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A series of long-chain imidazolium-based ionic liquids (ILs) 1-dodecyl-3-methylimidazolium chloride (1), 1,3-bis(octyloxycarbonylmethyl)imidazolium chloride (2) and 1-dodecyloxycarbonylmethyl-3-methyloxycarbonylmethylimidazolium chloride (3), were synthesized and evaluated as antimicrobials against a wide range of bacteria and fungi. Toxicological risks of selected compounds were assessed using the biomodels of various organizational and functional levels. All compounds demonstrated significant antibacterial and antifungal activity. The toxicity results indicate that ILs containing an ester functional group in the alkyl side chain exhibited much lower toxicity to D. magna and acetylcholinesterase inhibition than ILs with long alkyl chain without polar substituents, while toxicity toward Danio rerio was on a par. The HSA-binding properties of ILs have been investigated by FT-IR spectroscopy technique and the evidences have suggested that the test compounds could induce the protein unfolding and changes in the secondary structure of HSA. The docking studies were carried out to provide structural insights of the ILs–HSA-binding interactions. The docked compounds exhibit a high binding affinity to HSA and the hydrogen bonding, hydrophobic and electrostatic interactions played a major role in the process. ILs 2 and 3 may be perspective for further investigation as potential low-toxic biocides with high antimicrobial activity against reference and clinical multidrug-resistant strains.

Cationic polymer polyhexamethylene guanidine hydrochloride (PHMG-Cl) is promising biocide that combines a broad spectrum of antimicrobial activity, mod-erate toxicity, as well as reasonable cost. It is widely used as an effective disinfect-ant in cooling systems, swimming pools, and hospitals, personal hygiene products, etc. Recently PHMG-Cl was found to have pronounced anti-inflammatory and wound healing properties and therefore may be used for the treatment of chronic wounds and thermal burns. This may indicate the antioxidant activity of polymeric biocide. In this study, PHMG-Cl has been synthesized by melt polycondensation of guanidine hydrochloride and 1,6-hexamethylenediamine. The structure of the cati-onic polymer was confirmed by 1H NMR and IR spectroscopy. The viscosity-average molecular weight of PHMG-Cl was found to be 10700. The antioxidant activity of PHMG-Cl has been studied by using different methods. In the methylene blue (MB) dye test, the oxidation of MB by hydroxyl radicals generating in Fenton’s system was found to decrease in the presence of PHMG-Cl in a molar ratio to MB of 5:1 and 10:1 (by 26 % and 38 %, respectively). At the same time, complete dye oxidation was observed when guanidine hydrochloride was used instead of PHMG-Cl. The antioxidant activity of PHMG-Cl has also been studied in the model system of radical chain oxidation of benzyl alcohol (BA). In this system, alkyl and peroxyl radicals are formed. The antioxidant activity was determined by a decrease of the initial rate of oxygen absorption during the initiated oxidation of BA. The introduc-tion of PHMG-Cl into the oxidized system in the concentrations ranged from 1.3·10-3 - 1.6·10-2 mol/l decreased the oxidation rate of BA by 4.5–88 %. This result demonstrates that PHMG-Cl effectively inhibits radical chain oxidation of BA. However, further research is needed to elucidate the mechanism of free radical de-activation by a polymer biocide.

Background: The incidence of invasive fungal infections caused by Candida spp. has increased continuously in recent decades, especially in populations of immunocompromised patients or individuals hospitalized with serious underlying diseases. Therefore, the goal of our study was the search for new potent Candida albicans inhibitors via the development of QSAR models that could speed up this search process. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and experimentally tested. Furthermore, the toxicity of the studied compounds was determined in vitro using acetylcholinesterase enzyme as a biological marker. Methods: The classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors on the Online Chemical Modeling Environment (OCHEM) platform. Аntifungal properties of the investigated compounds were performed using standard disk diffusion method. The enzyme inhibitory action of the compounds was determined by modified Ellman's method using acetylcholinesterase from the electric organ of Electrophorus electricus. Results: Three classification QSAR models were developed by the WEKA-RF, k-NN and ASNN methods using the ALogPS, E-State indices and Dragon v.7 descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA = 80-91%. All compounds demonstrated good antifungal properties against Candida spp. and slight inhibition of the acetylcholinesterase activity. Conclusion: The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against Candida spp. Furthermore, 1,3-oxazol-4- yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.

