Abstract
The aim of this study was to construct a nanostructured lipid system as a strategy to improve the in vitro antibacterial activity of copper(II) complexes. New compounds with the general formulae [CuX2(INH)2]·nH2O (X = Cl− and n = 1 (1); X = NCS− and n = 5 (2); X = NCO− and n = 4 (3); INH = isoniazid, a drug widely used to treat tuberculosis) derived from the reaction between the copper(II) chloride and isoniazid in the presence or absence of pseudohalide ions (NCS− or NCO−) were synthesized and characterized by infrared spectrometry, electronic absorption spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, elemental analysis, melting points and complexometry with 2,2′,2′′,2′′′-(Ethane-1,2-diyldinitrilo)tetraacetic acid (EDTA). The characterization techniques allowed us to confirm the formation of the copper(II) complexes. The Cu(II) complexes were loaded into microemulsion (MEs) composed of 10% phase oil (cholesterol), 10% surfactant [soy oleate and Brij® 58 (1:2)] and 80% aqueous phase (phosphate buffer pH = 7.4) prepared by sonication. The Cu(II) complex-loaded MEs displayed sizes ranging from 158.0 ± 1.060 to 212.6 ± 1.539 nm, whereas the polydispersity index (PDI) ranged from 0.218 ± 0.007 to 0.284 ± 0.034. The antibacterial activity of the free compounds and those that were loaded into the MEs against Staphylococcus aureus ATCC® 25923 and Escherichia coli ATCC® 25922, as evaluated by a microdilution technique, and the cytotoxicity index (IC50) against the Vero cell line (ATCC® CCL-81TM) were used to calculate the selectivity index (SI). Among the free compounds, only compound 2 (MIC 500 μg/mL) showed activity for S. aureus. After loading the compounds into the MEs, the antibacterial activity of compounds 1, 2 and 3 was significantly increased against E. coli (MIC’s 125, 125 and 500 μg/mL, respectively) and S. aureus (MICs 250, 500 and 125 μg/mL, respectively). The loaded compounds were less toxic against the Vero cell line, especially compound 1 (IC50 from 109.5 to 319.3 μg/mL). The compound 2- and 3-loaded MEs displayed the best SI for E. coli and S. aureus, respectively. These results indicated that the Cu(II) complex-loaded MEs were considerably more selective than the free compounds, in some cases, up to 40 times higher.
Highlights
The ability of bacteria to acquire resistance to drugs that are used as therapeutic agents has become a significant problem because there is a daily increase in the microbial resistance to the currently used antibiotics [1]
This study reports the preparation and spectroscopic characterization of three copper(II) complexes containing isoniazid (INH) as a ligand, Figure 1: [CuCl2(INH)2] ̈ H2O (1), Figure 2, [Cu(NCS)2(INH)2] ̈ 5H2O (2), Figure 3 and [Cu(NCO)2(INH)2] ̈ 4H2O (3), Figure 4, and the incorporation of these compounds into a nanostructured lipid system consisting of 10% phase oil, 10% surfactant [soy oleate and Brij 58 (1:2)] and 80% aqueous phase
The synthesis, characterization, and antibacterial activity of copper(II) complexes bearing an isoniazid ligand that were incorporated into nanostructured lipid system were reported in this work
Summary
The ability of bacteria to acquire resistance to drugs that are used as therapeutic agents has become a significant problem because there is a daily increase in the microbial resistance to the currently used antibiotics [1]. The prospects for the use of antimicrobial drugs in the future are still uncertain and require the search for new compounds with potential activity against pathogenic bacteria and fungi [2]. It has long been recognized that copper compounds are capable of inhibiting a wide variety of fungi and bacteria [3,4]. The Cu(II) ion has a tendency to interact with molecules to yield coordination compounds with different properties, including antibacterial activity. A coordination compound or metallic complex is the product of a Lewis acid-base reaction in which neutral molecules or anions (called ligands) bind to a central metal atom (or ion) by coordinate covalent bonds [5]
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