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. 2022 Nov 23;7(48):44458–44469. doi: 10.1021/acsomega.2c06833

Efficient Antibacterial Dimeric Nitro Imidazolium Type of Ionic Liquids from a Simple Synthetic Approach

Pandurangan Ganapathi †, Kilivelu Ganesan †,*, Mahendiran Dharmasivam ‡, Mohammed Mujahid Alam §, Amanullah Mohammed ∥
PMCID: PMC9730758  PMID: 36506216

Abstract

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Synthesis of dimeric nitro-substituted imidazolium salts under the conventional/solvent-free method is reported. The solvent-free method is more important than the conventional one because of its shorter reaction time, higher yield from easily available starting material, environmental safety, and so forth. Counter anion exchange is carried out using inorganic salt, which is dissolved in deionized water at room temperature. In antibacterial studies, dimeric nitro-substituted imidazolium cations with bromide counter anions showed excellent inhibition against E. coli and P. aeruginosa bacteria. These experimental results were further supported by molecular docking studies. All the compounds (3–6) (a–d) showed excellent antibacterial activity than the standard drugs (gentamycin, nalidixic acid, oflaxacin, ciproflaxacin, and amikacin). Molecular docking studies showed strong hydrogen bonding, polar and hydrophobic interactions between the dimeric imidazolium salts, and Escherichia coli/Pseudomonas aeruginosa/Proteus vulgaris/Staphylococcus aureus receptors.

1. Introduction

Ionic liquids are potential and interesting application-oriented molecules. Ionic liquids consist of hydrophobic units, which are pharmaceutically active and a hydrophilic unit, which is easily soluble in water; hence, ionic liquids are used in pharma industries.1 Imidazolium/pyridinium salt formation from sp2 nitrogen of heterocyclic aromatic moieties is more useful for making ionic liquids.2 The sp2-hybridized nitrogen containing five-/six-membered heterocyclic components constitutes the larger segment in ionic liquid preparation. Imidazole/pyridine core-based organic cations are commonly used for the synthesis of ionic liquids.3−5 Monomeric imidazolium/pyridinium type of ionic liquids showed moderate to excellent anti-inflammatory, anticancer, and antifungal activities.6,7 Imidazolium/pyridinium cations with various counter anion type of ionic liquids are used in various applications such as in catalysts, corrosion inhibitors, food chemistry, and pharma industries.8−14 Alkyl propargyl- and silyl alkyl-substituted imidazolium, piperidinium, and pyrrolidinium types of ionic liquids are prepared and their antibacterial response against Gram-positive bacteria are tested. Flexible longer alkyl chain-substituted ionic liquids showed higher cytotoxicity than the shorter alkyl-substituted imidazolium salt because of their lipophilicity behavior.15

Pyrrolidinium and piperidinium salts showed lesser antibacterial response than the imidazolium salts.16 Longer alkyl-substituted imidazolium salt, 1-decyl-3-cinnamylimidazolium chloride, is easily attracted to the phospholipid bilayer than the methyl-substituted −3-cinnamylimidazolium chloride because of its longer alkyl-substituted imidazolium salts, which are more hydrophobic.17 Pernak and co-workers reported that substituted alkoxy imidazolium salts showed an antimicrobial response against fungi rods and cocci and mentioned that higher alkyl-substituted imidazolium salts showed a very active response against cocci.18 Gram-negative and Gram-positive pathogens have negative charges in their surface, which is a phospholipid bilayer, so imidazolium/pyridinium types of ionic liquids are easily linked to the outer membrane.19−21 Hadni and Elhallaoui reported that molecular modeling studies with substituted azaaurones derivatives showed an inhibitory response against cytochromes under two-dimensional (2D) and three-dimensional (3D)-quantitative structure-activity relationship (QSAR)analysis.22

The application of molecular modeling calculation is a very useful and impressive finding in the drug discovery area.23,24 Poly(lactic-co-glycolic acid)-based chitosan-functionalized nanoparticles are prepared using the imidazolium type of ionic liquids for the drug delivery process under the emulsion solvent diffusion process.25 Structural alterations of adenosine deaminase were obtained using alkyl and allyl group fused imidazolium chloride with the assistance of the molecular dynamics and docking model.26,27 Hydrophobic organic cations and hydrophilic inorganic anions of imidazolium/pyridinium-based ionic liquids act as cationic surfactants in aqueous medium and also showed an antimicrobial response against Gram-positive and Gram-negative pathogens. Aljuhani et al. reported that 3/4 of methyl pyridinium iodide with amide linger units is prepared under conventional as well as microwave methods and its anticancer and molecular docking properties are studied.28 Longer alkyl-substituted piperidinium salt showed excellent antimicrobial activity against human pathogenic microorganisms than the simple alkyl-substituted hydroxy piperidinium salts.29,30

Based on the literature report, we wish to prepare dimeric-substituted imidazolium ionic liquids under the conventional and solvent-free solid-supported method and evaluate the hydrophilic and lipophilic segments containing dimeric-substituted imidazolium salts as antibacterial agents against human pathogenic microorganisms and docking analysis.

