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Silver ciprofloxacin (CIPAG): a successful combination of chemically modified antibiotic in inorganic–organic hybrid

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Abstract

The new silver(I) ionic, water soluble, compound {[Ag(CIPH)2]NO3∙0.75MeOH∙1.2H2O} (CIPAG) was obtained by reacting silver(I) nitrate with the antibiotic ciprofloxacin (CIPH). The complex was characterized by m.p., mid-FT-IR, 1H-NMR, UV–Vis spectroscopic techniques. The crystal structures of both CIPAG and the hexahydrated neutral free drug {[CIPH]∙6(H2O)} (2) were characterized by X-ray crystallography. Two neutral ligands are datively bonded to the metal ion through the piperidinic nitrogen atoms forming a cationic {[Ag(CIPH)2]+} counter part which is neutralized by a nitrate group. The antibacterial effect of CIPAG and the commercially available hydrochloric salt of the antibiotic ({[CIPH + 2 ]∙Cl−} (3)) were tested against the bacterial species Pseudomonas aeruginosa (PAO1), Staphylococcus epidermidis (St. epidermidis) and Staphylococcus aureus (St. aureus) by the mean of minimum inhibitory concentration, minimum bactericidal concentration and their inhibitory zone (IZ). The influence of CIPAG and 3 against the formation of biofilm of PAO1 or St. aureus was also evaluated by mean of biofilm elimination concentration. The IZ caused by CIPAG which has been loaded in poly-hydroxyethylmethacrylate, is determined. The genotoxicity of CIPAG and 3 is tested in vitro against normal human corneal epithelial cells (HCET cells), by the presence of micronucleus in HCET cells and in vivo by mean of Allium cepa test.

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Abbreviations

2 :

Neutral hexahydrated 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid

3 :

Protonated chloride ionic salt of 1-cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid

BEC:

Biofilm elimination concentration

CIP:

1-Cyclopropyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid

CIPAG :

{[Ag(CIPH)2]NO3∙0.75MeOH∙1.2H2O}

EGDMA:

Ethylene glycol dimethacrylate

HCET:

Normal human corneal epithelial cells

HEMA:

Hydroxyethyl methacrylate

IZ:

Inhibitory zone

MBC:

Minimum bactericidal concentration

MD:

Molecular dynamics

MI:

Mitotic Index

MIC:

Minimum inhibitory concentration

MN:

Micronucleus

Mtb:

Mycobacterium tuberculosis

PAO1:

Pseudomonas aeruginosa

poly-HEMA:

Poly-hydroxyethylmethacrylate

SRB assay:

Sulforhodamine B assay

St. aureus :

Staphylococcus aureus

St. epidermidis :

Staphylococcus epidermidis

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Acknowledgements

(1) This work was carried out in partial fulfillment of the requirements for an M.Sc. thesis of I.M. within the graduate program in Medicinal Chemistry under the supervision of SKH. (2) CNB and SKH would like to thank the Unit of Bioactivity Testing of Xenobiotics, of the University of Ioannina, for providing access to the facilities. (3) CNB and SKH would like to thank the Atherothrombosis Research Centre of the University of Ioannina for providing access to the fluorescence microscope. (4) The COST Action CA15114 “Anti-Microbial Coating Innovations to prevent infectious diseases (AMICI)” is acknowledged for the stimulating discussions. (5) Ciprofloxacin hydrochloric salt was purchased from Help Pharmaceutical which is acknowledged. HCET cells were kindly provided by Dr Maria Notara (Research Fellow, Dept. of Ophthalmology, University Hospital of Cologne, Germany) who is acknowledge. (6) The synthesis of CIPAG is protected by Greek patent No. 108941. The authors of this paper are included to the patent’s inventors.

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Authors and Affiliations

  1. Section of Inorganic and Analytical Chemistry, Department of Chemistry, University of Ioannina, 45110, Ioannina, Greece

    I. Milionis, C. N. Banti & S. K. Hadjikakou

  2. Cancer Biobank Center, University of Ioannina, Ioannina, Greece

    I. Sainis

  3. Institute of Nanoscience and Nanotechnology, NCSR “Demokritos”, Agia Paraskevi, Attikis, Greece

    C. P. Raptopoulou & V. Psycharis

  4. Medical Physics Laboratory, Medical School, University of Ioannina, Ioannina, Greece

    N. Kourkoumelis

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  1. I. Milionis
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Milionis, I., Banti, C.N., Sainis, I. et al. Silver ciprofloxacin (CIPAG): a successful combination of chemically modified antibiotic in inorganic–organic hybrid. J Biol Inorg Chem 23, 705–723 (2018). https://doi.org/10.1007/s00775-018-1561-9

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