International Journal of Molecular Sciences Review Quaternary Ammonium Compounds (QACs) and Ionic Liquids (ILs) as Biocides: From Simple Antiseptics to Tunable Antimicrobials Anatoly N. Vereshchagin * , Nikita A. Frolov , Ksenia S. Egorova, Marina M. Seitkalieva and Valentine P. Ananikov * N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow, Russia; [email protected] (N.A.F.); [email protected] (K.S.E.); [email protected] (M.M.S.) * Correspondence: [email protected] (A.N.V.); [email protected] (V.P.A.) Abstract: Quaternary ammonium compounds (QACs) belong to a well-known class of cationic biocides with a broad spectrum of antimicrobial activity. They are used as essential components in surfactants, personal hygiene products, cosmetics, softeners, dyes, biological dyes, antiseptics, and disinfectants. Simple but varied in their structure, QACs are divided into several subclasses: Mono-, bis-, multi-, and poly-derivatives. Since the beginning of the 20th century, a significant amount of work has been dedicated to the advancement of this class of biocides. Thus, more than 700 articles on QACs were published only in 2020, according to the modern literature. The structural variability and diverse biological activity of ionic liquids (ILs) make them highly prospective for developing new Citation: Vereshchagin, A.N.; Frolov, types of biocides. QACs and ILs bear a common key element in the molecular structure–quaternary N.A.; Egorova, K.S.; Seitkalieva, positively charged nitrogen atoms within a cyclic or acyclic structural framework. The state-of-the-art M.M.; Ananikov, V.P. Quaternary research level and paramount demand in modern society recall the rapid development of a new Ammonium Compounds (QACs) and generation of tunable antimicrobials. This review focuses on the main QACs exhibiting antimicrobial Ionic Liquids (ILs) as Biocides: From and antifungal properties, commercial products based on QACs, and the latest discoveries in QACs Simple Antiseptics to Tunable and ILs connected with biocide development. Antimicrobials. Int. J. Mol. Sci. 2021, 22, 6793. https://doi.org/10.3390/ ijms22136793 Keywords: quaternary ammonium compound; ionic liquid; antibacterial; antimicrobial; biocide Academic Editors: Iolanda Francolini and Antonella Piozzi 1. Introduction Received: 20 May 2021 For many years, quaternary ammonium compounds (QACs) have been included Accepted: 16 June 2021 in most antiseptics and disinfectants and used in various areas, from household and Published: 24 June 2021 agriculture to medicine and industry [1]. The COVID-19 pandemic that broke out in 2020 led to a significant increase in the Publisher’s Note: MDPI stays neutral widespread use of sanitizers, including QACs. Recent studies have shown that more than with regard to jurisdictional claims in 90% of the dust samples analyzed during the pandemic contained QACs, and their average published maps and institutional affil- concentration doubled compared to the pre-COVID period [2]. It is to be expected that with iations. the further progression of the pandemic, this number will increase, although the virucidal effect of QACs on SARS-CoV-2 requires further research [3]. The constant presence of subinhibitory concentrations of QACs on various working surfaces, together with the frequent use of QACs, increases the risk of the development Copyright: © 2021 by the authors. of a resistant bacterial environment, which will lead to a plummet of the effectiveness of Licensee MDPI, Basel, Switzerland. popular antiseptics and disinfectants. The solution to this problem can be found in the This article is an open access article synthesis of new QACs, which exhibit superior antibacterial, antifungal, and antiviral distributed under the terms and properties. conditions of the Creative Commons The structure of QACs consists of a positively charged nitrogen atom with four or Attribution (CC BY) license (https:// three substituents and one double bond. The core QAC structure can contain one (mono- creativecommons.org/licenses/by/ QAC), two (bis-QAC), or more (multi-QAC, poly-QAC) charged nitrogen atoms, including 4.0/). Int. J. Mol. Sci. 2021, 22, 6793. https://doi.org/10.3390/ijms22136793 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 77 Int. J. Mol. Sci. 2021, 22, 6793 2 of 82 The structure of QACs consists of a positively charged nitrogen atom with four or three substituents and one double bond. The core QAC structure can contain one (mono- QAC), two (bis-QAC), or more (multi-QAC, poly-QAC) charged nitrogen atoms, includ- ingthose those in heterocyclic in heterocyclic compounds compounds (piperidine, (piperidine, pyridine, pyridine, imidazole, imidazole, etc.). etc.). One One or or more more of ofthe the substituents substituents are are usually usually long long aliphatic aliphatic chains chains containingcontaining atat least ten carbon atoms. atoms. In the case of bis-QACs, multi-QACs, and poly-QACs, the structure that connects the In the case of bis-QACs, multi-QACs, and