Synthesis and Characterization of Metal Complexes of Different Antibiotics and their Biological Activities

Abstract

Antibiotics are the most important invention in the field of medicine which is crucial in fighting against infectious diseases. Metal complexes also known as coordination complexes contain a central metal atom or ion around which ligands bearing neutral or negative charge have bonded. Metal coordination compounds of antibiotics with improved bioactivity can play a vital role in searching for new antibiotics to combat drug-resistant life-threatening infectious bacteria. In this work, the complexations of four different antibiotics with biologically important metals Cu, Ni, and Ag were done. The antibiotics were ceftibuten dihydrate (CFT), cefpodoxime proxetil (CFP), cefuroxime axetil (CFU), and gemifloxacin mesylate (GMX). The physical properties of all the newly prepared metal complexes were studied. Different types of spectroscopic methods (UV-Vis, FTIR, and NMR), elemental analysis as well as diverse thermo-analytical techniques

(TG,

DTG, DTA, and DSC) were used to characterize the synthesized metal complexes. Paper disc diffusion assay was used for in vitro antimicrobial study of the antibiotic ligands and their metal complexes. In FT-IR spectra of all the metal complexes of CFT, a separation value of the carboxylate group frequency, ∆ν>200 cm -1 was found. Also, significant changes in the frequencies of the 3

nitrogen atom of the beta-lactam ring as well as a broad band in the range of 3200 – 3600 cm -1 were observed. The obtained FT-IR data suggested that metal ions were involved in coordination through carboxylate oxygen, the beta-lactam ring nitrogen atom of CFT antibiotic and water molecule. The different degradation patterns in the TG curve of the metal complexes from the precursor antibiotic were also supportive of the characterization of new metal complexes. On the other hand, CFP antibiotic acts as a tridentate ligand where the β-lactam carbonyl group, 2 o amide carbonyl group, and 1 o amine group are involved in the metalcoordination

process. FT-IR study of CFP antibiotic and its metal complexes revealed the shifting of frequency of the β-lactam carbonyl group and appearing of new absorption bands in the range 575-605 cm -1 and 430-480 cm which are due to the formation of new metal-oxygen and metal-nitrogen bonds. Significant changes in the chemical shift value of characteristic proton (-NH and -NH-) which are directly involved in coordination as well as the protons nearer to the binding site also occurred due to complexation. A broad band in the frequency range 3200-3600 cm -1 in IR spectra and a weight loss of around 7% at the temperature of 150 o C in TG curves of the metal complexes are indicative of coordinated water in the metal complexes. The CFU antibiotic also formed metal complexes through the participation of the oxygen atom of the β-lactam (C=O) group and the oxygen atom 2 o amide group. All analytical results including physical properties, FT-IR data, 1 H NMR data, thermo-analytical results, and also EA data confirmed the successful interaction of metal ions to ligand antibiotics. GMX is a quinolone-type antibiotic. Like other quinolones, it interacts with metal ions through the carboxyl group and carbonyl group of the nearest position. The absence of carboxyl stretching frequency (1714 cm -1 ) and the presence of two new bands in IR spectra of the GMX-metal complexes indicated the participation of the -COOH group in complexation with the metal ions. Moreover, the absence of a signal of proton at 11.0 ppm in the 1 H NMR spectrum of the complexes suggested the nonparticipation of –COOH group in the coordination process. The antibiotic-metal complexes were found to be thermally more stable than the precursor antibiotic. The EA data also give evidence for the formation of new metal complexes with 1:2 metal-to-ligand stoichiometries. The bactericidal activity of antibiotics may increase upon chelation with metal ions. This is due to the increased lipo-solubility of the metal complexes as compared to ligands. In this work, a total of 12 bacterial strains and two fungal strains were used for biological study. Among all the newly synthesized metal complexes, the Ag(I)CFT, Ag(I)-GMX, Cu(II)-CFT

and Cu(II)-CFU complexes showed excellent and enhanced activity compared to the precursor antibiotic against most of the microbes. The Ag(I)-CFP and Ni(II)-CFP complexes show similar but significant activity as the parent CFP antibiotic against most of the microbes. However, Ag(I)-CFP showed increased activity against Styphylococcus aureus and Enterobacter faecium, and a decreased activity was observed by Cu(II)-CFP complex. The Cu(II)-CFT complex was found to be 15 times more active against S. aureus and 1.6 times more active against S. typhi. On the contrary, an enhanced activity against Candida sp. and E. coli 0157 was observed by Cu(II)-GMX and Ni(II)- GMX, respectively.