Ceftriaxone-based Schiff base transition metal(II) complexes. Synthesis, characterization, bacterial toxicity, and DFT calculations. Enhanced antibacterial activity of a novel Zn(II) complex against S. aureus and E. coli

doi:10.1016/j.jinorgbio.2021.111519

Journal of Inorganic Biochemistry

Volume 223, October 2021, 111519

https://doi.org/10.1016/j.jinorgbio.2021.111519 Get rights and content

Highlights

•
A new polydentate Schiff base using ceftriaxone and 2,6-diaminopyridine was prepared.
•
Metal complexes with a ceftriaxone-derived Schiff base were prepared and characterized.
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Zinc(II) complex showed better antibacterial activity against E. coli and S. aureus.

Abstract

From the reaction of ceftriaxone 1 antibiotic with 2,6-diaminopyridine 2 a ceftriaxone-based Schiff base (H₂L,3) was obtained and its transition metal complexes were synthesized. Spectroscopic and physicochemical techniques, namely, UV–visible, FT-IR, ¹H NMR, EPR, mass spectrometry, molar conductance, magnetic susceptibility and density functional theory (DFT) calculations, together with elemental and thermal analyses, were used to find out the binding mode and composition of these complexes. The ceftriaxone-based Schiff base 3 behaves as a monoanionic tridentate N,N,O ligand. Spectral and magnetic data suggest an octahedral geometry for all complexes and the general formulae [M(HL)(OAc)(H₂O)₂] (M(II) = Mn²⁺ 4, Co²⁺ 5, Ni²⁺ 6, Cu²⁺ 7, Zn²⁺ 8), are proposed for them. All compounds were screened for antibacterial activity using both the agar disc diffusion method and the minimal inhibitory concentration (MIC). It was found that complex 8 exhibited the most promising bactericidal activity against S. aureus (MIC = 0.0048 μmol/ml) and E. coli (MIC = 0.0024 μmol/ml). It is more active than the free ligand 1 (MIC = 0.0560 μmol/ml for S. aureus and 0.0140 μmol/ml for E. coli). These MIC results were compared with those obtained using similar zinc(II) Schiff base complexes, and with the values obtained using ceftriaxone conjugated with silver and gold nanoparticles (NPs), using earlier published data. Synthesized metal complexes exhibited LC₅₀ values >1000 ppm indicating their nontoxicity against brine shrimp nauplii (Artemia Salina).

Graphical abstract

From the reaction of ceftriaxone 1 with 2,6−diaminopyridine 2 a N,N,O tridentate ceftriaxone−based Schiff base 3 was obtained. Novel transition metal complexes 4−8 containing 3 were synthesized, characterized and tested for toxicity and antibacterial activity. E. coli and S. aureus are very sensitive to zinc(II) complex 8.

Introduction

There is a pressing need for a new generation of antimicrobial agents, which can be used against multidrug-resistant microbial infections. Various approaches have been used to improve the bactericidal activity of antibiotics, among them coordination of metal ions with ligands containing drugs is a promising strategy that has proved to be very successful against a range of bacterial strains [1,2]. Transition metal complexes exhibit a wide variety of coordination properties and bioactivities, and the ability to form specific interactions with other biomolecules [3,4]. Thus the coordination of metal ions with antibiotic-based Schiff bases would prevent development of resistance by bacteria, enabling novel mechanisms of action and enhance the antimicrobial property of the antibiotic. Conjugation of antibiotics to silver and gold NPs [[5], [6], [7]] had also shown increased antibacterial activities against gram-positive and gram-negative bacteria [8,9].

Endometritis is the most common nosocomial infection that occurs postpartum, which has high morbidity and has become one of the difficult problems of recovery after delivery [10]. Staphylococcus aureus and Escherichia coli are the leading cause of postpartum infection. Ceftriaxone, is a third-generation cephalosporin used for the treatment of a number of bacterial infections including endometritis and urinary tract infections. The most common side effects include allergic reactions, gallbladder disease, and seizures [11].

Developments of new chemotherapeutic Schiff bases are attracting the attention of medicinal chemists. Many studies have been reported of the biological activity of Schiff bases, including their anticancer [[12], [13], [14]], antibacterial [[15], [16], [17]], antifungal [18] and antioxidant [9,19] properties. Toward this end, the interactions of some antibiotic-based Schiff bases with transition metals have been investigated [[20], [21], [22], [23], [24]]. In order to enhance the antibacterial activity against S. aureus and E. coli of ceftriaxone, we report herein the preparation, characterization, and antibacterial activity of Schiff base transition metal complexes containing 3 derived from the condensation of ceftriaxone, 1, with 2,6-diaminopyridine, 2. The chemical structure of 1 is shown in Fig. 1.

