The structure – Activity correlation in the family of dicationic imidazolium surfactants: Antimicrobial properties and cytotoxic effect
Introduction
Due to the widespread occurrence of multidrug-resistant infectious agents, there is a demand to search for safe chemical compounds, which will form the basis of new drugs. Surfactants containing imidazolium fragment attract attention of researchers in the field of chemotherapy, because these compounds often exhibit high antimicrobial activity [[1], [2], [3], [4], [5], [6]]. Functionalization of imidazolium surfactants with various substituents makes it possible to modify their hydrophilic-lipophilic balance and aggregation properties, as well as to tune their biological activity. Dicationic imidazolium surfactants are of a particular interest [[7], [8], [9]]. They represent a large class of geminal surfactants with two hydrophobic tails and two positively charged head groups covalently linked by a spacer fragment. Gemini surfactants display superior properties to corresponding monocationic analogues: they more effectively reduce the surface tension at the phase boundary, have an order of magnitude lower critical micelle concentration (CMC), possess high solubility, and high wetting and solubilization effects [[10], [11], [12], [13], [14], [15]]. These properties of dicationic surfactants predetermine their broad application as solubilizers and adjuvants, nanocontainers and nanoreactors, as well as non-viral vectors for gene delivery into cells of a living organism. Dicationic surfactants also show antimicrobial effect, which is maximum in compounds with a tail length C10-C12 [16,17]. In contrast, monocationic amphiphiles, whose antimicrobial activity shows a positive trend with an increasing the carbon chain length, reach maximum activity in case of tetra- or hexadecyl compounds, above which a so-called ‘cut off effect’ is observed [3,4,18,19].
The structure of head group and spacer fragment plays an important role in the aggregation behavior and properties of gemini surfactants [[20], [21], [22]]. There is a large body of recent literature data on the aggregation behavior of imidazolium dicationic surfactants in solutions, in which CMC values and adsorption parameters are determined [1,23,24]. There is a few information about their solubilization effect and complexation with proteins and DNA [1,[25], [26], [27], [28], [29]]. By contrast, an information on the antimicrobial properties of such compounds is fragmentary. However, some data on dicationic imidazolium surfactants indicate their significant potential. Thus, the study of 3,3′(α,ω-dioxaalkyl)-bis(1-alkylimidazolium) chlorides showed the high efficiency of this surfactants against Staphylococcus aureus, Enterococcus faecalis, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Pseudomonas aeruginosa, Candida krusei, and Candida albicans [30,31]. In addition, antimicrobial effect was demonstrated for a series of new dicationic imidazolium surfactants containing amide group in the spacer fragment, which depends on the length of hydrophobic tail. High antifungal activity of these compounds against Candida albicans, one of the main opportunistic pathogens that cause a wide range of human diseases, should particularly be noted [32].
In this regard, the development of new effective microbicides based on dicationic imidazolium surfactants and the search of structure–biological activity relationship is an important and promising problem. Taking into account the wide use of amphiphilic compounds in cancer chemotherapy for the preparation of nanoparticles with target agents and antitumor drugs [[33], [34], [35], [36]], the investigation of antimicrobial properties of imidazolium surfactants should be extended by their cytotoxicity study.
The aim of this work is to identify new bioactive surfactants that can be used in pharmacology and medicine. For this purpose, a detailed study of antimicrobial, hemolytic and cytotoxic activity of a number of dicationic alkylimidazolium surfactants of the m-s-m (Im) series with a variable length of the hydrophobic radical and a varying distance between the head groups was carried out (Fig. 1).
Section snippets
Alkylimidazoles and bis-imidazolium salts. General remarks
Alkylimidazoles and bis-imidazolium salts were made according to Scheme 1.
This scheme is known from literature [37,38], but some details look incomplete or controversial. That is why detailed synthetic description provided for representative examples. Structure and purity of final and intermediary compounds were confirmed by 1H NMR and IR spectra, and appropriate results of elemental analysis.
Step 1. N-Dodecylimidazole.
In a high form beaker (250 ml), imidazole (8.19 g; 0.120 M) was dissolved in
Antimicrobial activity of test compounds
Table 1 summarizes results on the antibacterial activity of geminis under study. The compounds were tested for antibacterial (bacteriostatic and bactericidal) activity against a number of Gram-positive S. aureus 209P (Sa), B. сereus 8035 (Вс) and Gram-negative bacteria E. coli F-50 (Ec), Pseudomonas aeruginosa 9027 (Ра) including methicillin-resistant strains of S. aureus (MRSA-Sa). Antifungal activity was studied on Trichophyton mentagrophytes var. gypseum 1773, Aspergillus niger 1119 and
Conclusion
The antimicrobial, hemolytic and cytotoxic activities of dicationic imidazolium surfactants with a variable length of a hydrophobic group and spacer fragment have been studied. It has been shown that the nature of a hydrophobic tail is the main structural factor affecting the antimicrobial activity of the compounds, while the length of the spacer fragment has practically no effect on their biological properties. The compounds have displayed high antimicrobial activity against a wide range of
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
This work is supported by the Russian Science Foundation (grant № 19-73-30012).
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