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Synthesis, Structure and Antimicrobial Properties of Novel Benzalkonium Chloride Analogues with Pyridine Rings

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Synthesis, Structure and Antimicrobial Properties of Novel Benzalkonium Chloride Analogues with Pyridine Rings molecules Article Synthesis, Structure and Antimicrobial Properties of Novel Benzalkonium Chloride Analogues with Pyridine Rings Bogumił Brycki 1,*, Izabela Małecka 1, Anna Koziróg 2 and Anna Otlewska 2 1 Laboratory of Microbiocides Chemistry, Faculty of Chemistry, Adam Mickiewicz University in Poznan, Umultowska 89b, 61-614 Pozna´n,Poland; [email protected] 2 Institute of Fermentation Technology and Microbiology, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Wólcza´nska171/173, 90-924 Łód´z,Poland; [email protected] (A.K.); [email protected] (A.O.) * Correspondence: [email protected]; Tel.: +48-61-829-1694 Academic Editor: Derek J. McPhee Received: 9 December 2016; Accepted: 9 January 2017; Published: 13 January 2017 Abstract: Quaternary ammonium compounds (QACs) are a group of compounds of great economic significance. They are widely used as emulsifiers, detergents, solubilizers and corrosion inhibitors in household and industrial products. Due to their excellent antimicrobial activity QACs have also gained a special meaning as antimicrobials in hospitals, agriculture and the food industry. The main representatives of the microbiocidal QACs are the benzalkonium chlorides (BACs), which exhibit biocidal activity against most bacteria, fungi, algae and some viruses. However, the misuses of QACs, mainly at sublethal concentrations, can lead to an increasing resistance of microorganisms. One of the ways to avoid this serious problem is the introduction and use of new biocides with modified structures instead of the biocides applied so far. Therefore new BAC analogues P13–P18 with pyridine rings were synthesized. The new compounds were characterized by NMR, FT-IR and ESI-MS methods. PM3 semiempirical calculations of molecular structures and the heats of formation of compounds P13–P18 were also performed. Critical micellization concentrations (CMCs) were determined to characterize the aggregation behavior of the new BAC analogues. The antimicrobial properties of novel QACs were examined by determining their minimal inhibitory concentration (MIC) values against the fungi Aspergillus niger, Candida albicans, Penicillium chrysogenum and bacteria Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa. The MIC values of N,N-dimethyl-N-(4-methylpyridyl)-N-alkylammonium chlorides for fungi range from 0.1 to 12 mM and for bacteria, they range from 0.02 to 6 mM. Keywords: quaternary ammonium salts; benzalkonium chlorides; biocides; antimicrobial resistance; minimal inhibitory concentration; critical micellization concentrations 1. Introduction Quaternary ammonium compounds (QACs) are a group of cationic surfactants widely used in household, agricultural, clinical and industrial products. QACs are surface active organic compounds containing at least one long hydrocarbon substituent attached covalently to a positively charged quaternary nitrogen atom. The other substituents can be alkyl, aromatic, ether or ester groups. Owing to the varied structures and a wide span of hydrophilic–lipophilic balance QACs are extensively used as emulsifiers [1], dispersants [2,3], fabric softeners [4], cosmetic ingredients [5] and phase transfer catalysts [6,7], gene delivery agents [8], antimicrobial [9,10] and anticorrosion [11,12] agents. Among a large number of cationic surfactants, examples of which are shown in Figure1, benzalkonium chlorides 3 deserve the special attention due to their unique biocidal properties. Molecules 2017, 22, 130; doi:10.3390/molecules22010130 www.mdpi.com/journal/molecules Molecules 2017, 22, 130 2 of 12 Molecules 2017, 22, 130 2 of 12 They were presented for the first time as antimicrobial agents by Domagk in 1935 [13]. Nowadays, they arewere widely presented used for as the disinfectants first time as antimicrobial and antiseptics, agents as by well Domagk as preservatives in 1935 [13]. Nowadays, for ophthalmic, they are nasal widely used as disinfectants and antiseptics, as well as preservatives for ophthalmic, nasal and and inhalationalMolecules 2017, 22 drugs., 130 They are also active substances in medicines for throat and mouth2 infections. of 12 inhalational drugs. They are also active substances in medicines for throat and mouth infections. The The mechanism of their biocidal action toward most bacteria, fungi and algae is based on adsorption mechanism of their biocidal action toward most bacteria, fungi and algae is based on adsorption of of thewere alkylammonium presented for the cation first time on as the antimicrobial bacterial cell agents surface, by Domagk diffusion in 1935 through [13]. Nowadays, the cell wall they and are then