In our previous work, a number of new nitrogen-containing bisphosphonates (N-BPs) with high predicted and experimental antifungal activity were presented as potential Candida albicans farnesyl pyrophos­phate synthase (FPPS) inhibitors. To confirm this hypothesis, a homologous C. albicans FPPS model with high-quality scores has been developed and used in present work to study the molecular mechanism of nit­rogen-containing bisphosphonates action as anti-Candida agents. The known FPPS inhibitors ammonium 2-(Pyridin-2-ylamino)ethylidene-1,1-bisphosphonate, risedronate and alendronate were used in molecular docking analysis. The molecular docking analysis of the new N-BPs demonstrated a number of common features of all ligand’s interaction in the active center of FPPS C. albicans. It is established that the ligands phosphonate groups are the key elements in the formation of the stable ligand-protein complexes with binding energy in a range (ΔG) from –6.6 to –7.1 kcal/mol due to a significant number of electrostatic, hydrogen and metal-acceptor bonds. It is confirmed that the new studied N-BPs 1 and 3 with high anti-Candida activity are FPPS inhibitors.

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 − 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.

Background: Due to the increase of multidrug-resistant microorganisms, the search for biologically active molecules does not stop. In the present study, we developed the effective QSAR model which allows a quick search of new potential Staphylococcus aureus inhibitors in the series of quaternary phosphonium salts. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and examined to confirm their antibacterial properties and the accuracy of the forecast. Furthermore, the toxicity of the investigated compounds was evaluated. Methods: The predictive QSAR model was developed using Artificial Neural Network approach. Antibacterial properties of the investigated compounds were performed using standard disk diffusion method. The toxicity of the compounds was determined in vivo using zebrafish (Danio rerio) and in vitro on acetylcholinesterase (AChE) enzyme as the test models. Results: The predictive ability of the regression model was tested by cross-validation, giving the cross-validated coefficient q2=0.82. Derivatives of 1,3-oxazol-4-yltriphenylphosphonium salts predicted as active were synthesized and screened for their antibacterial activities. All compounds demonstrated antibacterial activity according to the prediction. The toxicity tests indicated that all investigated samples were less toxic than well-known cationic surfactants. Conclusion: The most promising compound 2b exhibited strong antibacterial activity together with low toxicity and can be considered as a new efficient biocidal agent for future investigation. In addition, the proposed QSAR model can be used for predicting and designing novel potential S. aureus inhibitors among ionic liquids/salts.

The interaction between human serum albumin (HSA) and synthesized imidazolium and pyridinium based ionic liquids (ILs), as good potential microbial growth inhibitors, was investigated by spectroscopic techniques combined with molecular docking analysis. All compounds were significant active against the tested bacterial and fungal strains. FT-IR spectroscopy indicated that the interaction of HSA with ILs generates considerable changes in protein secondary structure. The results of the molecular docking study showed that the studied ILs are able to firmly bind in the subdomain IIA of HSA with almost equal binding affinity (about −6.23 kcal/mol). Investigated HSA–ILs complex binds through hydrogen bonding or/and cation-π interactions. This study provides a better understanding of the binding of imidazolium and pyridinium based ILs to HSA and opens the way for their further biological and pharmaceutical investigations as candidates with antimicrobial properties.

A new polymeric biocide polyhexamethylene guanidine (PHMG) molybdate has been synthesized. The obtained cationic polymer has limited water solubility of 0.015 g/100 mL and is insoluble in paint solvents. The results of acute toxicity studies indicate moderate toxicity of PHMG molybdate, which has a median lethal dose at 48 h of 0.7 mg/L for Daphnia magna and at 96 h of 17 mg/L for Danio rerio (zebrafish) freshwater model organisms. Commercial ship paint was then modified by the addition of a low concentration of polymeric biocide 5% (w/w). The painted steel panels were kept in Dnipro River water for the evaluation of the dynamics of fouling biomass. After 129-d exposure, Bryozoa dominated in biofouling of tested substrates, forming 86% (649 g/m2 ) of the total biomass on control panel surfaces. However, considerably lower Bryozoa fouling biomass (15 g/m2 ) was detected for coatings containing PHMG molybdate. Dreissenidae mollusks were found to form 88% (2182 g/m2 ) of the fouling biomass on the control substrates after 228 d of exposure, whereas coatings containing PHMG molybdate showed a much lower biomass value of 23.6 g/m2 . The leaching rate of PHMG molybdate in water was found to be similar to rates for conventional booster biocides ranging from 5.7 μg/cm2 /d at the initial stage to 2.2 μg/cm2 /d at steady state. Environ Toxicol Chem 2017;36:2543-2551. © 2017 SETAC.

