Authors gratefully acknowledge the financial support of grant received from ICMR, Government of India, Delhi-110029 [No./ICMR/ 52/06/2022-BIO/BMS]. Authors would also like to thank the University Science &#38; Instrumentation facility (USIC), University of Delhi, for extending the analytical help. Kajal Sharma acknowledges the financial support received from the Department of Science and Technology through INSPIRE scheme (IF200397).

NOTE: 1-Hexadecylquinolin-1-ium bromide{[C16quin]Br} was synthesized as described previously by Sharma et al.13.
1. Preparation and sterilization of glass apparatus 
NOTE: This should be done at least 1 day prior to setting up the reaction for the synthesis of the desired compound.
<ol>
	<li>Wash a 24/29, 250 mL, two-neck round bottom flask (RB) thoroughly, along with other glass apparatus such as measuring cylin...

Synthesis of Quinoline-Based Ionic Liquids for Antimicrobial Applications

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V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Applications+of+ionic+liquids+in+electrochemical+sensors+and+biosensors.">Applications of ionic liquids in electrochemical sensors and biosensors.</a> Int J Electrochem. 2012 (9), 112-125 (2012).</li><li>Must, I., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ionic+liquid-based+actuators+working+in+air:+The+effect+of+ambient+humidity.">Ionic liquid-based actuators working in air: The effect of ambient humidity.</a> Sens Actuat B: Chemical. 202 (3), 114-122 (2014).</li><li>Ray, A., Saruhan, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+ionic+liquids+for+batteries+and+supercapacitors.">Application of ionic liquids for batteries and supercapacitors.</a> Materials. 14 (11), 2942 (2021).</li><li>Alashkar, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+critical+review+on+the+use+of+ionic+liquids+in+proton+exchange+membrane+fuel+cells.">A critical review on the use of ionic liquids in proton exchange membrane fuel cells.</a> Membranes. 12 (2), 178 (2022).</li><li>Busetti, A., Crawford, R. J., Ivanova, E. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Antimicrobial+and+antibiofilm+activities+of+1-alkylquinolinium+bromide+ionic+liquids.">Antimicrobial and antibiofilm activities of 1-alkylquinolinium bromide ionic liquids.</a> Green Chem. 12 (3), 420-425 (2010).</li><li>Sharma, K., Sharma, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vitro+anti-biofilm+activity+and+the+artificial+chaperone+activity+of+quinoline-based+ionic+liquids.">In vitro anti-biofilm activity and the artificial chaperone activity of quinoline-based ionic liquids.</a> Colloids Surfaces B: Biointer. 235, 113773 (2024).</li><li>Qashou, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Antiproliferative+activities+of+lipophilic+fluoroquinolones-based+scaffold+against+a+panel+of+solid+and+liquid+cancer+cell+lines.">Antiproliferative activities of lipophilic fluoroquinolones-based scaffold against a panel of solid and liquid cancer cell lines.</a> Asian Paci J Cancer Prevent. 23 (5), 1529-1538 (2022).</li><li>Patel, H. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+new+mannich+products+bearing+quinoline+nucleus+using+reusable+ionic+liquid+and+antitubercular+evaluation.">Synthesis of new mannich products bearing quinoline nucleus using reusable ionic liquid and antitubercular evaluation.</a> Green Sust Chem. 5 (4), 137-144 (2015).</li><li>Joshi, D. R., Adhikari, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=An+overview+on+common+organic+solvents+and+their+toxicity.">An overview on common organic solvents and their toxicity.</a> J Pharm Res Int. 28 (3), 1-18 (2019).</li><li>Sanchez, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Air+and+breath+analysis+for+the+assessment+of+exposure+to+solvent+emissions+in+university+chemistry+laboratories.">Air and breath analysis for the assessment of exposure to solvent emissions in university chemistry laboratories.</a> Atm Pollut Res. 10 (6), 1795-1802 (2019).</li><li>Sowmiah, S., Esperanca, J. M. S. S., Rebelo, L. P. N., Afonso, C. A. 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Lately, ILs have divulged various promising implementations in the field of biochemical sciences including protein refolding/ chaperone activity, drug delivery vehicles, and/or catalysts in several organic reactions. Their intriguing physicochemical properties, such as tunability, biocompatibility, solubility, sustainability, stability, etc., have made them potential candidates for the development of novel therapeutic agents20. The proposed research visualizes AMR as a matter of grave concern and ...

