Metal binding and antibacterial activity of ciprofloxacin complexes

Four novel cobalt(II), copper(II), nickel(II) and zinc(II) complexes of the fluoroquinolone antibiotic ciprofloxacin have been prepared. The compounds were characterized by IR, UV-Visible, molar conductivity and elemental analyses. In all of the complexes, the drug ligand, ciprofloxacin (CFL) was coordinated through two carbonyl oxygen atoms. Octahedral and square-planar geometries have been proposed for the cobalt(II), nickel(II) and zinc(II), and copper(II) complexes, respectively. In vitro tests of susceptibility to these metal complexes showed stronger activity than that of ciprofloxacin against Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae and Bacillus dysenteriae.     

Synthesis, antimycobacterial and antibacterial activity of ciprofloxacin derivatives containing a N-substituted benzyl moiety

We report herein the design and synthesis of a series of novel ciprofloxacin (CPFX) derivatives with remarkable improvement in lipophilicity by introducing a substituted benzyl moiety to the N atom on the C-7 piperazine ring of CPFX. Antimycobacterial and antibacterial activity of the newly synthesized compounds was evaluated. Results reveal that compound 4f has good in vitro activity against all of the tested Gram-positive strains including MRSA and MRSE (MICs: 0.06-32μg/mL) which is two to eightfold more potent than or comparable to the parent drug CPFX (MICs: 0.25-128μg/mL), Gram-negative bacteria P. aeruginosa (MICs: 0.5-4μg/mL) and M. tuberculosis H37Rv ATCC 27294 (MIC: 1μg/mL).     

DNA binding,prominent photonuclease activity and antibacterial PDT of cobalt(II) complexes of phenanthroline based photosensitizers

Abstract

The chemistry of Co(II) complexes showing efficient light induced DNA cleavage activity, binding propensity to calf thymus DNA and antibacterial PDT is summarized in this article. Complexes of formulation [Co(mqt)(B)₂]ClO₄ 1–3 where mqt is 4-methylquinoline-2-thiol and B is N,N-donor heterocyclic base, viz. 1,10-phenanthroline (phen 1), dipyrido[3,2-d:2′,3′-f]quinoxaline (dpq 2) and dipyrido[3,2-a:2′,3′-c]phenazine (dppz 3) have been prepared and characterized. The DNA-binding behaviors of these three complexes were explored by absorption spectra, viscosity measurements and thermal denaturation studies. The DNA binding constants for complexes 1, 2 and 3 were determined to be 1.6?×?10³?M^?1, 1.1?×?10⁴?M^?1 and 6.4?×?10⁴?M^?1 respectively. The experimental results suggest that these complexes interact with DNA through groove binding mode. The complexes show significant photocleavage of supercoiled (SC) DNA proceeds via a type-II process forming singlet oxygen as the reactive species. Antimicrobial photodynamic therapy was studied using photodynamic antimicrobial chemotherapy (PACT) assay against E. coli and all complexes exhibited significant reduction in bacterial growth on photoirradiation.     

Zinc complexes of benzothiazole-derived Schiff bases with antibacterial activity

Reaction of 2-acetamidobenzaldehyde with 2-amino-, 2-amino-4-methyl-, 2-amino-4-methoxy-, 2-amino-4-chloro-, 2-amino-6-nitro- and 2-amino-6-methylsufonylbenzothiazole afforded a series of Schiff bases. These compounds have been used for complexation reactions to obtain Zn(II) chelates having the same metal ion but different anions of the type [Zn(L)2]Xn [L = Schiff base derivative, X = SO4, NO3, C2O4 and CH3CO2 and n = 1 or 2] These complexes (Table I) have been characterized by physical, spectral, and analytical data. The Schiff bases act tridentately and their metal complexes were proposed to possess an octahedral geometry. To evaluate the antibacterial role of the anion, these compounds have been screened for antibacterial properties against pathogenic strains such as Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa.     

