Elsevier

Journal of Molecular Structure

Volume 1139, 5 July 2017, Pages 407-417
Journal of Molecular Structure

New silver(I) complex with diazafluorene based ligand: Synthesis, characterization, investigation of in vitro DNA binding and antimicrobial studies

https://doi.org/10.1016/j.molstruc.2017.03.042Get rights and content

Highlights

  • Synthesis and characterization of new Ag(I) complex by Diazafluorene Based Ligand.

  • Evidence for metallointercalation by in vitro DNA binding studies.

  • Excellent in vitro antibacterial performance against various bacteria.

Abstract

A novel diazafluorene based complex with silver, [Ag(dian)2]NO3, where dian is N-(4,5-diazafluoren-9-ylidene)aniline, has been prepared and characterized by elemental analysis, IR spectroscopy, 1HNMR, UV–Vis spectroscopy and cyclic voltammetry. In order to explore the relationship between the structure and biological properties, DNA binding propensity and in vitro antibacterial property have also been studied. The mode of DNA-complex interaction has been investigated by electronic absorption titration, luminescence titration, competitive binding experiment, effect of ionic strength, thermodynamic studies, viscometric evaluation, circular dichroism spectroscopy and cyclic voltammetry. The results reveal that the complex binds to CT-DNA in a moderate intercalation capability with the partial insertion of a planar dian ligand between the base stacks of double-stranded DNA with binding constant (Kb) of 2.4 × 105 M−1. The viscosities and CD spectra of the DNA provide strong evidence for the intercalation. An in vitro antibacterial efficacy of the Ag(I) complex on a series of Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) indicates that the complex exhibits a marked antibacterial activity. The minimum inhibitory concentrations of the complex indicate that it exhibits much higher antibacterial effect on standard bacterial strains of Escherichia coli and Staphylococcus aureus than those of silver nitrate, silver sulfadiazine. The bacterial inhibitions of the silver(I) complex are closely agreed to its DNA binding affinities.

Introduction

In recent years, more attentions focused on the coordination compounds as metallopharmaceuticals with antitumor activity [1]. It culminated with the discovering of cisplatin and its derivatives as the antitumor drug and carried on with the finding of novel other non-platinum based chemotherapeutic agents [2]. These pharmaceuticals emerging from the interface of inorganic chemistry, biochemistry, pharmacology, and toxicology [3], have achieved access over traditional organic drugs.

When complexation occurs, biological activity such as the anticancer property of ligands is extremely enhanced [4]. The charges, shapes, and trend of binding to nucleic acid sites of the coordination complexes make them good probes to examine DNA structure and potentially helpful reagents in the designing of the site-specific drugs. Many biological experiments on the most anticancer and antiviral drugs have demonstrated that DNA is the primary intracellular target of the drug because DNA interacts with small molecules [5]. Subsequently, it can cause DNA damage in cancer cells by preventing their division so the cell will die [6]. Studies of metal complexes, which react at specific sites along a DNA strand provide development of chemotherapeutic reagents [7], sensitive chemical probes for the structure of DNA [8], and tools for analyzing genetic systems by the molecular biologist [5]. In this regard, transition metal complexes stand out as good candidates for artificial nucleases because of their diverse ability to recognize and react selectively with particular sites of DNA.

As mentioned above, small molecules can interact with DNA, it can be via covalent and noncovalent mode. Several weak non-covalent interaction modes exist, including intercalation, groove binding, and external electrostatic effects [9]. The main mode among these interactions which related to the antitumor activity of metal complexes is named intercalation. It is based on parameters such as the planarity of the chelating ligands, donor atoms, the geometry and the metal ions of metal complex [10], [11]. Accordingly, a detailed study of the interaction mode of complexes with DNA is the basis for designing more efficient and novel anticancer drugs [3]. It may occur that the complexes bind DNA through a combination of binding modes; it exactly depends on the structural characteristics of the compounds [12]. In this way, many techniques have been used to study the interaction of metal complexes with DNA, such as UV–Vis spectroscopy [11], fluorimetery [4], circular dichroism spectroscopy [13], dynamic viscosity [13], cyclic voltammetry [14] and IR spectroscopy [15], because the interactions of a small molecule with DNA can be readily monitored by changes in characteristic bands (either their intensities and positions) or the dynamic viscosity of DNA.