The monumental growth in the world population accounts for a tremendous increment in the consumption of a vast array of commodities over the past few years, including food, medicaments, as well as other crucial products for the sustenance of mortal organisms. This has invigorated the quest for novel chemical compounds with exceptionally specialized, ecologically sound, and beneficial properties worldwide. Ionic Liquids (ILs) have proved to be felicitous in this regard. The implication of these compounds in the scientific domain has bolstered new ventures in research in contemporary chemical technologies1. In contrast to the conventional approaches, the utilization of ILs not only facilitates progressive reaction conditions but also promotes a customized strategy to get to grips with various biochemical challenges related to experimental research and development2.
Typically, ILs are stable salts constituting cations (organic) and anions (inorganic), possessing a melting point below 100 &#176;C3. Abiding by the 12 principles of green chemistry, empirically, these are convincing substitutes to the customary organic solvents4. The astounding properties associated with the utilization of these compounds encompass great intrinsic conductivity, polarity, solvating tendency, thermal stability, non-volatility, acidity/basicity, hydrophilicity/ hydrophobicity, and tunability, making ILs best suited for experimental research5.
Apart from the expansive applications of various classes of ILs in modern organic synthesis6, catalysis7, and various electrochemical processes involving sensors8, actuators9, batteries10, and fuel cells11, over the past few years, this class of compounds has been given momentous recognition in the field of biomedicine in light of AMR. Current probations reveal that ILs based on imidazolium, pyridine, choline, and pyrrole are extremely effective as therapeutic agents owing to their high charge and hydrophobicity12. However, quinoline-based counterparts are still considered to be most potent against the pathogenic microbes12. Additional biomedical applications accompanying this class of ILs include artificial chaperone activity13, cytotoxicity against cancerous cells14 as well as an excellent drug-carrying capacity15.
Conventionally, the fabrication of ILs involves the utilization of highly toxic solvent mediums such as dichloromethane, benzene, carbon tetrachloride, dichloroethylene, etc.16, hindering the biocompatibility and elevating the toxicity of the compound, making them undesirable for biological use. Additionally, the use of harmful solvents in the reaction media not only slows down the reaction time but also increases the unintentional production of waste byproducts released into the environment17. Moreover, the dissolvent used in the reaction media also influences the pH of the final product; hence, its removal at the end of the reaction is vital, especially when the desired compound is intended to be used for protein-related biological systems. Hence, keeping away from the usage of such solvent is favorable in the realm of green chemistry.
In this study, we report the one-pot synthesis of a biocompatible and non-toxic13 IL, namely, 1-Hexadecylquinolin-1-ium bromide, using a greener route. The present strategy omits the utilization of a molecular solvent, leveraging the self-solvating ability of the IL formed within the reaction mixture, promoting high reaction efficiency and chemical yield. Menschutkin reaction18forms the basis of the&#160;current synthesis methodology. The purity of the synthesized compound is probed using NMR and IR spectroscopy. The pharmacokinetic profile of the compound and toxicity were investigated through the ADMET studies. Furthermore, the antimicrobial potential of the synthesized IL against the pathogenic Candida albicans strain has also been demonstrated in the study.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>1-bromohexadecane</td>
			<td>Merck</td>
			<td>CAS no.112-82-3</td>
			<td>95% pure (as determined by HPLC analysis)</td>
		</tr>
		<tr>
			<td>Ethyl acetate</td>
			<td>Merck</td>
			<td>CAS no. 205-500-4</td>
			<td>95% pure (as determined by HPLC analysis)</td>
		</tr>
		<tr>
			<td>Nuclear Magnetic Resonance (NMR) spectrometer</td>
			<td>Jeol, Model: JNM-ECZ 400S</td>
			<td>Nil</td>
			<td>Nil</td>
		</tr>
		<tr>
			<td>Quinoline</td>
			<td>Merck</td>
			<td>CAS no.91-22-5</td>
			<td>95% pure (as determined by HPLC analysis)</td>
		</tr>
		<tr>
			<td>Toluene</td>
			<td>Merck</td>
			<td>CAS no. 108-88-3</td>
			<td>95% pure (as determined by HPLC analysis)</td>
		</tr>
	</tbody>
</table>