The regression QSAR models were built to predict the antimicrobial activity of new thiazole derivatives. Compounds with high predicting activity were synthesized and evaluated against Gram-positive and Gram-negative bacteria and fungi. 1,3-Thiazole-4-ylphosphonium salts 4 and 5 displayed good antibacterial properties and high antifungal activity. The predictions are in a good agreement with the experiment results, which indicate the good predictive power of the created QSAR models.

Quantitative structure-activity relationships (QSAR) of imidazolium ionic liquids (ILs) as inhibitors of C. albicans collection strains (IOA-109, KCTC 1940, ATCC 10231) have been studied. Predictive QSAR models were built using different descriptor sets for a set of 88 ionic liquids with known minimum inhibitory concentrations (MIC) against C. albicans. We applied the state-of-the-art QSAR methodologies such as WEKA Random Forest (RF) as a binary classifier, Associative Neural Networks (ASNN) and k-Nearest Neighbors (k-NN) to build continuum non-linear regression models. The obtained models were validated using a 5-fold cross-validation approach and resulted in the prediction accuracies of 80% ± 5.0 for the classification models and q2 = 0.73-0.87 for the non-linear regression models. Biological testing of newly synthesized 1,3-dialkylimidazolium ionic liquids with predicted activity was performed by disco-diffusion method against C. albicans ATCC 10231 M885 strain and clinical isolates C. albicans, C. krusei and C. glabrata strains. The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models within the applicability domain of new imidazolium ionic liquids.

Online Chemical Modeling Environment (OCHEM) was used for QSAR analysis of a set of ionic liquids (ILs) tested against multi-drug resistant (MDR) clinical isolate Acinetobacter baumannii and Staphylococcus aureus strains. The predictive accuracy of regression models has coefficient of determination q2 = 0.66 &minus, 0.79 with cross-validation and independent test sets. The models were used to screen a virtual chemical library of ILs, which was designed with targeted activity against MDR Acinetobacter baumannii and Staphylococcus aureus strains. Seven most promising ILs were selected, synthesized, and tested. Three ILs showed high activity against both these MDR clinical isolates.

Water immiscible ionic liquid 1-dodecyl-3-methylimidazolium tetrafluoroborate (DMIM-BF 4 ) and its inclusion complex with β-cyclodextrin (β-CD) in molar ratio 1:1 have been synthesized. The formation of DMIM-BF 4 /β-CD complex was confirmed by FT-IR analysis, 1 H NMR analysis, and differential scanning calorimetry data. Our results indicate that the aliphatic tail of DMIM-BF 4 is included into β-CD inner cavity whereas imidazolium ring is located outside the torus. Moreover, the weak interaction between polar components of ionic liquid and hydrophilic outer surface of β-CD has also been detected. The standard agar disk diffusion method was performed to evaluate antimicrobial efficiency of the obtained compounds against Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922) and Pseudomonas aeruginosa (ATCC-27853), Candida albicans (M 885 ATCC 10231) and its clinical isolate test-cultures. It has been found that both DMIM-BF 4 and DMIM-BF 4 /β-CD complex possess high antimicrobial activity as revealed by similar zone inhibition values against all tested microorganisms. The acute toxicity studies on Danio rerio (zebrafish) model organism showed that the pure ionic liquid DMIM-BF 4 is slightly toxic compound having LD 50 value of 7 mg/L, whereas DMIM-BF 4 /β-CD complex has considerably reduced toxicity (LD 50 = 100 mg/L) and therefore have potentially wider application areas.

Predictive QSAR models for the inhibitors of B. subtilis and Ps. aeruginosa among imidazolium-based ionic liquids were developed using literary data. The regression QSAR models were created through Artificial Neural Network and k-nearest neighbor procedures. The classification QSAR models were constructed using WEKA-RF (random forest) method. The predictive ability of the models was tested by fivefold cross-validation; giving q(2) = 0.77-0.92 for regression models and accuracy 83-88% for classification models. Twenty synthesized samples of 1,3-dialkylimidazolium ionic liquids with predictive value of activity level of antimicrobial potential were evaluated. For all asymmetric 1,3-dialkylimidazolium ionic liquids, only compounds containing at least one radical with alkyl chain length of 12 carbon atoms showed high antibacterial activity. However, the activity of symmetric 1,3-dialkylimidazolium salts was found to have opposite relationship with the length of aliphatic radical being maximum for compounds based on 1,3-dioctylimidazolium cation. The obtained experimental results suggested that the application of classification QSAR models is more accurate for the prediction of activity of new imidazolium-based ILs as potential antibacterials.