Section snippets

Materials and methods

Solvents and chemicals were of analytical grade and used as received without further purification. Precautions were taken to exclude moisture and oxygen during the synthesis and handling of compounds. The compounds Mn(OAc)₂.4H₂O, Co(OAc)₂.4H₂O, Ni(OAc)₂.4H₂O, Cu(OAc)₂, Zn(OAc)₂.2H₂O and ceftriaxone were purchased from Aldrich Chemical Co. Conductivity measurements were carried out using a WTW Conductimeter Bridge. Thin layer chromatography was carried out using TLC plates coated with silica

Synthesis of 2,6-diaminopyridinideneceftriaxone H₂L, 3

To a solution of 1 (1 mmol, 554.6 mg) in ethanol (25 ml) was added a solution of 2 (1 mmol, 109.1 mg) in ethanol (15 ml). The reaction mixture was heated and refluxed under nitrogen atmosphere for 4 h. It was then left to stand overnight. Solvent was then removed by rotary evaporation until a precipitate appeared. The solid was removed by filtration, washed with water, ethanol and ether, dried under reduced pressure and recrystallized from hot ethanol to get the pure Schiff base 3. Yield 65%

Results and discussion

The synthetic route of ceftriaxone-based Schiff base 3 and metal complexes 4–8 are illustrated in Scheme 1. The C double bond O lactam group of 1 was allowed to react with the amino group available in 2 to obtain the ceftriaxone-based Schiff base ligand 3. The Schiff base and its metal complexes 4–8 were isolated as amorphous solids in good yields. The Schiff base 3 and complexes 4 and 8 are yellow while 5 is red wine and 6 and 7 are gray in colour. The elemental analyses of the synthesized products were in

Conclusions

From the reaction of free 1 with 2 a Schiff base 3 and its metal complexes 4–8 have been synthesized. The complexes were octahedral and the coordination to metal occurs through the carboxylate, azomethine and pyridine moieties. The complex 8 has higher antibacterial activity than the free 1 against E. coli and S. aureus showing that it has a good activity as antibacterial. These are important results since they show that combining metal ions with antibiotic-based Schiff base ligands with N,N,O

Corresponding author declaration

I, the corresponding author of this manuscript, certify that the contributors' and conflicts of interest statements included in this paper are correct and have been approved by all coauthors.

I further confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

Declaration of Competing Interest

The authors declare that there is no conflict of interest.

Acknowledgements

The authors want to express their sincere thanks to the Universidad de Oriente. Universidad de Playa Ancha and the University of Baghdad for support.

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Ceftriaxone-based Schiff base transition metal(II) complexes. Synthesis, characterization, bacterial toxicity, and DFT calculations. Enhanced antibacterial activity of a novel Zn(II) complex against S. aureus and E. coli

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials and methods

Synthesis of 2,6-diaminopyridinideneceftriaxone H2L, 3

Results and discussion

Conclusions

Corresponding author declaration

Declaration of Competing Interest

Acknowledgements

Coord. Chem. Rev.

J. Clust. Sci.

J. Nanopart. Res.

Anaerobe

Inorg. Chem. Commun.

Eur. J. Med. Chem.

Russ. J. Coord. Chem.

J. Mol. Struct. Teochem

Chem. Phys. Lett.

Int. J. Biol. Macromol.

Polyhedron

Spectrochim. Acta A

Polyhedron

Spectrochim. Acta A

Polyhedron

Polyhedron

Polyhedron

J. Pharm. Sci.

Inorg. Chim. Acta

J. Inorg. Biochem.

Inorg. Chim. Acta

Spectrochim. Acta

J. Electroanal. Chem.

Comput. Theor. Chem.

Eur. J. Med. Chem.

Spectrochim. Acta A

Spectrochim. Acta A

J. Ethnopharmacol.

Antibiotics

J. Coord. Chem.

Appl. Biochem. Biotechnol.

J. Nanopart. Res.

New J. Chem.

Biointerface Res. Appl. Chem.

Monatsh. Chem.

Biochem. Res. Int.

Bioinorg. Chem. Appl.

Chem. Sci. Trans.

Org. Chem. Res.

Appl. Organomet. Chem.

Appl. Organomet. Chem.

Appl. Organomet. Chem.

Inorg. Nano-Met. Chem.

Appl. Organomet. Chem.

Appl. Organomet. Chem.

Gaussian 09

J. Chem. Inf. Model.

Gaussview, Version 5

Synthesis of 2,6-diaminopyridinideneceftriaxone H₂L, 3