2. Results and Discussion

2.1. Synthesis of Flexible Substituted Dimeric Imidazolium Salts

The N-alkylation reaction is carried out between 1,4-dibromo butane/m-xylene dibromide and 2-methyl-5-nitro imidazole in the presence of one equivalence of NaOH in dry acetonitrile under refluxing conditions for 6–7 h and afforded N-alkylated dimeric imidazole 1 and 2 in 95% of yield after the purification process (Scheme 1). Compounds 1 and 2 are treated with benzyl/4-nitrobenzyl bromide in the presence of CH3CN under refluxing conditions for 10 h and afforded 84% of dimeric-substituted imidazolium bromide 3a–6a (Scheme 1). The same reaction is tried without the solvent under solid-phase silica-supported muffle furnace conditions. Fortunately, the solvent-free method is a more advantageous method than the conventional method such as easy work up, absence of organic solvents, and lesser reaction period with higher yields (Scheme 1).

Scheme 1. Synthesis of Flexible Substituted Dimeric Imidazolium Saltsa.

Scheme 1

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Reagent and conditions: CA, conventional approach: CH3CN, reflux, 10–12 h, 84–89%, SSA, silica-supported approach: muffle furnace, 100 °C, 5–6 h, 88–93%.

When we change various counter anions in the dimeric-substituted imidazolium bromide, the physical properties are also changed. Two equivalents of inorganic salts (KPF6, NaBF4, and LiCF3SO3) and bromide counter anions containing dimeric-substituted imidazolium salt are dissolved in double-deionized water and stirred at room temperature for 1 h and it gives anion-exchanged product of compounds 3–6 (b–d) in good yield (Scheme 1). We have used Soxhlet extraction with dry THF to remove unwanted inorganic salts (LiBr, KBr, and NaBr) and then tested with an aqueous AgNO3 solution. Fortunately, we did not get any pale-yellow precipitate. All the synthesized compounds are fully characterized by various spectral and analytical methods (Table 1).

Table 1. Properties of the Synthesized Dimeric Imidazolium Salts.

2.1.

2.1.

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2.2. Antibacterial Activity

Flexible linear alkylated quinolinium salts showed antibacterial efficacy against human pathogenic bacteria.31 Antibacterial efficacy is purely based on the length of the alkyl chain. While altering the alkyl chain length of quinolinium salts from the lower to higher alkyl group, the antibacterial activity is also changed.32−35 We have studied the antibacterial screening of dimeric-substituted imidazolium cations with various counter anions against Gram-negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus vulgaris) and Gram-positive (Staphylococcus aureus, Enterococcus faecalis) microorganisms and it showed excellent inhibition than that available in the literature.36 Antibacterial screening of dimeric-substituted imidazolium salts has been examined by well/disc diffusion methods using Mueller Hinton Agar (MHA).37

The stock solutions of samples are prepared using dimethyl sulfoxide (DMSO) as the solvent in 1 mg/mL. We have prepared various concentrations of stock solution from 25 μg/well (7.692 × 10–4 mmol/mL), 50 μg/well (1.54 × 10–3 mmol/mL), 75 μg/well (2.31 × 10–3 mmol/mL), and 100 μg/well (3.08 × 10–3 mmol/mL) in DMSO. The bacterial inoculum is adjusted to the 0.5 scale of McFarland standard.38 The dilutions of dimeric-substituted imidazolium salts are loaded into respective wells of the MHA plate. Gentamicin (30 μg/well), nalidixic acid (30 μg/well), ofloxacin (30 μg/well), ciprofloxacin (30 μg/well), and amikacin (30 μg/well) are used as standard drugs for the comparison.39 The MHA plates are incubated at 37 °C for 18–24 h. The zone of inhibition is measured in mm using a Vernier caliper and compared with the standard drug disc. Dimeric-substituted imidazolium salts showed much more bacterial efficacy than the available literature.40,41

2.2.1. Determination of Minimum Inhibitory Concentration

Minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) are determined using the microdilution method using Mueller Hinton broth (MHB).

2.2.2. Well Diffusion Technique

Antimicrobial activities of dimeric imidazolium salts against Gram-negative/positive microorganisms under the well diffusion technique.42 Dimeric imidazolium salts of compound 3–6(a–d) are screened for their microbial activities under the well diffusion method (zone of inhibition in diameters). We have prepared 16 substituted dimeric imidazolium salts; among these, nitro-substituted dimeric imidazolium salts showed excellent inhibition than the simple dimeric imidazolium salts (Table 2).

