Elsevier

Inorganica Chimica Acta

Volume 364, Issue 1, 15 December 2010, Pages 125-131
Inorganica Chimica Acta

Synthesis and antimicrobial studies of silver N-heterocyclic carbene complexes bearing a methyl benzoate substituent

Dedicated to Arnold L. Rheingold.
https://doi.org/10.1016/j.ica.2010.08.008Get rights and content

Abstract

Due to the properties of silver as an antimicrobial, our research group has synthesized many different silver carbene complexes. Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized by in situ carbene formation using silver acetate as the base in the reaction. The new compounds were fully characterized by several methods including NMR spectroscopy and X-ray crystallography. Preliminary antimicrobial efficacy studies against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli were conducted. The results of this study demonstrated antimicrobial efficacy of the two complexes comparable to silver nitrate, showing their potential for use in the treatment of bacterial infections.

Graphical abstract

Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized, characterized by NMR and X-ray crystallography, and tested for their antimicrobial properties.

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Introduction

Silver has a long standing use as an antimicrobial agent, particularly in modern medicine for the prevention and treatment of bacterial infections associated with severe burn wounds [1]. This is evidenced by the use of silver sulfadiazine, trademarked as Silvadene®, in burn wards worldwide since 1968 [1], [2], [3]. Silver has many properties that make it an attractive candidate for use as a medicinal agent. It is present in the human body in single digit μg/L concentrations despite no known biological function [4]. This fact indicates that the body can tolerate the presence of silver in low doses without toxic effect. In fact, its low toxicity is one of the greatest advantages of silver over other medicinally relevant metals. A cosmetic condition known as argyria, which is a blue-gray discoloration of the skin caused by extreme excess exposure of silver salts, is one of the only known side effects [5], [6]. In general silver does not accumulate in the body, but rather is readily excreted, an important aspect for its use as a potential internalized therapeutic agent.

The first silver carbene was isolated by Arduengo et al. in 1993 [7]. The synthesis involved first isolating the free carbene by using a strong base such as KH or KOtBu, followed by the reaction of the free carbene with silver triflate. Although it is possible to generate a stable free carbene in this manner, the conditions required resulted in decomposition when applied to complexes with methylene groups α to the nitrogen of the N-heterocyclic carbene (NHC) [8], [9], [10]. Due to this complication Wang and Lin developed a method of creating metal carbenes in situ using silver oxide [11]. The synthesis began with an imidazolium cation and deprotonation was done using the silver salt as the base. These milder conditions lead to a more versatile method for making silver carbene complexes that remain stable under aerobic conditions.

Due to its promise as an antimicrobial, our research group has focused delivering silver by coupling silver (I) to NHCs to increase its stability in the body. The complexes developed by our research group have been synthesized by in situ carbene formation using silver acetate as a basic silver salt. The silver carbene complexes (SCCs) have utilized different backbones and substituents to allow for changes in water stability, water or organic solubility, and low toxicity of the degradation products. Most of these SCCs are stable to aerobic conditions, as well as in solution. They have been tested against a variety of bacterial species and have all shown effectiveness in vitro while some have also shown in vivo efficacy [12], [13], [14], [15], [16], [17], [18], [19], [20].

Herein we report the synthesis of two new SCCs utilizing the methyl-3-methylbenzoate group as a substituent on theobromine and 4,5-dichloroimidazole. Theobromine is a biocompatible natural product found in chocolate and 4,5-dichloroimidazole has been shown to give added stability to the silver complexes due to the electron withdrawing nature of the chloride groups of the backbone [15]. The benzoate group as a substituent serves as a site to complex targeting groups that can aid in the delivery of the compound to bacteria cells in the body. These two SCCs have been successfully synthesized, characterized, and tested for their stability and antimicrobial activity.

Section snippets

Materials and general methods

All reactions were carried out under aerobic conditions. 4,5-Dichloroimidazole, theobromine, iodomethane, methyl-3-bromomethyl benzoate, silver acetate, and silver nitrate were purchased from Alfa Aesar. All solvents were purchased from Fisher Scientific. All products and solvents were used as received without further purification. LB Brother Miller (DIFCO) and Bacto-agar (DIFCO) were prepared according to manufacturer’s instructions and sterilized before use. 1H and 13C NMR were collected on a

Synthesis and characterization of 3

The synthesis of the theobromine derivative 3 was developed by adapting synthetic procedures previously established in our group based on the electronics of the theobromine building block [16]. The N1 nitrogen in theobromine (Fig. 1a) is a good nucleophile when it is deprotonated making it a possible site for attachment of different substituents. The nucleophilicity of the N1 nitrogen is much greater than that of the N9 making it more likely to obtain single substituted products. Previous

Conclusion

Two new silver carbene complexes were successfully synthesized and characterized. The results of the preliminary MIC studies conducted on these complexes showed concentrations comparable to silver nitrate, a proven antimicrobial agent. This demonstrates the potential of these complexes as agents in the treatment of bacterial infections. The benzoate substituent on these compounds could further be reacted with targeting moieties to allow for targeted delivery of the compounds to bacterial

Acknowledgments

This work was supported by The University of Akron, The University of Akron Center for Silver Therapeutics Research, the National Institute of Allergies and Infectious Diseases (1 R01 A106785601) and The National Institute of General Medical Sciences (1 R01 GM86895-01). We wish to thank the Ohio Board of Regents and the National Science Foundation for funds used to purchase the 500 MHz NMR instrument (CHE-0341701 and DMR-0414599) and the Bruker-Nonius Apex CCD X-ray diffractometer (CHE-0116041)

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