widelythe alkylammonium used as disinfectants cation on and the antiseptics, bacterial cell as suwellrface, as diffusionpreservatives through for ophthalmic,the cell wall nasal and thenand binding and disruption of cytoplasmatic membrane. Damage to the membrane results in a release of inhalationalbinding and drugs. disruption They of are cytoplasmatic also active substances membrane. in Damagemedicines to for the throat membrane and mouth results infections. in a release The of potassium ions and other cytoplasmatic constituents, finally leading to the death of the cell [14–17]. mechanismpotassium ions of their and biocidalother cytoplasmatic action toward constituents, most bacteria, finally fungi leading and algaeto the is death based of on the adsorption cell [14–17]. of the alkylammonium cation on the bacterial cell surface, diffusion through the cell wall and then binding and disruption of cytoplasmatic membrane. Damage to the membrane results in a release of potassium ions and other cytoplasmatic constituents, finally leading to the death of the cell [14–17]. FigureFigure 1. 1.Examples Examples of of antimicrobial antimicrobial quaternaryquaternary ammonium ammonium halides: halides: alkylpyridinium alkylpyridinium (1); (1); alkyltrimethylammoniumalkyltrimethylammonium (2); (2 benzalkonium); benzalkonium ( 3(3);); dialkyldimethylammoniumdialkyldimethylammonium (4) (and4) and diesteralkonium diesteralkonium (5). (5). However, in recent years there have been frequent reports of cases of increasing resistance of Figure 1. Examples of antimicrobial quaternary ammonium halides: alkylpyridinium (1); However,certain microorganism in recent years strains there to the have biocidal been activi frequentty of benzalkonium reports of cases chlorides of increasing [18–21]. The resistance use of of alkyltrimethylammonium (2); benzalkonium (3); dialkyldimethylammonium (4) and diesteralkonium (5). certaininappropriate microorganism concentrations strains toof benzalkonium the biocidalactivity chlorides of and benzalkonium incomplete removal chlorides of residues [18–21 of]. these The use of inappropriatemicrobiocidesHowever, concentrations afterin recent finishing years the there of disinfection benzalkonium have been pr frequentocess chlorides exposes reports andmicroorganisms of incompletecases of increasing to removal prolonged resistance of contact residues of of thesecertainwith microbiocides sublethal microorganism doses after of strains finishingBACs. toThis the the contributes biocidal disinfection activi to thety processdevelopmentof benzalkonium exposes of defensive chlorides microorganisms mechanisms [18–21]. The to and use prolonged the of contactinappropriateemergence with sublethal of concentrationsstrains doses of microorganisms of of BACs. benzalkonium This exhibiting contributes chlorides resistanceto and the incomplete developmentto benzalkonium removal of chloridesdefensiveof residues as mechanismsof well these as cross-resistance to certain other antibiotics [22,23]. This fact creates a serious epidemiological threat, and themicrobiocides emergence after of strainsfinishing of the microorganisms disinfection process exhibiting exposes resistance microorganisms to benzalkonium to prolonged chloridescontact as especially in medical facilities, manifested by an increase in morbidity and mortality among patients wellwith as cross-resistance sublethal doses toof BACs. certain This other contributes antibiotics to the [22 development,23]. This fact of createsdefensive a seriousmechanisms epidemiological and the [24]. One of the way to overcome this serious negative side effect is a periodically application of new threat,emergence especially of strains in medical of microorganisms facilities, manifested exhibiting by resistance an increase to benzalkonium in morbidity chlorides and mortality as well as among cross-resistancemicrobiocides with to certain modified other structures. antibiotics [22,23]. This fact creates a serious epidemiological threat, patients [24]. One of the way to overcome this serious negative side effect is a periodically application especiallyTo meet in medical this challenge facilities, we manifested have proposed by an aincrease modification in morbidity of benzalkonium and mortality chlorides among based patients on of new microbiocides with modified structures. [24].the introduction One of the way of nitrogen to overcome atoms this into serious the aromatic negative ring. side For effect that is reason a periodically a series of application novel quaternary of new microbiocidesToammonium meet this compounds challengewith modified weP13– havestructures.P18 with proposed variable a modificationalkyl chain length of benzalkonium and bearing pyridine chlorides rings based instead on the introductionof phenylTo meet of rings nitrogen this were challenge synthesized. atoms we into have In the
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