Wound-dressing materials with antibacterial activity from electrospun polyurethane-dextran nanofiber mats containing ciprofloxacin HCl

Dextran is a versatile biomacromolecule for preparing electrospun nanofibrous membranes by blending with either water-soluble bioactive agents or hydrophobic biodegradable polymers for biomedical applications. In this study, an antibacterial electrospun scaffold was prepared by electrospinning of a solution composed of dextran, polyurethane (PU) and ciprofloxacin HCl (CipHCl) drug. The obtained nanofiber mats have good morphology. The mats were characterized by various analytical techniques. The interaction parameters between fibroblasts and the PU-dextran and PU-dextran-drug scaffolds such as viability, proliferation, and attachment were investigated. The results indicated that the cells interacted favorably with the scaffolds especially the drug-containing one. Moreover, the composite mat showed good bactericidal activity against both of Gram-positive and Gram-negative bacteria. Overall, our results conclude that the introduced scaffold might be an ideal biomaterial for wound dressing applications.     

Metal complexes with the quinolone antibacterial agent N-propyl-norfloxacin: synthesis, structure and bioactivity

Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, pr-norfloxacin, with VO(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Zn(2+), MoO(2)(2+), Cd(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques while molecular mechanics calculations for Fe(3+), VO(2+) and MoO(2)(2+) complexes have been performed. In all complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA resulting to a B-->A DNA transition. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show equal or decreased biological activity in comparison to the free pr-norfloxacin except UO(2)(pr-norf)(2) which shows better inhibition against S. aureus.     

Antineoplastic and antibacterial activity of some mononuclear Ru(II) complexes

These ligands (L) show a bidentate behavior, forming octahedral ruthenium complexes. The title complexes were subjected to in-vivo anticancer activity tests against a transplantable murine tumor cell line, Ehrlich's Ascitic Carcinoma (EAC) and in-vitro antibacterial activity against several Gram positive and Gram negative bacterial strains. [Ru(bpy)2(ihqs)]Cl2 and [Ru(bpy)2 (hc)]Cl2 (where bpy = 2,2'-bipyridine, ihqs = 7-iodo-8hydroxy quinoline-5-sulphonic acid and hc = 3-hydroxy coumarin) showed promising antitumor activity. Treatment with these complexes prolonged the life span of EAC bearing mice as well as decreased their tumor volume and viable ascitic cell count. All the tested complexes exhibited mild to moderate antibacterial activity.     

Metal binding to ligands: cadmium complexes with glutathione revisited

We studied the interaction of gamma-L-glutamyl-L-cysteinyl-glycine (glutathione, GSH) with cadmium ions (Cd(2+)) by first performing classical potentiometric pH titration measurements and then turning to additional spectroscopic methods. To estimate the residual concentrations of free cadmium, we studied the competition of glutathione with a Cd(2+)-sensitive dye, either an absorbing dye (murexide) or a fluorescent one (FluoZin-1), and consistent results were obtained with the two dyes. In KCl-containing Tes, Mops, or Tris buffer at pH 7.0 to 7.1 and 37 degrees C (and at a total Cd(2+) concentration of 0.01 mM), results suggest that free cadmium concentration is halved when the concentration of glutathione is approximately 0.05 mM; this mainly reflects the combined apparent dissociation constant for the Cd(glutathione) 1:1 complex under these conditions. To identify the other complexes formed, we used far-UV spectroscopy of the ligand-to-metal charge transfer absorption bands. The Cd(glutathione)(2) 1:2 complex predominated over the 1:1 complex only at high millimolar concentrations of total glutathione and not at low submillimolar concentrations of total glutathione. The apparent conditional constants derived from these spectroscopy results made it possible to discriminate between sets of absolute constants that would otherwise have simulated the pH titration data similarly well in this complicated system. Related experiments showed that although the Cl(-) ions in our media competed (modestly) with glutathione for binding to Cd(2+), the buffers we had chosen did not bind Cd(2+) significantly under our conditions. Our experiments also revealed that Cd(2+) may be adsorbed onto quartz or glass vessel walls, reducing the accuracy of theoretical predictions of the concentrations of species in solution. Lastly, the experiments confirmed the rapid kinetics of formation and dissociation of the UV-absorbing Cd(glutathione)(2) 1:2 complexes. The methods described here may be useful for biochemists needing to determine conditional binding constants for charge transfer metal-ligand complexes under their own conditions.     