green synthesis of quinoline-based ionic liquid

The ever-growing menace of Antimicrobial Resistance (AMR) jeopardizes the potency of the prevailing antibiotics against the relentlessly sprouting infections spawned by bacteria, viruses, parasites as well as fungi, posing a great threat to human health and well-being. In this regard, several novel molecules have proved their mettle, with Ionic Liquids (ILs) being one of the most eco-friendly, non-volatile, and thermally stable alternatives to the existing antimicrobials, possessing high solvating potential as well as low vapor pressure. Moreover, the utilization of these entities in both stabilizing as well as destabilizing protein structures and enhancing enzymatic activity has further raised their potential in the biomedical industry. With this in view, we present the green synthesis and characterization of quinoline-based IL, owing to its immense antimicrobial potency, with low cytotoxicity and great artificial chaperone activity. Here, maneuvering the one-pot synthesis approach in solvent-free, greener reaction conditions not only ameliorated the reaction efficiency but also augmented the chemical yield. The purity of the synthesized IL was corroborated using 1H Nuclear Magnetic Resonance (NMR), 13C NMR, and Infrared (IR) spectroscopy. The biological potential of the synthesized compound is further validated by analyzing its Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties and authenticated using disc diffusion assay.

Author Spotlight: Advancing Antimicrobial Resistance Research with Innovative Approaches and Synthetic Compounds

Green Synthesis of Quinoline-Based Ionic Liquid

Antimicrobial resistance is a complex global health threat that requires a multifaceted research approach. AMR research aims to better understand the phenomena, develop effective interventions, and mitigate the global health threat posed by antimicrobial resistance. The field of AMR has seen significant advancements in recent years with researchers exploring innovative approaches to combat the growing global health threat.Research is being done to develop antibiotic therapies, alternative approaches, improve diagnostics, infection preventions, et cetera. A variety of technologies are being employed to x-ray, research and development in the field of AMR, such as genomics and bioinformatics, nanotechnology for drug delivery and biosensors, artificial intelligence and machine learning to analyze data and patterns related to AMR. We're currently working on reducing the reaction time and optimizing the speed of the reaction under desired conditions, keeping the purity of the product our topmost priority.Over the years, a large number of synthetic compounds have been fabricated with the potential to be utilized as antimicrobial agents. However, their synthesis involves the use of several harmful chemical solvents imparting their own potency over the test organisms, enhancing their toxicity and limiting their applications in the field of biomedical chemistry.

Figure 2&#160;represents the reaction scheme of the Menschutkin reaction involved in bringing about the synthesis process. 1-Hexadecylquinolin-1-ium bromide, thus synthesized, was characterized using NMR and IR spectroscopy. The oily product so acquired is expected to exhibit 1H NMR (400 MHz, CDCl3) at &#948; 9.34 (d, 1H), 8.21 (d, 1H), 7.80 (t, 1H), 7.30-7.35 (m, 3H), 7.20 (d, 1H), 5.00 (t, 2H), 2.00 (p,2H), 1.30-1.35 (m, 26H), 1 (t, 3H), as demonstrated in <strong cla...

