Synthesis, spectral, thermal and antimicrobial studies of some new tri metallic biologically active ceftriaxone complexes

Abstract

Iron, cobalt, nickel and copper complexes of ceftriaxone were prepared in 1:3 ligand:metal ratio to examine the ligating properties of the different moieties of the drug. The complexes were found to have high percentages of coordinated water molecules. The modes of bonding were discussed depending on the infrared spectral absorption peaks of the different allowed vibrations. The Nujol mull electronic absorption spectra and the magnetic moment values indicated the Oh geometry of the metal ions in the complexes. The ESR spectra of the iron, cobalt, and copper complexes were determined and discussed. The thermal behaviors of the complexes were studied by TG and DTA techniques. The antimicrobial activities of the complexes were examined and compared to that of the ceftriaxone itself.

Introduction

Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad-spectrum activity against Gram-positive and Gram-negative bacteria. Ceftriaxone sodium is marketed by Hoffman–La Roche under the trade name Rocephin, as well as under various other names in several countries. Ceftriaxone (Rocephin) is widely used in the treatment of many conditions including acute otitis media, gonorrhea, meningitis, and infections of the skin and lower respiratory tract. It is indicated for use in both adults and children. In July, 2007 the FDA along with the manufacturer issued a safety alert addressing new information regarding the concomitant use of intravenous (I.V.) ceftriaxone and calcium containing products in neonates [1], [2], [3]. A small number of post-marketing reports had identified cases of fatal reactions in neonates caused by the precipitation of calcium–ceftriaxone complexes in the lungs and kidneys of both term and premature neonates. The patients had received I.V. doses of ceftriaxone and calcium solutions (sometimes even in different lines). More recently, a September 2007 MedWatch alert expanded the warning to include patients of all ages. In addition, it recommended avoiding the administration of ceftriaxone and calcium containing products within 48 h of each other, even in different infusion lines or at different sites. There is currently no data on the risk of combining intramuscular (I.M.) ceftriaxone with I.V. or oral calcium salts. It has long been established that ceftriaxone can produce biliary sludge or pseudolithiasis (most commonly in children). High concentrations of ceftriaxone are known to bind with calcium and form insoluble stones. This has occurred not only in the biliary system, but in the kidneys as well. Several cases of ceftriaxone-induced nephrolithiasis have appeared in the literature. In one study, 4 of 51 children receiving I.M. or I.V. ceftriaxone developed small, asymptomatic kidney stones that resolved spontaneously in three of the four patients. The study did not describe use of concomitant calcium solutions or products. In another trial, kidney stones were reported in 4 of 284 pediatric patients receiving I.V. ceftriaxone. Again, little data was presented regarding concomitant administration of calcium salts. Based on FDA reports and previous documentation of the formation of insoluble precipitates, ceftriaxone should probably not be administered within 48 h of calcium salts [1], [2], [3]. This gave me a strong push to study the ligating properties of the ceftriaxone drug as well as to start with the coordination ability of iron, cobalt, nickel and copper especially as a series of papers was published concerning with the synthesis and physicochemical studies of many complexes [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. The literature survey about the chemistry of ceftriaxone complexes was not rich as expected from its structure [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40] where it has many functional groups may form many coordination bonds with a central metal ion.

Ceftriaxone has a systematic IUPAC name of: (6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[(2-methyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4-triazin-3-yl)thio]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and it has molecular formula of: C₁₈H₁₈N₈O₇S₃ with a molecular weight of 554.58 amu. It can be represented by the following structure:

The charge density of the ceftriaxone is calculated using HF with STO-3G basis set by Hyper chemistry program and gathered in Table 1.