Synthesis, crystal structure, antibacterial assay and DNA binding activity of new binuclear Cu(II) complexes with bridging oxamidate

Two new binuclear copper complexes, [Cu₂(oxpn)(bpy)(pic)(H₂O)](pic) (1) and [Cu₂(oxpn)(Me₂bpy)(pic)](pic) (2) [H₂oxpn = N,N′-bis(3-aminopropyl)oxamide; Hpic = 2,4,6-trinitrophenol; bpy = 2,2′-bipyridine; Me₂bpy = 4,4′-dimethyl-2,2′-bipyridine], have been synthesized and characterized by elemental analyses, conductivity measurements, IR, UV-visible spectroscopy and single crystal X-ray analyses. Both complexes have similar molecular structures. In complex 1, the central two Cu(II) atoms are bridged by cis-oxpn²⁻ with the Cu1-Cu2 separation of 5.221 Å and the polyhedron of each copper atom is a square-pyramid. Similarly, complex 2 is a cis-oxpn²⁻-bridged binuclear complex with the Cu1-Cu2 separation of 5.196 Å. Cu1(II) central atom situated in a tetrahedral geometry is four-coordinated and Cu(II) atom situated in a square-pyramidal geometry is five-coordinated. Hydrogen bonding interactions and π-π stacking interactions link the binuclear copper complex 1 or 2 into a 2D infinite network. The antibacterial assays indicate that the two complexes showed better activities than their ligands. The interactions of the two binuclear complexes with herring sperm DNA (HS-DNA) have been studied by UV absorption titration, fluorescence titration and viscosity measurements. The results suggest that the two binuclear complexes bind to HS-DNA via an intercalative mode.     

Metal binding modes of Alzheimer's amyloid beta-peptide in insoluble aggregates and soluble complexes

Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's disease. Zn(II) induces the Abeta aggregation at acidic-to-neutral pH, while Cu(II) is an effective inducer only at mildly acidic pH. We have examined Zn(II) and Cu(II) binding modes of Abeta and their pH dependence by Raman spectroscopy. The Raman spectra clearly demonstrate that three histidine residues in the N-terminal hydrophilic region provide primary metal binding sites and the solubility of the metal-Abeta complex is correlated with the metal binding mode. Zn(II) binds to the N(tau) atom of the histidine imidazole ring and the peptide aggregates through intermolecular His(N(tau))-Zn(II)-His(N(tau)) bridges. The N(tau)-metal ligation also occurs in Cu(II)-induced Abeta aggregation at mildly acidic pH. At neutral pH, however, Cu(II) binds to N(pi), the other nitrogen of the histidine imidazole ring, and to deprotonated amide nitrogens of the peptide main chain. The chelation of Cu(II) by histidine and main-chain amide groups results in soluble Cu(II)-Abeta complexes. Under normal physiological conditions, Cu(II) is expected to protect Abeta against Zn(II)-induced aggregation by competing with Zn(II) for histidine residues of Abeta.     

All-D-cecropin B: Synthesis,conformation, lipopolysaccharide binding,and antibacterial activity

Cecropin B (LCB) is a natural peptide with antibacterial and antifungal properties. The enantiomer of LCB, containing all-D amino acids (DCB), was synthesized to examine its antibacterial and binding properties. The conformation of DCB was compared to its enantiomer by circular dichroism. Both the L- and D-peptides showed an identical induction of -helical secondary structure. However, binding studies between Lipopolysaccharide (LPS) and DCB or LCB were studied with a dimethylmethylene blue spectrophotometric assay, showing the two enantiomeric peptides differed in their interaction with LPS. Antibacterial activity of DCB was determined against three Gram-negative bacteria, Pantoea agglomerans (ATCC 27996), Escherichia coli (ATCC 8739), and Pseudomonas aeruginosa (ATCC 17648), giving comparable results to LCB.     