In the present work, we elucidate the green synthesis of quinoline-based Ionic Liquid (IL), namely, 1-Hexadecylquinolin-1-ium bromide {[C16quin]Br} by mixing quinoline with an excess of 1-Bromohexadecane, along with its detailed characterization using Nuclear Magnetic Resonance and Infrared spectroscopic measurements.

The ever-growing menace of Antimicrobial Resistance (AMR) jeopardizes the potency of the prevailing antibiotics against the relentlessly sprouting ...

green-synthesis-of-quinoline-based-ionic-liquid

Research

JoVE Journal

Chemistry

Synthesis, Purification, and Characterization of 1-Hexadecylquinolin-1-ium Bromide with Antimicrobial Evaluation Against Candida albicans

To begin, preheat an oil bath to 80 degrees Celsius on a hot plate with a magnetic stirrer. Then with the help of a tube retort stand, half immerse the round bottom flask in the oil bath. Seal the upper mouth of the flask with a cork containing a purging needle connected to a syringe and an attached nitrogen balloon.Tightly seal the other neck of the flask to prevent the leakage of nitrogen from the reaction medium. Preheat the entire assembly to 80 degrees Celsius in an inert atmosphere maintained through nitrogen purging. Pour 0.1 molar quinoline and 0.105 molar 1-bromohexadecane into the reaction system.Stir the mixture continuously at 2, 500 to 3, 000 RPM for three days under an inert environment and constant temperature. Next, dissolve the obtained solid in a one is to two toluene ethyl ethanoate mixture. Cool the mixture to minus 15 degrees Celsius in a deep freezer.To filter the mixture, attach a Buchner funnel to a vacuum pump and a filter flask through tubing. Place a polypropylene filter membrane with a pore size of 0.45 micrometers at the bottom of the funnel. Pour a small amount of the solvent mixture through the filter to create a proper seal.After filtering, gradually pour cold toluene through the funnel to wash the filtered product. Measure one to 10 milligrams of the compound and dissolve it in one milliliter of deuterated chloroform. Using a one milliliter syringe, inject the dissolved compound into an NMR tube.To predict ADMET properties, open the ADMET Lab 2.0 software and enter the canonical SMILES of the desired ionic liquid. Execute the program to obtain various parameters validating the biological potential of the compound. Subculture fungal strain of Candida albicans in yeast peptone dextrose broth for 16 hours at 37 degrees Celsius under shaking.Meanwhile, pour 25 milliliters of freshly prepared yeast peptone dextrose containing 15%agar into a 90 millimeter Petri plate, and allow the medium to solidify. Using a glass spreader spread approximately 100 microliters of freshly prepared fungal inoculum over the media surface. After five to seven minutes, use forceps to place a sterile circular paper disc of five to six millimeters in the center of the plate.Add 50 microliters of 0.1 millimolar synthesized ionic liquid water as solvent control and amphotericin B as positive control onto the disc. Place the plate in a refrigerator for 30 minutes to ensure proper diffusion of the ionic liquid into the agar. Incubate the plate at 37 degrees Celsius for 24 hours.The next day, use a scale to measure the zone of inhibition. Using the given formula, calculate the area under the zone of inhibition. In the proton NMR spectra, the 1-hexadecylquinolin-1-ium-bromide product exhibited the expected proton signals at delta values of 9.34 and 7.20 confirming the structure of the synthesized compound.The carbon 13 NMR spectra of 1-hexadecylquinolin-1-ium-bromide demonstrated clear signals at delta 143, 131, and 29 PPM. The compound exhibited significant antifungal potential against Candida albicans as demonstrated by a pronounced zone of inhibition in the disc diffusion assay.

520 Views.  University of Delhi.  In the present work, we elucidate the green synthesis of quinoline-based Ionic Liquid (IL), namely, 1-Hexadecylquinolin-1-ium bromide {[C16quin]Br} by mixing quinoline with an excess of 1-Bromohexadecane, along with its detailed characterization using Nuclear Magnetic Resonance and Infrared spectroscopic measurements. 

Synthesis of Quinoline-Based Ionic Liquids for Antimicrobial Applications

Summary