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Proceeding Paper

Perspectives on Synthetic Adducts (Salts) of NitroxolineTM and 2-Aminoquinolin-8-ol as Promising Antibacterial Agents †

Department of Chemistry, Institute of Chemistry and Environmental Sciences, Faculty of Natural Sciences, University of St. Cyril and Methodius in Trnava, Námästie J. Herdu 2, SK-917 01 Trnava, Slovakia
*
Author to whom correspondence should be addressed.
Presented at the 28th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-28), 15–30 November 2024; Available online: https://sciforum.net/event/ecsoc-28.
Chem. Proc. 2024, 16(1), 92; https://doi.org/10.3390/ecsoc-28-20260
Published: 15 November 2024

Abstract

:
The threatening phenomenon of antibiotic failure in the future determines the intensive research of antibacterial active compounds, which are promising candidates as antibiotics. Quinolines, with only the representative in clinical practice being NitroxolineTM, are, in addition to being effective beta-lactams, macrolides, tetracyclines, and other antibiotic categories, forgotten antibiotics. The antibacterial efficiency of NitroxolineTM and 2-aminoquinolin-8-ol on eight selected highly resistant bacterial species that are the most problematic (Klebsiella ssp., Enterococcus ssp., Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus) could lead to higher solubility and thus bioavailability and increased antibacterial effects. In the first phase, the basic salts of NitroxolineTM, with sodium hydroxide, benzylamine, 4-(aminomethyl)pyridine, and other primary amines, were synthesized. In the second phase, the corresponding acidic salts of 2-aminoquinolin-8-ol were synthesized with the following acids: oxalic acid, pyrazine-2,3-dicarboxylic acid, chelidonic acid, quinaldic acid, 3,5-dinitrosalycilic acid, quinoline-2-carboxylic acid, quinoline-3-carboxylic acid, kynurenic acid, and xanthurenic acid. NitroxolineTM and 2-aminoquinolin-8-ol both demonstrated moderate antibacterial effects, with the average value for the eight mentioned bacterial strains being 16 mg/L (84 μM) and 50 mg/L (301 μM), respectively. The synthetized salts of both quinolinols demonstrated significantly higher solubility and slightly increased antibacterial activity. The identity and purity of the prepared products were determined by NMR and IR spectroscopy. The MW values of both quinolinols are relatively low and offer better use of the largest molecule limit, defined by Lipinski’s rule of five at 500 g/M. The options of amines and acids offer the achievement of quaternary salts with improved antibacterial activity.

1. Introduction

8-hydroxyquinolines (8OHQs) are the one of the subjects of intensive research. Its antibacterial activity has been well known for several centuries because it has been part of the formulation of disinfectants in army medicine. 8OHQs are known to be produced by the roots of several plants, such as Broussonetia zeylanica or Allium stipitatum, grown in the Mediterranean region of Europe [1]. 8OHQs have been the subject of intensive research over the last four decades up to now, as documented by several patent inventions [2,3] as well as original, scientific papers [4,5,6,7]. The only clinically approved and launched antibiotic of this structural group is NitroxolineTM (NQ), prescribed for the therapy of urinary system infections [8,9,10]. Numerous collections of 8OHQ derivatives (n ≥ 100) were screened from the eight most problematic clinical isolates with clearly defined mechanisms of resistance from our previous research (data not yet published). Surprisingly, moderate antibacterial effect was observed with our “alert collection” of selected bacterial strains. The moderate antibacterial effect, with no known mechanism (except for the ion chelating effect in bacterial cells, which has been published), is the main motivation for the applications of our current research and this paper. The published category [2,11] of NQ or 8OHQ salts seems to be from at least two points of view—antibacterial activity and increasing solubility in polar solvents and water.