poly-QACs, the structure that connects the charged nitrogen atoms (the head or nucleus fragment) is called a spacer or linker, and charged nitrogen atoms (the head or nucleus fragment) is called a spacer or linker, and the alkyl chains extending from the heads (if they are present in the molecule) are called the alkyl chains extending from the heads (if they are present in the molecule) are called tails (Figure1). QACs are generally water-soluble and stable. The counterion in these tails (Figure 1). QACs are generally water-soluble and stable. The counterion in these com- compounds usually does not affect the biological activity but often impacts the solubility pounds usually does not affect the biological activity but often impacts the solubility of of the biocide. The majority of the registered QACs contain chloride or bromide as anions. the biocide. The majority of the registered QACs contain chloride or bromide as anions. Due to their amphiphilic nature, QACs are able to form micelles. The critical concentration Due to their amphiphilic nature, QACs are able to form micelles. The critical concentration of micelle formation (CCM) is one of the important characteristics of these substances. of micelle formation (CCM) is one of the important characteristics of these substances. Figure 1. GeneralGeneral structures structures and types of QACs. TheThe first first studies studies of of QACs QACs as as antibacterial antibacterial ag agentsents were carried out at the beginning of thethe 20th 20th century. century. Hexamethylenetetramine deri derivativesvatives exhibited exhibited an an inin vitro bactericidal effecteffect [4–6]. [4–6]. With With the the discovery discovery of of benzalkonium benzalkonium chloride (BAC) in 1935 [7], [7], QACs found applicationapplication in medicalmedical practice.practice. Subsequently,Subsequently, the the study study of of this this class class of compoundsof compounds has has led ledto the to discoverythe discovery of many of many valuable valuable properties properties of QACs, of QACs, due to due which to theywhich are they now are used now as usedsurfactants, as surfactants, personal personal hygiene hygiene products, products cosmetics,, cosmetics, softeners, softeners, dyes, biological dyes, biological dyes, and, dyes, of and,course, of course, antiseptics antiseptics and disinfectants and disinfectants with a widewith spectruma wide spectrum of action of [ 8action]. [8]. Therefore,Therefore, QACs QACs belong belong to to the group of biocides–chemical compounds designed to neutralize,neutralize, suppress, suppress, or or prevent prevent the action action of of harmful harmful organisms organisms by chemical or biological biological meansmeans [9]. [9]. As As an an example, example, in in2019, 2019, QACs QACs accounted accounted for forca. 11% ca. 11%of the of whole the whole biocide biocide mar- ketmarket in the in United the United States, States, which which equals equals ca. $192 ca. $192million million (Figure (Figure 2) [10].2)[ 10]. The U.S. biocide market has grown by ca. 12% since 2016. The global trade of biocides, including QACs, is expected to grow by 3.9% annually and to reach $10.5 billion in 2027, thus evidencing the relevance and popularity of the topic. In other countries, similar trends can be expected due to the unquestionable significance of QACs. Biocides are used in a wide variety of fields. Approximately 50% of biocide applica- tions in the global market are in the water purification and paint industry (Figure3)[ 10]. However, they also play an important role in the medical field [11]. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 77 Int. Int.J. Mol. J. Mol. Sci. 2021 Sci. 2021, 22, ,x22 FOR, 6793 PEER REVIEW 3 of 377 of 82 Figure 2. Biocide market in USA. The U.S. biocide market has grown by ca. 12% since 2016. The global trade of bio- cides, including QACs, is expected to grow by 3.9% annually and to reach $10.5 billion in 2027, thus evidencing the relevance and popularity of the topic. In other countries, similar trends can be expected due to the unquestionable significance of QACs. Biocides are used in a wide variety of fields. Approximately 50% of biocide applica- tions in the global market are in the water purification and paint industry (Figure 3) [10]. However, they also play an important role in the medical field [11]. Figure 2. BiocideFigure market 2. Biocide in USA. market in USA. The U.S. biocide market has grown by ca. 12% since 2016. The global trade of bio- cides, including QACs, is expected to grow by 3.9% annually and to reach $10.5 billion in 2027, thus evidencing the relevance and popularity of the topic. In other countries, similar trends can be expected due to the unquestionable significance of QACs. Biocides are used in a wide variety of fields. Approximately 50% of biocide applica- tions in the global market are in the water purification and paint industry (Figure 3) [10]. However, they also play an important role in the medical field [11].