Antimicrobial toxicity studies of ionic liquids leading to a ‘hit’ MRSA selective antibacterial imidazolium salt

Coleman, Deborah; Špulák, Marcel; Garcı́a, M. Teresa; Gathergood, Nicholas

doi:10.1039/c2gc16090k

Cited by 103 publications

(80 citation statements)

References 19 publications

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“…2 Readily biodegradable amino acid ILs. 15 Biodegradation values assessed by the CO 2 Headspace test ISO 14593. example, 1-methylimidazole), to yield the target ILs (4-15) ( Table 1). Compound 4 has been previously prepared by Gathergood et al in 98% yield using THF as the solvent, 15 however a slightly lower yield of 4 was obtained using diethyl ether (entry 1).…”

Section: Resultsmentioning

confidence: 99%

“…During the reaction condition optimisation for alkylating reagent 26 (see Table 3 for optimisation), metric analysis was also conducted on each of the reaction conditions (entries 1-4). The original conditions reported by Coleman et al 15 for the formation of 26 involving the use of two equivalents of triethylamine and purification by column chromatography led to a poor atom economy of 50% and an E-factor of 705.1. The solvent and mass intensities of the reaction are similarly affected.…”

Section: Green Chemistry Metricsmentioning

confidence: 98%

“…2). 15 This is in stark contrast to ILs containing an ester functional group, where facile breakdown to the carboxylic acid and conversion of the alcohol to CO 2 is widely reported. 25,36 However, even with these ester containing ILs, the carboxylic acid transformation product has been shown to persist after a 28 day CBT.…”

Section: Introductionmentioning

confidence: 95%

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Synthesis of a series of amino acid derived ionic liquids and tertiary amines: green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis

Jordan

Haiß

Špulák³

et al. 2016

Green Chem.

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A series of L-phenylalanine ionic liquids (ILs), L-tyrosine ILs, tertiary amino analogues and proposed transformation products (PTPs) have been synthesised. Antimicrobial toxicity data, as part of the green chemistry metrics evaluation and to supplement preliminary biodegradation studies, was determined for ILs, tertiary amino analogues and PTPs. Good to very good overall yields (76 to 87%) for the synthesis of 6 ILs from L-phenylalanine were achieved. A C 2 -symmetric IL was prepared from TMS-imidazole in a one-pot two-step method in excellent yield (91%). Synthesis of the L-tyrosine IL derivatives utilised a simple protection group strategy by using an extra equivalent of the bromoacetyl bromide reagent. Improvements in the synthesis of the α-bromoamide alkylating reagent from L-phenylalanine were achieved, directed by green chemistry metric analysis. A solvent switch from dichloromethane to THF is described, however the yield was 15% lower. Antimicrobial activity testing of L-phenylalanine ILs, L-tyrosine ILs, tertiary amino analogues and PTPs, against 8 bacteria and 12 fungi strains, showed that no compound had a high antimicrobial activity, apart from an L-proline analogue. In this exceptional case, the highest toxicity (IC 95 = 125 and 250 µM) was observed towards the two Gram positive strains Staphylococcus aureus and Staphylococcus epidermidis respectively. High antimicrobial activity was not found for the other bacteria or fungi strains screened. The limitations of the antimicrobial activity study is discussed in relation to SAR studies. Preliminary analysis of biodegradation data (Closed Bottle Test, OECD 301D) is presented. The pyridinium IL derivative is the preferred green IL of the series based on synthesis, toxicity and biodegradation considerations. This work is a joint study with Kümmerer and co-workers and the PTPs were selected as target compounds based on concurrent biodegradation studies by the Kümmerer group. For the comprehensive biodegradation and transformation product analysis see the accompanying paper.

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Section: Resultsmentioning

confidence: 99%

Section: Green Chemistry Metricsmentioning

confidence: 98%

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Synthesis of a series of amino acid derived ionic liquids and tertiary amines: green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis

Jordan

Haiß

Špulák³

et al. 2016

Green Chem.