Table 2. Antibacterial Assay of Dimeric Imidazolium Cations with Different Counter Anions, Compounds 3–6 (a–d) against Test Bacteria Using the Microdilution Method.
    Gram-negative organism
 Gram-positive organism
    E. coli K. pneumoniae P. aeruginosa P. vulgaris S. aureus E. faecalis
s. no standard drug MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC MIC MBC
1 gentamicin 10 10 20 20 10 10 10 10 10 10 20 20
2 nalidixic acid 10 10 10 10 10 10 10 10 10 10 10 10
3 oflaxacin 10 10 20 20 10 10 30 30 10 10 10 10
4 ciproflaxacin 10 10 10 10 10 10 50 50 10 10 10 10
5 amikacin 10 10 10 10 10 10 10 10 10 10 10 10
6 3a 20 20 30 30 20 20 40 40 20 20 50 50
7 3b 20 20 40 40 20 20 40 40 20 20 50 50
8 3c 20 20 40 40 20 20 40 40 20 20 50 50
9 3d 30 30 40 40 20 20 40 40 20 20 50 50
10 4a 20 20 30 30 20 20 40 40 20 20 50 50
11 4b 20 20 40 40 20 20 40 40 20 20 50 50
12 4c 20 20 40 40 20 20 40 40 20 20 50 50
13 4d 30 30 40 40 20 20 40 40 20 20 50 50
14 5a 20 20 30 30 20 20 30 30 20 20 50 50
15 5b 20 20 30 30 20 20 30 30 20 20 50 50
16 5c 30 30 30 30 20 20 30 30 20 20 50 50
17 5d 20 20 30 30 20 20 30 30 20 20 50 50
18 6a 20 20 20 20 20 20 20 20 20 20 50 50
19 6b 20 20 30 30 20 20 20 20 20 20 50 50
20 6c 20 20 30 30 20 20 20 20 20 20 50 50
21 6d 30 30 30 30 20 20 30 30 20 20 50 50
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The newly synthesized compounds annoy the respiration development of the cell and thus block the synthesis of proteins that inhibit further growth of the organism.43 Bacterial screening of more responsive nitro-substituted imidazolium salts against six different human pathogens is shown. Nitro-substituted dimeric imidazolium salts 4 (a–d) and 6 (a–d) showed greater antibacterial activity than others (Table 2). The observed results clearly indicate that the counter anion plays a crucial role in the antibacterial response. Bromide counter anions containing nitro-substituted dimeric imidazolium salts 4a, 6a showed effective inhibition against E. coli, P. aeruginosa, and S. aureus pathogens (Figure 1). Other imidazolium salts showed good to moderate responses against human pathogens (Figure 1). All the dimeric imidazolium salts showed excellent antibacterial activity against all bacterial strains when compared to standard drugs (Table 2). The nitro-substituted dimeric imidazolium salts enhance lipophilicity, which promotes its permeation through the lipid layer of the bacterial cell membranes (Figure 2).

Figure 1.

Figure 1

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Antibacterial activity of dimeric imidazolium salts; (a) zone of inhibition against E. coli with different concentrations of compounds 3a and 3d (25, 50, 75, and 100 μg/well); (b) zone of inhibition against K. pneumoniae with different concentrations of compounds 4a and 4b (25, 50, 75, and 100 μg/well); (c) zone of inhibition against P. aeruginosa with different concentrations of compounds 5a and 6a (25, 50, 75, and 100 μg/well), and (d) zone of inhibition against S. aureus with different concentrations of compounds 5d and 6b (25, 50, 75, and 100 μg/well).

Figure 2.

Figure 2

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Proposed simple membrane disruption mechanism.

2.2.3. Microdilution Technique

MIC and MBC of synthesized imidazolium salts against Gram-negative/Gram-positive human pathogens are studied under the microdilution technique.44 We have observed that compound 6a shows excellent antimicrobial activity against E. coli and P. vulgaris than that against S. aureus; other pathogens showed good to moderate activity (Table 2).

MIC and MBC values for dimeric imidazolium salts 3–6 (a–d) [10 μg/well (1.538 × 10–4 mmol/mL), 20 μg/well (3.07 × 10–4 mmol/mL), 30 μg/well (4.615 × 10–4 mmol/mL), 40 μg/well (6.153 × 10–4 mmol/mL), 50 μg/well (7.692 × 10–4 mmol/mL), 60 μg/well (9.230 × 10–4 mmol/mL), 70 μg/well (1.08 × 10–3 mmol/mL), and 80 μg/well (1.23 × 10–3 mmol/mL) gentamycin (8.357 × 10–4 mmol/mL), nalidixic acid (8.612 × 10–4 mmol/mL), oflaxacin (1.66 × 10–3 mmol/mL), ciproflaxacin (2.77 × 10–3 mmol/mL), and amikacin (3.415 × 10–4 mmol/mL)] concentrations against Gram-negative E. coli, K. pneumoniae, P. aeruginosa, and P. vulgaris and Gram-positive S. aureus, and E. faecalis human pathogens.

2.3. Binding Site Prediction via Docking Studies

Hydrogen bonding, ligand/nonligand bonding, and van der Waals bonding are studied using various protein sequences against synthesized dimeric imidazolium salts using computer-assisted docking studies. Figures 345 indicate how pathogens effectively bind with dimeric imidazolium salts 3–6 (a–d) via host–gust interactions (ligand bond, hydrogen bonding etc.). We have examined effective binding between compound 6c with E. coli. (Table 2). Escherichia coli as host for membrane protein structure determination: A comprehensive analysis of protein databases revealed using a unique membrane protein method (X-Ray diffraction), resolution (1.80 A°), crystal structure of DHFR 20% isopropanol, asymmetric-C1, monomer-A1, R-value free (0.253), strain K12, modeled residue count (318), total structure weight (37.17 kDa), macromolecule amount count 3020, and unique protein chain (1). PDB DOI: 10.2210/pdb5E8Q/pdb (Figure 4).

Figure 3.

Figure 3

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(a) 2D views; (a) S. aureus (PDB ID: 5ELZ) with compound 3c and (b) E. coli (PDB ID: 5E8Q) with compound 6c. We have used iGEMDOCK software for docking studies.

Figure 4.

Figure 4

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HB plots of (a) E. coli interacts with compound 3a; (b) P. vulgaris interacts with compound 3b; (c) P. aeruginosa interacts with compound 3b, and (d) S. aureus interacts with compound 3c.

