Norfloxacin and N-Donor Mixed-Ligand Copper(II) Complexes: Synthesis, Albumin Interaction, and Anti-Trypanosoma cruziActivity

Abstract

Copper(II) complexes with the first-generation quinolone antibacterial agent norfloxacin containing a nitrogen donor heterocyclic ligand 2,2′-bipyridine (bipy) or 1,10-phenanthroline (phen) were prepared and characterized by IR, EPR spectra, molar conductivity, and elemental analyses. The experimental data suggest that norfloxacin was coordinated to copper(II) through the carboxylato and ketone oxygen atoms. The interaction of the copper(II) complexes with bovine serum albumin (BSA) and human serum albumin (HSA) was investigated using fluorescence quenching of the tryptophan residues and copper(II) EPR spectroscopy. The results of fluorescence titration revealed that copper(II) complexes have a moderate ability to quench the intrinsic fluorescence of the albumins through a static quenching mechanism. EPR experiments showed that BSA and HSA Cu(II) sites compete with NOR for Cu(II)-bipy and Cu(II)-phen to form protein mixed-ligand complexes. Copper(II) complexes, together with the corresponding ligands, were evaluated for their trypanocidal activity in vitro against Trypanosoma cruzi, the causative agent of Chagas disease. The tests performed using bloodstream trypomastigotes showed that the Cu(II)-N-donor precursors and the metal complexes were more active than the free fluoroquinolone.

Supramolecular interaction of transition metal complexes with albumins and DNA: Spectroscopic methods of estimation of binding parameters

“…Indirect methods of fluorescence quenching are used, for the most part, to study metal complexes with albumins. The most widespread complexing metals whose binding is studied with these methods are Co [8,39,42,43,50] and Cu [44][45][46]51,131,141] the most widespread DNA-binding complexing metal is Cu. [44][45][46][47]49,141] As far as the constants are concerned, pK of the Stern-Volmer quenching constants are equal on the average to 5.…”

“…X-ray crystallography [23, 24, 40-48, 50, 136-138, 140-142, 145, 150, 151, 156-214] IR-spectroscopy [37, 41, 51, 54, 137, 140, 142, 145, 148, 149, 156, 158-161, 166-170, 172-174, 178, 179, 181, 182, 184-186, 188, 189, 191-198, 200, 202, 204, 205, 207-210, 215-233] Circular dichroism spectroscopy [8, 33-35, 39, 40, 142, 141, 143, 145-149, 163, 168, 169, 172, 179, 185, 189, 193, 196, 199, 202, 203, 206, 216, 219, 221, 223, 225, 226, 229, 231-239] EPR-spectroscopy [49,51,54,159,167,181,187,197,200,201,209,215,216,219,222,223,240] NMR-spectroscopy [37, 41, 52, 140, 142, 149, 155, 158, 161, 172, 179, 181, 183, 185, 188, 191, 192, 200, 202, 204, 205, 207, 209, 210, 214, 218-221, 223, 225, 227, 229-232, 236, 238, 241-243] Cyclic voltammetry [42-46, 48, 50, 54, 149, 151, 159, 164, 167, 173, 175, 176, 179, 184, 189, 208, 211-213, 221, 230, 240, 241, 244-247] X-ray crystallography, as a rule, is used for corroboration or specification of the structure of coordinated metal complexes themselves, [24,40,42] in particular, new biologically active compounds or earlier unknown coordination structures. [7,41,43,44,248] X-ray photoelectron spectroscopy for C, N, and O is used to obtain the information of the changes in the energy of atom bonds of these elements in the protein during the formation .…”

“…EPR-spectroscopy is used to obtain the information of the complex structure and symmetry, and enables to determine whether the complexes interacting with proteins are mononuclear, binuclear, or of mixed structures. [49,51,54] IR-spectroscopy allows to obtain additional information of which characteristic bands in the protein spectrum (more often Amide I and Amide II) shift during complex formation. Moreover, deconvolution of characteristic bands allows to estimate changes in the conformation of the proteins during supramolecular interaction.…”

“…The major attention in the case of metal complexes binding with proteins is paid to the therapeutic properties, and only in some cases the binding parameters were studied which, if necessary, were improved by changing temperature [8,23,[33][34][35][36][37][38][39] or selecting organic and inorganic coligands (mostly 1,10-phenantholine and bipyridyl) which bind with a complexing metal together with a drug molecule. [8,24,36,37,[39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] The complexes under study are mainly biligand complexes containing a drug ligand and coligand. The Figure 3 shows the distribution of the studing from the viewpoint of metals studied.…”

“…[252,253] The most widespread coligands are 1,10-phenanthroline and 2,2'bipyridyl since they (i) make it possible to form mixedligand complexes of a definite stoichiometry with many classes of targeted ligands, (ii) they are characterized by a sufficiently strong coordinate bond with a metal which excludes their free appearance in the organism, and (iii) they provide rather strong metal complex-protein binding, herewith at definite binding sites. [7,[42][43][44][45][46][47][48][49][50][51]155,244,248] The analysis of the research shows that the finding of supramolecular binding parameters is based on the most widespread methods of fluorescent and molecular absorption spectroscopy (spectrophotometry). Herewith, the methodological approaches used for estimation of thermodynamic and kinetic binding parameters are known enough (Stern-Volmer, Lineweaver-Burk, and Scatchard equations for spectrofluorimetry, Bjerrum function and actually Vierordt's method for spectrophotometry, etc.…”