2. Methods

All chemicals/NitroxolineTM, sodium hydroxide, benzylamine, 4-(aminomethyl)pyridine, 2-amino-8-quinoplinol, oxalic acid, pyrazine-2,3-dicarboxylic acid, chelidonic acid, quinaldic acid, 3,5-dinitrosalycilic acid, quinoline-2-carboxylic acid, quinoline-3-carboxylic acid, xanthurenic acid, and kynurenic acid, as well as solvents for synthesis 2-propanol and tetrahydrofuran, were purchased from Meck/Sigma-Aldrich (St. Louis, MO, USA), and were of the highest purity grade.
All syntheses were carried out through the mixing (10 mL) of 100 mM solutions of both reactants, dissolution in THF (2-propanol eventually) at room temperature for 24 h in darkness, followed by filtration, washing, and drying of the synthetized crystals. The identity and purity of the prepared products were determined by 1H NMR spectroscopy in denatured methanol (with Me4Si as an internal standard) and IR spectroscopy using KBr.
The solubility of the prepared salts and parent compounds (NitroxolineTM and 2A8OHQ) was determined gravimetrically from saturated solutions at 25 °C, after filtration and evaporation.
The antibacterial activity of the prepared salts was screened using eight bacterial strains: Klebsiella pneumonae of two different strains, No. 4498 and 4352; Klebsiella oxytoca, strain No. 3541; Klebsiella aerogenes, strain No. 500; Pseudomonas aeruginosa, strain No. 3396; Acinetobacter baumannii, strain No. 3333; vancomycin-resistant Enterococcus, strain No. 636; and Staphylococcus aureus, strain No. 1942, in accordance with the CLSI standard.

3. Results

In the first phase, three basic salts of NitroxolineTM with sodium hydroxide, benzylamine, 4-(aminomethyl)pyridine, and other primary amines were synthesized. In the second phase, nine corresponding acidic salts of 2-aminoquinolin-8-ol were synthesized with the following acids: oxalic acid, pyrazine-2,3-dicarboxylic acid, chelidonic acid, quinaldic acid, 3,5-dinitrosalycilic acid, quinoline-2-carboxylic acid, quinoline-3-carboxylic acid, xanthurenic acid, and finally kynurenic acid (Table 1).
Mainly, monocarboxylic aromatic acids with higher pKa values were selected for random synthesis of the salts of 2-aminoquinolin-8-ol. The products were brown or yellow crystals with moderate yield (50–75%) of sufficient purity (over 95%). The solubility of the prepared salts was within a narrow range of values and has evidently increased compared to the “parent” molecule; the solubility of NitroxolineTM vs. NitroxolineTM salts was 0.03 g/L vs. 0.5–1 g/L. Similarly, the solubility was 0.2 g/L for 2A8OHQ vs. about 2 g/L for its salts.
All compounds of sufficient amount and purity were subjected to evaluation of antibacterial activity with eight selected bacterial strains that cause nosocomial, problematic infections. The results of the antibacterial activity of the standards NQ and 2A8OHQ, 12 prepared salts, and 2 parent compounds are in Table 2.
The results presented in Table 2 show that all the prepared salts are comparable or have lower MIC values, which means higher antibacterial activity. From the achieved results, it is evident that there are moderate effects from both the compounds and the prepared salts from their “parent” compounds.

4. Discussion

This short paper revealed the simple synthesis of the prospective salts of “parent” molecules/compounds, particularly NitroxolineTM and 2-aminoquinolin-8-ol. Whereas NitroxolineTM is well known and frequently covered in publications, a somewhat-documented, clinically applied antibiotic, 2-aminoquinolin-8-ol, is a less potent yet moderately effective antibacterial compound, holding promise for more effective derivatives or salts. This study represents only a brief, preliminary screening of three salts of Nitroxoline and nine salts of 2A8OHQ to demonstrate a representation of this direction. The significant increase in water solubility (at least ten times) and conservation or improvement in antibacterial potency is strongly evident.