Figure 5.

Figure 5

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Molecular modeling views. (a) E. coli interacts with compound 3b; (b) P. aeruginosa interacts with compound 3c; (c) P. vulgaris interacts with compound 5a, and (d) S. aureus interacts with compound 6a.

Three amino acids such as SER 49 (B), ARG 52 (B), and ARG 57 (B) showed effective binding with dimeric imidazolium nitrogen and oxygen (Figure 4b). Among these amino acids, the nitro-substituted dimeric imidazolium cation with PF6– anion 6c showed effective binding interaction such as (3.24 Å), (3.06 Å), and (3.40 Å) with amino acids (Tables 3, S5–S7; Figure 3b). Two more bonding with dimeric imidazolium salt 3c such as THR 26 (A) (3.40 Å) and HIS 228 (A) (3.18 Å) with imidazolium nitrogen and oxygen (Table 3; Figure 4a) was observed, whereas the unsubstituted dimeric imidazolium cation with the PF6– anion showed moderate binding with proteins with simple/nitro-substituted dimeric imidazolium salts (Tables S2–S7). Hydrogen bonding studies with nitro-substituted imidazolium bromide against various pathogens like E. coli., P. aeruginosa, P. vulgaris, and S. aureus are carried out. Staphylococcus aureus was used as the host for membrane protein structure determination.

Table 3. Docking Results of the Compounds (3–6) (a–d) with Escherichia coli (PDB ID: 5e8q).

Escherichia coli
compounds est. free energy of binding (kcal/mol) est. inhibition constant, Ki (μM) vdW + H-bond + desolv energy electrostatic energy total intermol energy interact. surface
3a –5.85 51.86 –8.20 –0.78 –8.97 1072.69
3b –6.68 12.72 –10.14 –0.30 –10.44 1099.216
3c –5.38 114.59 –8.15 –0.50 –8.65 934.916
3d –5.71 65.29 –9.96 –0.61 –10.56 1086.296
4a –4.83 289.24 –6.92 –0.79 –7.71 979.75
4b –5.69 66.93 –8.53 –0.59 –9.12 1050.9
4c –5.43 105.22 –7.59 –0.54 –8.13 1011.923
4d –6.51 16.87 –8.84 –0.34 –9.18 1102.357
5a –4.39 609.69 –8.20 –0.63 –8.83 1008.806
5b –5.47 97.26 –7.51 –0.60 –8.11 1103.605
5c –5.67 70.33 –7.47 –0.53 –8.00 898.619
5d –6.22 27.60 –7.71 –0.65 –8.36 963.368
6a –5.34 121.85 –7.88 –0.77 –8.65 1067.07
6b –6.12 32.78 –9.94 +0.46 –9.48 1072.907
6c –5.18 159.09 –6.87 –0.22 –7.09 959.035
6d –5.26 140.35 –8.22 –0.29 –8.51 1058.343
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A comprehensive analysis of protein databases through the unique membrane protein method (X-ray diffraction) revealed resolution (1.80 A°) cyclic-C2, H, Homo2-mer-A2, R-Value free (0.207), strain NCTC 8325/PS47, modeled residue count (272), total structure weight (30.84 kDa), macromolecule amount count 2468, and unique protein chain (1). PDB DOI: 10.2210/pdb5ELZ/pdb. (Figure 5) Among these pathogens (Figures 345), the nitro-substituted dimeric imidazolium salts 4 (a–d) showed the highest intermolecular binding in the order E. coli > P. aeruginosa > P. vulgaris > S. aureus based on the number of hydrogen bonding, intermolecular energy, residues, and other physical parameters (Tables 2 and 3, S2–S7). Other dimeric imidazolium salts 3 (a–d) and 5 (a–d) have shown good to moderate values. HB plots give additional evidence for effective binding between various pathogenic microorganisms against dimeric imidazolium salts. HB plots of microorganisms of E. coli (5E8Q), P. aeruginosa (5EOE), P. vulgaris (5AVA), and S. aureus (5ELZ) for compounds 3a, 3b, and 3c, respectively (Figure 4), are given.

Molecular docking analysis suggested that significant binding affinity toward E. coli with compound 3b showed hydrogen bonding, hydrophobicity, and van der Waals bonding with different peptides (Tables 4, S5–S7; Figure 5a). Molecular docking studies are extended to P. aeruginosa with compound 3c which showed hydrogen bonding with nearly six different amino acids (Tables 3, S5–S7; Figure 5b). Interesting observations are made based on docking results which showed effective binding with P. vulgaris and S. aureus against compound 5a and 6a, respectively (Tables 2 and 3, S2–S7; Figure 5c,d). We conclude that the dimeric imidazolium salts showed effective antibacterial activity, hydrogen bonding, hydrophobicity, van der Waals bonding based on antibacterial and molecular docking studies.

Table 4. Molecular Docking Parameters of the Compounds (3–6) (a–d) with Escherichia coli (PDB ID: 5e8q).

