A, Neppolian B. Amine Functionalized Metal–Organic Framework Coordinated with Transition Metal Ions: d–d Transition Enhanced Optical Absorption and Role of Transition Metal Sites on Solar Light Driven H2 Production. Small. 2020;16(12):1–10.
  • 25. Turan N, Buldurun K. Synthesis, characterization and antioxidant activity of Schiff base and its metal complexes with Fe(II), Mn(II), Zn(II), and Ru(II) ions: Catalytic activity of ruthenium(II) complex. Eur J Chem. 2018;9(1):22–9.
  • 26. Sebastian M, Arun V, Robinson PP, Varghese AA, Abraham R, Suresh E, et al. Synthesis, structural characterization and catalytic activity study of Mn(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes of quinoxaline-2- carboxalidine-2-amino-5-methylphenol: Crystal structure of the nickel(II) complex. Polyhedron [Internet]. 2010;29(15):3014–20. Available from: http://dx.doi.org/10.1016/j.poly.2010.08.016
  • 27. Salazar-Medina AJ, Gámez-Corrales R, Ramírez JZ, González-Aguilar GA, Velázquez-Contreras EF. Characterization of metal-bound water in bioactive Fe(III)-cyclophane complexes. J Mol Struct. 2018;1154:225–31.
  • 28. Debus RJ. FTIR studies of metal ligands, networks of hydrogen bonds, and water molecules near the active site Mn4CaO5 cluster in Photosystem II. Biochim Biophys Acta - Bioenerg [Internet]. 2015;1847(1):19–34. Available from: http://dx.doi.org/10.1016/j.bbabio.2014.07.007
  • 29. Lakshmi S, Endo T, Siva G. Electronic (Absorption) Spectra of 3d Transition Metal Complexes. Adv Asp Spectrosc. 2012;3–48.
  • 30. Radoń M, Rejmak P, Fitta M, Bałanda M, Szklarzewicz J. How can [MoIV(CN)6]2-, an apparently octahedral (d)2 complex, be diamagnetic? Insights from quantum chemical calculations and magnetic susceptibility measurements. Phys Chem Chem Phys. 2015;17(22):14890–902.
  • 31. Lipinski CA. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.
  • 32. Syed Ali Fathima S, Paulpandiyan R, Nagarajan ER. Expatiating biological excellence of aminoantipyrine derived novel metal complexes: Combined DNA interaction, antimicrobial, free radical scavenging studies and molecular docking simulations. J Mol Struct [Internet]. 2019;1178:179–91. Available from: https://doi.org/10.1016/j.molstruc.2018.10.021
  • 33. Kuti JL. Optimizing Antimicrobial Pharmacodynamics: a Guide for Your Stewardship Program. Rev Médica Clínica Las Condes [Internet]. 2016;27(5):615–24. Available from: http://dx.doi.org/10.1016/j.rmclc.2016.08.001
  • 34. Coraça-Huber D, Dichtl S, Steixner S, Nogler M, Weiss G. Original Article Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci Coraça-Huber, Débora C. Pathog Dis. 2018;(June 2018)
Year 2022, Volume: 9 Issue: 4, 1309 - 1322, 30.11.2022
https://doi.org/10.18596/jotcsa.1142442