Author Contributions

Conceptualization, T.M. and R.G.; methodology, T.M.; software, T.M. and R.G.; validation, M.M.; formal analysis, M.M.; investigation, T.M. and R.G.; resources, T.M.; data curation, M.M.; writing—original draft preparation, T.M.; writing—review and editing, R.G. and M.M.; visualization, M.M.; supervision, R.G.; project administration, T.M.; funding acquisition, T.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by grants SRDA-20-0413 and NFP313010ATT2.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

References

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Table 1. Structures of NQ, 2A8OHQ, and synthesized salts.
Table 1. Structures of NQ, 2A8OHQ, and synthesized salts.
CodeCompoundStructure
NQNitroxolineTMChemproc 16 00092 i001
NQs1NitroxolineTM, natrium saltChemproc 16 00092 i002
NQs2NitroxolineTM salt with 4-benzylamineChemproc 16 00092 i003
NQs3NitroxolineTM salt with, 4-(aminomethyl)pyridineChemproc 16 00092 i004
2A8OHQ2-Amino-8-hydroxyquinolineChemproc 16 00092 i005
2A8OHQs12-Amino-8-hydroxyquinoline salt with oxalic acidChemproc 16 00092 i006
2A8OHQs22-Amino-8-hydroxyquinoline salt with 2,3-pyrazinedicarboxylic acidChemproc 16 00092 i007
2A8OHQs32-Amino-8-hydroxyquinoline salt with chelidonic acidChemproc 16 00092 i008
2A8OHQs42-Amino-8-hydroxyquinoline salt with quinalid acidChemproc 16 00092 i009
2A8OHQs52-Amino-8-hydroxyquinoline salt with 3,5-dinitrosalicylic acidChemproc 16 00092 i010
2A8OHQs62-Amino-8-hydroxyquinoline salt with quinoline-2-carboxylic acidChemproc 16 00092 i011
2A8OHQs72-Amino-8-hydroxyquinoline salt with quinoline-3-carboxylic acidChemproc 16 00092 i012
2A8OHQs82-Amino-8-hydroxyquinoline salt with xanthurenic acidChemproc 16 00092 i013
2A8OHQs92-Amino-8-hydroxyquinoline salt with kynurenic acidChemproc 16 00092 i014
Table 2. Antibacterial activity of NQ, 2A8OHQ and prepared salts.
Table 2. Antibacterial activity of NQ, 2A8OHQ and prepared salts.
Strain No./
Compound Code
MIC (mg/L)
449835415003396333363619424352
NQ32161616816832
NQs188123248412
NQs216168328848
NQs33288328848
2A8OHQ6464326432166464
2A8OHQs16432326432163264
2A8OHQs23232326432163264
2A8OHQs3643232643283264
2A8OHQs4323232643283264
2A8OHQs53232323232163264
2A8OHQs66432326432163264
2A8OHQs7643232643241664
2A8OHQs83232326432163264
2A8OHQs9643232643241664
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MDPI and ACS Style

Maliar, T.; Gašparová, R.; Maliarová, M. Perspectives on Synthetic Adducts (Salts) of NitroxolineTM and 2-Aminoquinolin-8-ol as Promising Antibacterial Agents. Chem. Proc. 2024, 16, 92. https://doi.org/10.3390/ecsoc-28-20260

AMA Style

Maliar T, Gašparová R, Maliarová M. Perspectives on Synthetic Adducts (Salts) of NitroxolineTM and 2-Aminoquinolin-8-ol as Promising Antibacterial Agents. Chemistry Proceedings. 2024; 16(1):92. https://doi.org/10.3390/ecsoc-28-20260

Chicago/Turabian Style

Maliar, Tibor, Renata Gašparová, and Mária Maliarová. 2024. "Perspectives on Synthetic Adducts (Salts) of NitroxolineTM and 2-Aminoquinolin-8-ol as Promising Antibacterial Agents" Chemistry Proceedings 16, no. 1: 92. https://doi.org/10.3390/ecsoc-28-20260

APA Style

Maliar, T., Gašparová, R., & Maliarová, M. (2024). Perspectives on Synthetic Adducts (Salts) of NitroxolineTM and 2-Aminoquinolin-8-ol as Promising Antibacterial Agents. Chemistry Proceedings, 16(1), 92. https://doi.org/10.3390/ecsoc-28-20260

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