Escherichia coli
compounds hydrogen bond polar hydrophobic
3a SER49 (−0.1668), MET20 (−1.3796) ILE14 (−1.1923), TRP22 (−0.8356) THR46 (−0.4967), PHE31 (−0.3694)
3b SER49 (−1.5087), TRP22 (−1.0884) LEU28 (−1.995), MET20 (−0.9881) THR46 (−0.6988), ALA7 (−0.3224)
3c SER49 (−0.7873), ARG52 (−0.7972) PHE31 (−1.1973), TRP22 (−0.9051) ILE50 (−0.9798), ASP27 (−0.0932)
3d THR46 (−0.903), ILE14 (−0.6501) ARG57 (−0.3933), ASP27 (−0.3227) ILE50 (−1.3732), LEU28 (−1.2423)
4a TRP22 (−0.7423), LEU28 (−1.4542) ARG52 (−0.2138), ILE50 (−1.0608) SER49 (−0.2088), LEU54 (−0.1187)
4b SER49 (−0.1243), ARG52 (−0.5894) LEU28 (−1.6218), PHE31 (−1.3547) TRP22 (−0.999), ASN23 (−0.7346)
4c TRP22 (−0.3554), ALA7 (−0.6851) MET20 (−1.1017), ILE50 (−0.8928) ARG52 (−1.1202), LEU28 (−0.8055)
4d SER49 (−0.4847), PHE31 (−0.9907) ARG52 (−0.668), LEU28 (−0.6818) MET20 (−1.744), ILE50 (−1.3742)
5a TRP22 (−0.8134), PHE31 (−1.1378) ILE50 (−1.1792), MET20 (−1.1416) THR46 (−0.7552), LEU54 (−0.1865)
5b SER49 (−0.5621), ASP27 (−0.1579) ILE14 (−0.7623), TYR100 (−0.655) THR46 (−0.6547), TRP22 (−0.4586)
5c MET20 (−1.214), ILE50 (−1.4158) TRP22 (−1.284), LEU28 (−1.104) ASN23 (−0.880), ARG52 (−0.475)
5d ARG52 (−1.0117), ARG57 (−0.3776) TRP22 (−0.1744), LEU28 (−2.242) PHE31 (−0.6146), LYS32 (−0.374)
6a ARG52 (−0.457) ILE50 (−1.8017), LEU28 (−1.072) PHE31 (−0.735), ASN23 (−0.572)
6b LEU24 (−0.6434), ASP27 (−0.647) PHE31 (−2.4713), LEU28 (−2.1923) TRP22 (−1.0719), LYS32 (−0.9413)
6c SER49 (−0.2458), ARG52 (−0.809) ILE50 (−1.9295), PHE31 (−0.9942) TRP22 (−1.0117), ARG57 (−0.9762)
6d SER49 (−0.542), ILE94 (−0.1453) LEU28 (−1.1261), TYR100 (−0.208) ARG52 (−3.0979), PHE31 (−0.9811)
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3. Conclusions

Dimeric-substituted imidazolium salts are prepared using benzyl/4-nitro benzyl bromide under the conventional/solvent-free method. We observed that the solvent-free method is more advantageous than the conventional one because of its shorter reaction time, higher yield, environmentally safe and easy work procedure, and so forth. The counter anion exchange is carried out using inorganic salt which is dissolved in deionized water at room temperature. Computer-assisted docking analysis was performed for unsubstituted/nitro-substituted dimeric imidazolium salts. In docking studies, effective binding occurred between proteins and dimeric imidazolium salts 3–6 (a–d) via hydrogen bonding with least energy levels. Nitro-substituted imidazolium salt 4b shows effective hydrogen bonding between SER 49 and TRP 22 with the lowest intermolecular energy at –6.68 against E. coli. Hydrogen bonding studies with nitro-substituted imidazolium bromide against various pathogens like E. coli, P. aeruginosa, P. vulgaris, and S. aureus are carried out. Among these pathogens, the nitro-substituted dimeric imidazolium salts 4 (a–d) showed the highest intermolecular binding in the order E. coli > P. aeruginosa > P. vulgaris > S. aureus based on the number of hydrogen bonding, intermolecular energy, residues, and other physical parameters. Other dimeric imidazolium salts 3 (a–d) and 5 (a–d) showed good to moderate values.

4. Experimental Section

4.1. General Procedure for N-Alkylation

2-Methyl-5-nitroimidazole (1.573 × 10–2 mmol; 2.05 equiv) is treated with slight excess amount of 1,4-dibromobutane/1,3-bis(bromomethyl)benzene (7.865 × 10–3 mmol; 1.0 equiv) in the presence of NaOH/CH3CN under refluxing conditions for 6–7 h to give compound 1/2 in a quantitative yield. We have tried the N-alkylation reaction between nitro-substituted dimeric imidazole 1/2 with benzylbromide/4-nitrobenzylbromide under a conventional route for about 10–12 h to give compounds 3a, 4a, 5a, and 6a in 88–93% yield.

4.2. General Procedures for Solid-Supported Solvent-Free Muffle Furnace Conditions

Required equivalents, as mentioned in the conventional method, were added in the absence of the solvent with 5 g of (80–120 mesh) silica gel followed by fine grinding using a mortar and pestle. The reaction mixture was kept in a muffle furnace at 100 °C.

4.3. General Procedure for the Anion Exchange Reaction

The N-alkylated product of quaternary ammonium bromide (1.0 equiv) is treated with NaBF4, KPF6, and LiCF3SO3 (2.05 equiv) in the presence of 10 mL of deionized water at room temperature under stirring for about 1 h to afford the anion-exchanged ionic liquids. After the anion exchange reaction, we have used Soxhlet extraction to remove metal bromide from ionic liquids using 100 mL of dry THF for about 1 h refluxtion to give ionic liquids 3–6 (b–d) in quantitative yield.