Cerium oxide and iron oxide nanoparticles abolish the antibacterial activity of ciprofloxacin against gram positive and gram negative biofilm bacteria

Metal oxide nanoparticles have been suggested as good candidates for the development of antibacterial agents. Cerium oxide (CeO₂) and iron oxide (Fe₂O₃) nanoparticles have been utilized in a number of biomedical applications. Here, the antibacterial activity of CeO₂ and Fe₂O₃ nanoparticles were evaluated on a panel of gram positive and gram negative bacteria in both the planktonic and biofilm cultures. Additionally, the effect of combining CeO₂ and Fe₂O₃ nanoparticles with the broad spectrum antibiotic ciprofloxacin on tested bacteria was investigated. Thus, minimum inhibitory concentrations (MICs) of CeO₂ and Fe₂O₃ nanoparticles that are required to inhibit bacterial planktonic growth and bacterial biofilm, were evaluated, and were compared to the MICs of the broad spectrum antibiotic ciprofloxacin alone or in the presence of CeO₂ and Fe₂O₃ nanoparticles. Results of this study show that both CeO₂ and Fe₂O₃ nanoparticles fail to inhibit bacterial growth and biofilm biomass for all the bacterial strains tested. Moreover, adding CeO₂ or Fe₂O₃ nanoparticles to the broad spectrum antibiotic ciprofloxacin almost abolished its antibacterial activity. Results of this study suggest that CeO₂ and Fe₂O₃ nanoparticles are not good candidates as antibacterial agents, and they could interfere with the activity of important antibiotics.     

Synthesis,characterization, redox behavior,DNA and protein binding and antibacterial activity studies of ruthenium(II) complexes of bidentate schiff bases

Two new ruthenium(II) complexes of Schiff base ligands (L) derived from cinnamaldehyde and ethylenediamine formulated as [Ru(L)(bpy)₂](ClO₄)₂, where L¹ = N,N’-bis(4-nitrocinnamald-ehyde)ethylenediamine and L² = N,N’-bis(2-nitrocinnamaldehyde)-ethylenediamine for complex 1 and 2, respectively, were isolated in pure form. The complexes were characterized by physicochemical and spectroscopic methods. The electrochemical behavior of the complexes showed the Ru(III)/Ru(II) couple at different potentials with quasi-reversible voltammograms. The interaction of the complexes with calf thymus DNA (CT-DNA) using absorption, emission spectral studies and electrochemical techniques have been used to determine the binding constant, K_b and the linear Stern–Volmer quenching constant, K_SV. The results indicate that the ruthenium(II) complexes interact with CT-DNA strongly in a groove binding mode. The interactions of bovine serum albumin (BSA) with the complexes were also investigated with the help of absorption and fluorescence spectroscopy tools. Absorption spectroscopy proved the formation of a ground state BSA-[Ru(L)(bpy)₂](ClO₄)₂ complex. The antibacterial study showed that the Ru(II) complexes (1 and 2) have better activity than the standard antibiotics but weak activity than the ligands.     

Iron(III) complexes: Preparation,characterization, antibacterial activity and DNA-binding

Iron(III) have been combined to well known quinolones (ciprofloxacin) and some Schiff bases with the help of coordination approach. Characterization of these compounds have been done using elemental analysis, magnetic measurements, thermogravimetric analysis, IR, UV-VIS, ¹H NMR and ¹³C NMR spectral investigation. Analytical studies suggest that the iron(III)-quinolone complexes assume a six-coordinated dimeric distorted octahedral geometry. All the compounds show a good antibacterial activity against broad range of bacteria like Bacillus cereus, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Salmonella typhi and Serratia marcescens, whereas no significant inhibition towards growth of fungal strains like Aspergillus Niger, Aspergillus flavus and Lasiodiplodia theobromae. Analyses of all these compounds show effective sperm herring DNA inhibition.     