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“…36 In fact, the minimal inhibitory concentration (MIC) values for imidazolium, pyridinium, phosphonium, and ammonium-based ILs regarding various types of bacteria and fungi show improved antimicrobial activities relative to conventional antimicrobial agents. 24,28,36,37 This antimicrobial activity has been found to be closely related to the length of the alkyl chain of the cation, with longer chains exhibiting greater antimicrobial efficacy. 12,34,37 However, this biological efficacy does not increase indefinitely with increasing chain length, and this phenomenon has been referred to as the cutoff effect.…”

Section: Introductionmentioning

confidence: 97%

Impact of Ionic Liquids in Aqueous Solution on Bacterial Plasma Membranes Studied with Molecular Dynamics Simulations

et al. 2014

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The impact of five different imidazolium-based ionic liquids (ILs) diluted in water on the properties of a bacterial plasma membrane is investigated using molecular dynamics (MD) simulations. Cations considered are 1-octyl-3-methylimidazolium (OMIM), 1-octyloxymethyl-3-methylimidazolium (OXMIM), and 1-tetradecyl-3-methylimidazolium (TDMIM), as well as the anions chloride and lactate. The atomistic model of the membrane bilayer is designed to reproduce the lipid composition of the plasma membrane of Gram-negative Escherichia coli. Spontaneous insertion of cations into the membrane is observed in all ILs. Substantially more insertions of OMIM than of OXMIM occur and the presence of chloride reduces cation insertions compared to lactate. In contrast, anions do not adsorb onto the membrane surface nor diffuse into the bilayer. Once inserted, cations are oriented in parallel to membrane lipids with cation alkyl tails embedded into the hydrophobic membrane core, while the imidazolium-ring remains mostly exposed to the solvent. Such inserted cations are strongly associated with one to two phospholipids in the membrane. The overall order of lipids decreased after OMIM and OXMIM insertions, while on the contrary the order of lipids in the vicinity of TDMIM increased. The short alkyl tails of OMIM and OXMIM generate voids in the bilayer that are filled by curling lipids. This cation induced lipid disorder also reduces the average membrane thickness. This effect is not observed after TDMIM insertions due to the similar length of cation alkyl chain and the fatty acids of the lipids. This lipid-mimicking behavior of inserted TDMIM indicates a high membrane affinity of this cation that could lead to an enhanced accumulation of cations in the membrane over time. Overall, the simulations reveal how cations are inserted into the bacterial membrane and how such insertions change its properties. Moreover, the different roles of cations and anions are highlighted and the fundamental importance of cation alkyl chain length and its functionalization is demonstrated.

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“…Gathergood and co-workers have recently studied amino acid-functionalized imidazolium salts on their activity towards MRSA (methicillin-resistant Staphylococcus aureus) [11]. Some of the salts were sufficiently active and additionally showed a reasonable level of biodegradibility.…”

Section: Introductionmentioning

confidence: 99%

BIOnic Liquids: Imidazolium-based Ionic Liquids with Antimicrobial Activity

Postleb

Stefanik

Seifert

et al. 2013

Zeitschrift Für Naturforschung B

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We have synthesized twelve new ionic liquids composed of an imidazolium-based cation in combination with an anion that shows antiobiotic or analgesic activity. These "BIOnic Liquids" have been tested towards their antibiotic activity in a standardized microbiological assay. A surprizingly large number of compounds shows high activity towards a set of bacteria which cannot be explained as simple cumulative effects. The general concept opens up completely new possibilities for the future development of pharmaceutically active compounds.

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Antimicrobial toxicity studies of ionic liquids leading to a ‘hit’ MRSA selective antibacterial imidazolium salt

Cited by 103 publications

References 19 publications

Synthesis of a series of amino acid derived ionic liquids and tertiary amines: green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis

Synthesis of a series of amino acid derived ionic liquids and tertiary amines: green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis

Impact of Ionic Liquids in Aqueous Solution on Bacterial Plasma Membranes Studied with Molecular Dynamics Simulations

BIOnic Liquids: Imidazolium-based Ionic Liquids with Antimicrobial Activity

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