4.3.1. 2-Methyl-1-(4-(2-methyl-5-nitro-1H-imidazol-1-yl)butyl)-5-nitro-1H-imidazole (1)

Yield: 2.30 g (95%); mp: 150–152 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.64–1.82 (q, 4H), 2.33 (s, 6H), 4.62–4.74 (t, 4H), 8.96 (s, 2H).13C NMR (100 MHz, DMSO-d6): δ = 17.1, 30.1, 51.8, 149.8, 150.4, 150.5. MS: m/z: 308; Anal. Calcd for C12H16N6O4: Calculated: C, 46.75; H, 5.23; N, 27.26. Found: C, 46.70; H, 5.19; N, 27.20.

4.3.2. 1-(3-((2-Methyl-5nitro-1H-imidazol-1-yl)methyl)benzyl)-2-methyl-5-nitro-1H-imidazole (2)

Yield: 2.8 g (98%);mp: 145–147 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.46 (s, 6H), 4.62 (s, 4H), 6.93–7.01 (m, 4H), 7.52 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 10.6, 38.3, 126.0, 127.9, 128.2, 130.5, 135.4, 140.3, 151.2. MS: m/z: 356; Anal. Calcd for C16H16N6O4: Calculated: C, 53.93; H, 4.53; N, 23.58. Found: C, 53.89; H, 4.48; N, 23.54.

4.3.3. 3-Benzyl-1-(4-(3-benzyl-2-methyl-5-nitro-1H-imidazoliumbromide-1-yl)butyl)-2-methyl-5nitro-1H-imidazoliumbromide (3a)

Yield: 1.89 g (90%); mp: 120–122 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.63–1.74 (q, 4H), 2.16 (s, 6H), 3.75–3.83 (t, 4H), 4.31 (s, 4H), 7.13–7.25 (m, 10), 7.90 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 14.4, 30.0, 40.0, 53.7, 124.8, 127.8, 129.4, 135.1, 146.3, 153.4, 158.1. MS: m/z: 650; Anal. Calcd for C26H30Br2N6O4: Calculated: C, 48.02; H, 4.65; N, 12.92. Found: C, 47.99; H, 4.60; N, 12.87.

4.3.4. 3-Benzyl-1-(4-(3-benzyl-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate-1-yl)butyl)-2-methyl-5nitro-1H-imidazoliumtetrafluoroborate (3b)

Yield: 0.51 g (94%); mp: 110–112 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.61–1.70 (q, 4H), 2.13 (s, 6H), 3.71–3.79 (t, 4H), 4.30 (s, 4H), 7.12–7.24 (m, 10), 7.88 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 14.3, 30.1, 40.2, 53.8, 124.7, 127.9, 129.3, 135.2, 146.2, 153.3, 158.0. MS: m/z: 664; Anal. Calcd for C26H30B2F8N6O4: Calculated: C, 47.02; H, 4.55; N, 12.65. Found: C, 46.97; H, 4.51; N, 12.59.

4.3.5. 3-Benzyl-1-(4-(3-benzyl-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate-1-yl)butyl)-2-methyl-5nitro-1H-imidazoliumhexafluorophosphate (3c)

Yield: 0.56 g (93%); mp: 97–99 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.60–1.71 (q, 4H), 2.14 (s, 6H), 3.70–3.81 (t, 4H), 4.32 (s, 4H), 7.10–7.23 (m, 10), 7.91 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 14.2, 30.2, 40.1, 53.6, 124.7, 127.7, 129.4, 135.0, 146.3, 153.2, 158.2. MS: m/z: 780; Anal. Calcd for C26H30F12N6O4P2: Calculated: C, 40.01; H, 3.87; N, 10.77. Found: C, 39.95; H, 3.83; N, 10.73.

4.3.6. 3-Benzyl-1-(4-(3-benzyl-2-methyl-5-nitro-1H-imidazoliumtrifluoromethanesulfonate-1-yl)butyl)-2-methyl-5nitro-1H-imidazoliumtrifluoromethanesulfonate (3d)

Yield: 0.83 g (84%); mp: °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.60–1.71 (q, 4H), 2.15 (s, 6H), 3.74–3.80 (t, 4H), 4.33 (s, 4H), 7.14–7.24 (m, 10), 7.91 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 14.4, 30.2, 40.3, 53.8, 124.6, 127.8, 129.2, 135.3, 146.1, 153.2, 158.2. MS: m/z: 788; Anal. Calcd for C28H30F6N6O10S2: Calculated: C, 42.64; H, 3.83; N, 10.66. Found: C, 42.59; H, 3.78; N, 10.60.

4.3.7. 1-(3-((3-Benzyl-2-methyl-5-nitro-1H-imidazoliumbromide-1-yl)methyl)benzyl)-3-benzyl-2-methyl-5-nitro-1H-imidazoliumbromide (4a)

Yield: 4.93 g (90%); mp: 127–129 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.36 (s, 6H), 4.65 (s, 4H), 5.51 (s, 4H), 7.05–7.14 (m, 4H), 7.25–7.35 (m, 10), 8.52 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 10.1, 45.1, 53.1, 121.1, 123.0, 124.9, 125.5, 126.7, 129.4, 132.2, 134.4, 135.9, 141.3, 152.4. MS: m/z: 698; Anal. Calcd for C30H30Br2N6O4: Calculated: C, 51.59; H, 4.33; N, 12.03. Found: C, 51.54; H, 4.28; N, 11.92.