Iron(III) complexes: preparation, characterization, antibacterial activity and DNA-binding

Iron(III) have been combined to well known quinolones (ciprofloxacin) and some Schiff bases with the help of coordination approach. Characterization of these compounds have been done using elemental analysis, magnetic measurements, thermogravimetric analysis, IR, UV-VIS, (1)H NMR and (13)C NMR spectral investigation. Analytical studies suggest that the iron(III)-quinolone complexes assume a six-coordinated dimeric distorted octahedral geometry. All the compounds show a good antibacterial activity against broad range of bacteria like Bacillus cereus, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Salmonella typhi and Serratia marcescens, whereas no significant inhibition towards growth of fungal strains like Aspergillus Niger, Aspergillus flavus and Lasiodiplodia theobromae. Analyses of all these compounds show effective sperm herring DNA inhibition.     

Metal heterodiene complexes

In this article a survey is given of novel results in the field of the chemistry of α-diimine complexes of some metal atoms of the main group, transition metal and post transition metal area. It is shown that α-diimines of the type RNC(R′)(R″)CNR (= R-DAB) and 2-C₅H₄NC(R′)NR (= R-Pyca) are very versatile with regards to both their coordination chemistry and chemical reactivity when coordinated to a metal or metal cluster. The type of reaction occurring depends critically on the type of metal(s), the other ligands present on the metal(s), the type of coordination of the α-diimines, and particularly on the steric and electronic properties of R,R′ and R″ situated on the R-DAB and R-Pyca ligands.     

Metal binding activity of the Escherichia coli hydrogenase maturation factor HypB

The formation of the [NiFe] metallocenter of Escherichia coli hydrogenase 3 requires the participation of proteins encoded by the hydrogenase pleiotropy operon hypABCDEF. The insertion of Ni(II) into the precursor enzyme follows the incorporation of the iron center and is the function of HypA, a Zn(II)-binding protein, and HypB, a GTPase. The Ni(II) donor and the mechanism of transfer of Ni(II) into the hydrogenase precursor protein are not known. In this study, we demonstrate that HypB is a nickel-binding protein capable of binding 1 equiv of Ni(II) with a K(d) in the sub-picomolar range. In addition, HypB has a weaker metal-binding site that is not specific for Ni(II) over Zn(II). Examination of the isolated C-terminal GTPase domain revealed that the high-affinity metal binding capability was severely abrogated but the low-affinity site was intact. By mutating conserved cysteine and histidine residues in E. coli HypB, we have localized the high-affinity Ni(II)-binding site to an N-terminal CXXCGC motif and the low-affinity metal-binding site to the GTPase domain. A model for the function of HypB during the Ni(II) loading of hydrogenase is proposed.     

Metal complexes with superoxide dismutase-like activity as candidates for anti-prion drug

Various compounds were evaluated for ability to inhibit the formation of the abnormal protease-resistant form of prion protein (PrP-res) in two cell lines infected with different prion strains. Examination of the structure-activity relationships indicated that compounds with copper-selective chelating ability and whose copper complexes have high SOD-like activity are candidates for anti-prion drug.     

Metal binding activity of pectin isolated from seagrass Zostera marina and its derivatives

Low esterified pectin was isolated from the seagrass Zostera marina. Dynamics of the isolation process for the pectin from this seagrass was investigated. Two pectin derivatives: galacturonide (A) with molecular weight 30.55 kDa and galacturonide (B) with molecular weight 3.94 kDa were obtained using acidic hydrolysis of the native pectin from Zostera marina. Molecular weight parameters (Mw, Mn, Mw/Mn) of this pectin and its derivatives as well as of commercial apple pectin were determined using gel-filtration chromatography method. Comparative assessment of Cd²⁺, Pb²⁺, Y³⁺-binding activity of the native Zostera pectin, galacturonides A and B, and commercial apple pectin was performed. The results showed that galacturonide A with molecular weight 30.55 kDa possesses highest metal-binding capacity and may be considered as a candidate for development of medicines with metal-binding activity.