Among the metal complexes, silver complexes have several priorities, which attract the attentions of biologists to take advantage of their exclusive characteristics. Very low concentrations (<2.3 μg L−1) of this metal exist in human body. Silver is absorbed through the skin, the lungs, mucus membranes and gastrointestinal tract [16]. Mainly complex forms of silver-protein are absorbed within the body but have no physiological or biochemical roles [17]. The body can endure high concentrations of silver. This metal has not be seen as a cumulative poison and the body can get rid of it through the urine and faeces. The preference for silver is due to its quite low toxicity in comparison to platinum, because there are still needs for new cancer treatments by minimum toxic effect to normal cells. Recently several in vitro anticancer silver complexes have been designed and studied [18]. Additionally, silver compounds were famous for their antibacterial properties over the centuries [19]. Also, they were generic treatments for tetanus and rheumatism in the 19th century and for colds and gonorrhea before the development of antibiotics in the early part of the 20th century [20]. Furthermore, silver compounds have large uses in infections in the burns, wounds, chronic ulcers, epilepsy, mental illness, and nicotine addiction [21], [22]. In the 20th century, silver became less favored with the manifestation of modern antibiotics. It has commonly been assumed that the antimicrobial properties of silver compounds depend on the releasing of the silver(I) ions which are biologically active [17]. The detailed mode of action of the Ag+ ion is still debatable [23]. Silver is being combined with many materials to give increased antimicrobial protection [24]. Previous researches have been performed to evaluate the antimicrobial activity of various silver(I) complexes containing ligands such as 1,10-phenanthroline (phen) and 1,10-phenanthroline-5,6-dione [25].

Schiff-bases are currently being extensively studied due to their biological and anticancer activity [26]. Several derivatives of 1,10-phenanthroline such as 4,5-diazafluoren-9-one (dafone) have attracted attentions owing perhaps to their DNA intercalation functions [9]. Many efforts were performed to tune the physical and chemical properties of the π system through chemical modification of the phenanthroline [27]. In the meantime, Schiff base N-(4,5-diazafluoren-9-ylidene) aniline ligand [28] which is a derivative of dafone and its complexes have been less considered. Based on what informed above and our interest in the chemistry of phen derivatives, and coupled with the later comment, we have begun to prepare silver complexes with this ligand and inquire their anticancer and antibacterial activities.

Section snippets

Methods and materials

All chemicals were of reagent grade quality and no need to further purification is required. Most of them were commercially available and purchased from Merck Company. 4,5-diazafluoren-9-one (dafone) was synthesized by the Henderson method [29]. Calf thymus DNA (CT-DNA) type I, was procured from Sigma Chemical Company in solid Na+ salt form and used as received. It was stored at 4°C.

Carbon, hydrogen and nitrogen contents (CHN Microanalysis) were determined on Eager 300 Summarize elemental

Synthesis and structural analysis

The synthetic procedures for the ligand and complex are depicted in Scheme 1. The dian ligand has been prepared previously and fully characterized with crystallographic and spectroscopic data [28], [37]. The X-ray crystal structure of it reveals that the 4,5- diazafluorenylidene unit is nearly planar which oriented at a dihedral angle of 75.75 (3)° with respect to the phenyl ring.

The d10 Ag(I) ion has no electronically imposed preference for any particular coordination geometry. Structures of

Conclusion

A new silver(I) complex, [Ag (dian)2]NO3 and dian ligand have been prepared and fully characterized. The DNA binding affinity of the complex was studied by electronic absorption titration, luminescence titration, competitive binding experiment, effect of ionic strength, thermodynamic studies, viscometric evaluation and circular dichroism spectroscopy. The results show that the complex binds to DNA by intercalation. This can be related to the several reasons such as coplanar aromatic rings of

Acknowledgement

We thank the University of USB for the financial support.

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