Abstract

References

  • 1. Orvig C, Abrams MJ. Medicinal inorganic chemistry: Introduction. Chem Rev. 1999;99(9):2202–3.
  • 2. MCB. Metals in chemical biology. Nat Chem Biol. 2008;4(3):143. 3. Afrasiabi Z, Sinn E, Kulkarni PP, Ambike V, Padhye S, Deobagakar D, et al. Synthesis and characterization of copper(II) complexes of 4-alkyl/aryl-1,2-naphthoquinones thiosemicarbazones derivatives as potent DNA cleaving agents. Inorganica Chim Acta. 2005;358(6):2023–30.
  • 4. Raman N, Sobha S, Mitu L. Synthesis, structure elucidation, DNA interaction, biological evaluation, and molecular docking of an isatin-derived tyramine bidentate Schiff base and its metal complexes. Monatshefte fur Chemie. 2012;143(7):1019–30.
  • 5. Rizzotto M. Metal Complexes as Antimicrobial Agents. A Search Antibact Agents. 2012;
  • 6. Chang EL, Simmers C, Knight DA. Cobalt complexes as antiviral and antibacterial agents. Pharmaceuticals. 2010;3(6):1711–28.
  • 7. Ventola CL. The antibiotic resistance crisis: causes and threats. P T J [Internet]. 2015;40(4):277–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25859123%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4378521%5Cnhttp://www.ncbi.nlm.nih.gov/pubmed/25859123%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4378521
  • 8. Ayipo YO, Osunniran WA, Babamale HF, Ayinde MO, Mordi MN. Metalloenzyme mimicry and modulation strategies to conquer antimicrobial resistance: Metal-ligand coordination perspectives. Coord Chem Rev [Internet]. 2022;453:214317. Available from: https://doi.org/10.1016/j.ccr.2021.214317
  • 9. Frei A. Metal complexes, an untapped source of antibiotic potential? Antibiotics. 2020;9(2).
  • 10. Tella AC, Obaleye JA. Metal complexes as antibacterial agents : Synthesis , characterization and antibacterial activity of some 3d metal complexes of sulphadimidine. Electron J Chem. 2010;2(1):1–16.
  • 11. Anacona JR, Ortega G. Metal-based antibacterial agents: Synthesis, characterization, and biological evaluation of ternary Mn(II) and Co(II) complexes containing sulfamethoxazole and cephalosporins. Synth React Inorganic, Met Nano-Metal Chem. 2015;45(3):363–9.
  • 12. Boechat N, Kover WB, Bastos MM, Romeiro NC, Silva ASC, Santos FC, et al. Design, synthesis, and biological evaluation of new 3-hydroxy-2-oxo-3- trifluoromethylindole as potential HIV-1 reverse transcriptase inhibitors. Med Chem Res. 2007;15(9):492–510.
  • 13. Osunniran WA, Obaleye JA, Tella AC, Amolegbe SA. Synthesis, characterization and in vitro antibacterial studies of novel transition metal (II) complexes of 2,5-diamino-2-(difluoromethyl)pentanoic acid hydrochloride hydrate. Orbital. 2018;10(5):367–80.
  • 14. Obaleye JA, Tella AC, Osunniran WA, Simon N, Omojasola PF. Synthesis, Characterization, Crystal Structure and Antimicrobial Evaluation of a Novel -M-X-M-X- Type Infinite Chain 1D Cu(II) Complex with Eflornithine Hydrochloride Hydrate as Ligand. J Inorg Organomet Polym Mater. 2014;24(5):827–35.
  • 15. Osunniran WA, Obaleye JA, Ayipo YO. Six Coordinate Transition Metal ( II ) Complexes of Mixed Ligands of. Jordan J Chem. 2018;13(3):149–57.
  • 16. Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7(October 2016):1–13.
  • 17. Okasha RM, Al Shaikh NE, Aljohani FS, Naqvi A, Ismail EH. Design of novel oligomeric mixed ligand complexes: Preparation, biological applications and the first example of their nanosized scale. Int J Mol Sci. 2019;20(3).
  • 18. Ayipo YO, Obaleye JA, Badeggi UM. Novel Metal Complexes of Mixed Piperaquine-Acetaminophen and Piperaquine-Acetylsalicylic acid : Synthesis , Characterization and Antimicrobial Activities. J Turkish Chem Soc A. 2017;4(1):313–26.
  • 19. Limbago B. M100-S11, Performance standards for antimicrobial susceptibility testing. Clin Microbiol Newsl. 2019;23(6):49.
  • 20. WikiBook. Test for Anions [Internet]. WikiBook. 2020. Available from: https://en.wikibooks.org/wiki/Inorganic_Chemistry/Qualitative_Analysis/Tests_for_anions#The_brown_ring_test