4.3.8. 1-(3-((3-Benzyl-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate-1-yl)methyl)benzyl)-3-benzyl-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate (4b)

Yield: 0.47 g (94%); mp: 120–122 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.33 (s, 6H), 4.64 (s, 4H), 5.49 (s, 4H), 7.04–7.13 (m, 4H), 7.23–7.33 (m, 10), 8.51 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 10.2, 45.3, 53.0, 121.3, 123.1, 124.8, 125.4, 126.6, 129.3, 132.1, 134.3, 135.8, 141.2, 152.3. MS: m/z: 712; Anal. Calcd for C30H30B2F8N6O4: Calculated: C, 50.59; H, 4.25; N, 11.80. Found: C, 50.54; H, 4.21; N, 11.74.

4.3.9. 1-(3-((3-Benzyl-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate-1-yl)methyl)benzyl)-3-benzyl-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate (4c)

Yield: 0.50 g(86%); mp: 105–107 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.34 (s, 6H), 4.63 (s, 4H), 5.50 (s, 4H), 7.03–7.12 (m, 4H), 7.24–7.34 (m, 10), 8.50 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 10.0, 45.2, 53.2, 121.2, 123.2, 124.7, 125.3, 126.5, 129.2, 132.1, 134.2, 135.8, 141.0, 152.2. MS: m/z: 828; Anal. Calcd for C30H30F12N6O4P2: Calculated: C, 43.49; H, 3.65; N, 10.14. Found: C, 43.46; H, 3.61; N, 10.09.

4.3.10. 1-(3-((3-Benzyl-2-methyl-5-nitro-1H-imidazoliumtrifluoromethanesulfonate-1-yl)methyl)benzyl)-3-benzyl-2-methyl-5-nitro-1H-imidazoliumtrifluoromethanesulfonate (4d)

Yield: 0.52 g (87%); mp: 90–92 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.35 (s, 6H), 4.62 (s, 4H), 5.49 (s, 4H), 7.01–7.11 (m, 4H), 7.20–7.30 (m, 10), 8.47 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ = 10.2, 45.0, 53.3, 121.0, 123.2, 124.6, 125.4, 126.6, 129.4, 132.3, 134.5, 135.8, 141.2, 152.5. MS: m/z: 836; Anal. Calcd for C32H30F6N6O10S2: Calculated: C, 45.93; H, 3.61; N, 10.04. Found: C, 45.89; H, 3.57; N, 10.00.

4.3.11. 3-(4-Nitrobenzyl)-1-(4-(3-(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumbromide-1-yl)butyl))-2-methyl-5nitro-1H-imidazoliumbromide (5a)

Yield: 2.40 g (88%); mp: 145–147 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.80–1.95 (q, 4H), 2.28 (s, 6H), 4.04–4.11 (t, 4H), 4.65 (s, 4H), 7.23 (s, 2H), 7.59–7.61 (d, 4H), 8.19–8.22 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 14.9, 30.9, 42.4, 53.7, 119.1, 130.5, 139.3, 147.4, 153.3, 156.0, 157.8. MS: m/z: 740; Anal. Calcd for C26H28Br2N8O8: Calculated: C, 42.18; H, 3.81; N, 15.14. Found: C, 42.15; H, 3.77; N, 15.10.

4.3.12. 3-(4-Nitrobenzyl)-1-(4-(3-(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate-1-yl)butyl))-2-methyl-5nitro-1H-imidazoliumtetrafluoroborate (5b)

Yield: 0.53 g (85%); mp: 130–132 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.79–1.94 (q, 4H), 2.27 (s, 6H), 4.01–4.09 (t, 4H), 4.61 (s, 4H), 7.25 (s, 2H), 7.57–7.60 (d, 4H), 8.17–8.20 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 14.8, 30.7, 42.3, 53.6, 119.2, 130.4, 139.4, 147.3, 153.2, 156.1, 157.6. MS: m/z: 754; Anal. Calcd for C26H28B2F8N8O8: Calculated: C, 41.41; H, 3.73; N, 14.86. Found: C, 41.37; H, 3.69; N, 14.81.

4.3.13. 3-(4-Nitrobenzyl)-1-(4-(3-(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate-1-yl)butyl))-2-methyl-5nitro-1H-imidazolium hexafluorophosphate (5c)

Yield: 0.65 g (89%); mp: 118–120 °C; 1H NMR (400 MHz, DMSO-d6): δ = 1.78–1.93 (q, 4H), 2.25 (s, 6H), 4.01–4.08 (t, 4H), 4.60 (s, 4H), 7.37 (s, 2H), 7.58–7.61 (d, 4H), 8.16–8.20 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 14.7, 30.8, 42.5, 53.5, 119.3, 130.3, 139.2, 147.2, 153.1, 156.2, 157.7. MS: m/z: 870; Anal. Calcd for C26H28F12N8O8P2: Calculated: C, 35.87; H, 3.24; N, 12.87. Found: C, 35.82; H, 3.20; N, 12.82.