  • 21. Gichumbi JM, Friedrich HB, Omondi B. Application of arene ruthenium(II) complexes with pyridine-2-carboxaldimine ligands in the transfer hydrogenation of ketones. J Mol Catal A Chem [Internet]. 2016;416:29–38. Available from: http://dx.doi.org/10.1016/j.molcata.2016.02.012
  • 22. Otero V, Sanches D, Montagner C, Vilarigues M, Carlyle L, Lopes JA, et al. Characterisation of metal carboxylates by Raman and infrared spectroscopy in works of art. J Raman Spectrosc. 2014;45(11–12):1197–206.
  • 23. Modec B, Podjed N, Lah N. Beyond the simple copper(II) coordination chemistry with quinaldinate and secondary amines. Molecules. 2020;25(7).
  • 24. Karthik P, Shaheer ARM, Vinu A, Neppolian B. Amine Functionalized Metal–Organic Framework Coordinated with Transition Metal Ions: d–d Transition Enhanced Optical Absorption and Role of Transition Metal Sites on Solar Light Driven H2 Production. Small. 2020;16(12):1–10.
  • 25. Turan N, Buldurun K. Synthesis, characterization and antioxidant activity of Schiff base and its metal complexes with Fe(II), Mn(II), Zn(II), and Ru(II) ions: Catalytic activity of ruthenium(II) complex. Eur J Chem. 2018;9(1):22–9.
  • 26. Sebastian M, Arun V, Robinson PP, Varghese AA, Abraham R, Suresh E, et al. Synthesis, structural characterization and catalytic activity study of Mn(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes of quinoxaline-2- carboxalidine-2-amino-5-methylphenol: Crystal structure of the nickel(II) complex. Polyhedron [Internet]. 2010;29(15):3014–20. Available from: http://dx.doi.org/10.1016/j.poly.2010.08.016
  • 27. Salazar-Medina AJ, Gámez-Corrales R, Ramírez JZ, González-Aguilar GA, Velázquez-Contreras EF. Characterization of metal-bound water in bioactive Fe(III)-cyclophane complexes. J Mol Struct. 2018;1154:225–31.
  • 28. Debus RJ. FTIR studies of metal ligands, networks of hydrogen bonds, and water molecules near the active site Mn4CaO5 cluster in Photosystem II. Biochim Biophys Acta - Bioenerg [Internet]. 2015;1847(1):19–34. Available from: http://dx.doi.org/10.1016/j.bbabio.2014.07.007
  • 29. Lakshmi S, Endo T, Siva G. Electronic (Absorption) Spectra of 3d Transition Metal Complexes. Adv Asp Spectrosc. 2012;3–48.
  • 30. Radoń M, Rejmak P, Fitta M, Bałanda M, Szklarzewicz J. How can [MoIV(CN)6]2-, an apparently octahedral (d)2 complex, be diamagnetic? Insights from quantum chemical calculations and magnetic susceptibility measurements. Phys Chem Chem Phys. 2015;17(22):14890–902.
  • 31. Lipinski CA. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol. 2004;1(4):337–41.
  • 32. Syed Ali Fathima S, Paulpandiyan R, Nagarajan ER. Expatiating biological excellence of aminoantipyrine derived novel metal complexes: Combined DNA interaction, antimicrobial, free radical scavenging studies and molecular docking simulations. J Mol Struct [Internet]. 2019;1178:179–91. Available from: https://doi.org/10.1016/j.molstruc.2018.10.021
  • 33. Kuti JL. Optimizing Antimicrobial Pharmacodynamics: a Guide for Your Stewardship Program. Rev Médica Clínica Las Condes [Internet]. 2016;27(5):615–24. Available from: http://dx.doi.org/10.1016/j.rmclc.2016.08.001
  • 34. Coraça-Huber D, Dichtl S, Steixner S, Nogler M, Weiss G. Original Article Iron chelation destabilizes bacterial biofilms and potentiates the antimicrobial activity of antibiotics against coagulase-negative Staphylococci Coraça-Huber, Débora C. Pathog Dis. 2018;(June 2018)
There are 33 citations in total.

Details

Primary Language English
Subjects Inorganic Chemistry
Journal Section Articles
Authors

Yusuf Ayipo 0000-0001-5951-9788

Publication Date November 30, 2022
Submission Date July 8, 2022
Acceptance Date September 20, 2022
Published in Issue Year 2022 Volume: 9 Issue: 4

Cite

Vancouver Ayipo Y. Heteroleptic Transition Metal Complexes of Eflornithine Hydrochloride Monohydrate: Synthesis, Characterization, in silico and in vitro Biological Studies. JOTCSA. 2022;9(4):1309-22.