4.3.14. 3-(4-Nitrobenzyl)-1-(4-(3-(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazolium trifluoromethanesulfonate-1-yl)butyl))-2-methyl-5nitro-1H-imidazolium trifluoromethanesulfonate (5d)

Yield: 0.63 g (90%); mp: 90–92 °C. 1H NMR (400 MHz, DMSO-d6): δ = 1.81–1.96 (q, 4H), 2.29 (s, 6H), 4.03–4.10 (t, 4H), 4.64 (s, 4H), 7.34 (s, 2H), 7.56–7.58 (d, 4H), 8.17–8.20 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 14.6, 30.9, 42.5, 53.5, 119.0, 130.4, 139.3, 147.5, 153.1, 156.2, 157.7. MS: m/z: 878; Anal. Calcd for C28H28F6N8O14S2: Calculated: C, 38.27; H, 3.21; N, 12.75. Found: C, 38.22; H, 3.17; N, 12.70.

4.3.15. 1-(3-((3-(-Nitrobenzyl)-2-methyl-5-nitro-1H-imidazoliumbromide-1-yl)methyl)benzyl)-3(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumbromide (6a)

Yield: 5.75 g (93%); mp: 120–122 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.22 (s, 6H), 4.04 (s, 4H), 5.36 (s, 4H), 6.93–7.05 (m, 4H), 7.22 (s, 2H), 7.78–7.82 (d, 4H), 8.19–8.22 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 11.7, 44.5, 52.9, 120.9, 126.4, 129.0, 130.4, 131.7, 135.1, 137.4, 139.4, 148.1, 152.8, 155.5. MS: m/z: 788; Anal. Calcd for C30H28Br2N8O8: Calculated: C, 45.70; H, 3.58; N, 14.21. Found: C, 45.65; H, 3.54; N, 14.16.

4.3.16. 1-(3-((3-(-Nitrobenzyl)-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate-1-yl)methyl)benzyl)-3(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumtetrafluoroborate (6b)

Yield: 0.45 g (89%); mp: 110–112 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.20 (s, 6H), 4.03 (s, 4H), 5.33 (s, 4H), 6.91–7.03 (m, 4H), 7.21 (s, 2H), 7.76–7.80 (d, 4H), 8.18–8.21 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 11.6, 44.4, 52.6, 120.8, 126.2, 129.1, 130.3, 131.5, 135.2, 137.3, 139.2, 148.0, 152.7, 155.3. MS: m/z: 802; Anal. Calcd for C30H28B2F8N8O8: Calculated: C, 44.92; H, 3.52; N, 13.97. Found: C, 44.89; H, 3.47; N, 13.94.

4.3.17. 1-(3-((3-(-Nitrobenzyl)-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate-1-yl)methyl)benzyl)-3(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumhexafluorophosphate (6c)

Yield: 0.48 g (84%); mp: 101–103 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.21 (s, 6H), 4.01 (s, 4H), 5.34 (s, 4H), 6.92–7.04 (m, 4H), 7.20 (s, 2H), 7.77–7.81 (d, 4H), 8.17–8.20 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 11.7, 44.3, 52.7, 120.6, 126.3, 129.3, 130.2, 131.6, 135.0, 137.2, 139.3, 148.2, 152.6, 155.4. MS: m/z: 918; Anal. Calcd for C30H28F12N8O8P2: Calculated: C, 39.23; H, 3.07; N, 12.20. Found: C, 39.19; H, 3.02; N, 12.14.

4.3.18. 1-(3-((3-(-Nitrobenzyl)-2-methyl-5-nitro-1H-imidazoliumtrifluoromethanesulfonate-1-yl)methyl)benzyl)-3(4-nitrobenzyl-2-methyl-5-nitro-1H-imidazoliumtrifluoromethanesulfonate (6d)

Yield: 0.48 g (82%); mp: 87–89 °C; 1H NMR (400 MHz, DMSO-d6): δ = 2.19 (s, 6H), 4.02 (s, 4H), 5.35 (s, 4H), 6.90–7.02 (m, 4H), 7.19 (s, 2H), 7.75–7.79 (d, 4H), 8.16–8.19 (d, 4H). 13C NMR (100 MHz, DMSO-d6): δ = 11.8, 44.4, 52.8, 120.7, 126.5, 129.2, 130.1, 131.4, 135.0, 137.3, 139.0, 148.3, 152.7, 155.6. MS: m/z: 926; Anal. Calcd for C32H28F6N8O14S2: Calculated: C, 41.47; H, 3.05; N, 12.09. Found: C, 41.42; H, 3.01; N, 12.04.

Acknowledgments

K.G. and P.G. thanks Dr. N. Arunagirinathan, Assistant Professor, and Dr. N. Vijaykanth, Research scholar, PG & Research Department of Biology and Biotechnology, Presidency College, Chennai-5, for microbial and docking studies. M.M.A. and M.A. thank the Deanship of Research, King Khalid University, Saudi Arabia, for Small Research Group under the grant number R. G. P. 1/339/1443.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c06833.

  • Characterization data for 3a, 4a, 5a, and 6a. Antibacterial screening and docking results of the compounds (3–6) (a–d) (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao2c06833_si_001.pdf (602.4KB, pdf)

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