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. Author manuscript; available in PMC: 2023 Mar 1.
Published in final edited form as: Med Chem Res. 2022 Feb 5;31(3):474–484. doi: 10.1007/s00044-022-02855-5

Merging antimicrobial and visible emission properties within 1,3,4-trisubstituted-1,2,3-triazolium salts

Connor A Lejcher 1, Eric M Villa 1, James T Fletcher 1
PMCID: PMC9417110  NIHMSID: NIHMS1783364  PMID: 36033131

Abstract

Bioactive molecules displaying visible wavelength emission can be useful for bioimaging, chemosensing and photodynamic therapy applications. Reported herein are 1,3,4-trisubsituted-1,2,3-triazolium salts displaying both antimicrobial and visible emission properties. Using a click chemistry approach, 2-fluorenyl, 1-naphthyl, 2-naphthyl, 2-anthracenyl and 1-pyrenyl units were incorporated at the N1 position, imparting visible emission properties to their triazolium bromide salts with Stokes shifts greater than 100 nm relative to the emission of their triazole precursors. The increasing size of such hydrophobic aryl units impacts minimum inhibitory concentration (MIC) values against Gram-positive bacteria, Gram-negative bacteria and yeast, and can be counterbalanced by hydrophobic substituent variation at other positions of the molecule in order to preserve bioactivity. Among the series of compounds studied are analogs displaying blue, green and yellow colored emission and MIC values as low as 0.4 μM (Gram-positive bacteria), 8 μM (Gram-negative bacteria) and 2 μM (yeast). XRD analysis validates the regioselective benzylation at the N3 position of the 1,2,3-triazole ring and the ability of such compounds to associate through dimeric intermolecular π-stacking interactions.

Keywords: Antibacterial; Antifungal; Emission; 1,2,3-Triazole; Triazolium Salt

Graphical Abstract

graphic file with name nihms-1783364-f0007.jpg

Introduction

The evolution of antibiotic resistant pathogens remains one of the strongest threats to public health, warranting the identification of new tools to understand and combat such infections.1,2 Similarly, antiseptic resistance is also of notable concern.3 Quaternary ammonium compounds (QACs) such as benzalkonium chloride and cetylpyridnium chloride have been used for more than 100 years in antiseptic applications such as surface decontaminants and antimicrobial soaps.4–6 In recent years an uptick in QAC resistant bacteria has been observed, with ongoing debate on the mechanisms of such resistance.7–10 In order to maintain therapeutic options for treating such infections as well as combat the proliferation of resistant organisms in sterile environments, there is an ongoing need for the discovery of new classes of small molecules displaying antimicrobial properties and for the development of molecular tools providing mechanistic insight towards antibiotic and antiseptic resistance.11,12

Aliphatic 1,2,3-triazolium salts were recently reported to display antimicrobial properties against Gram-positive bacteria, Gram-negative bacteria and yeast in a substituent dependent manner.13 Among the reported organic salts, it was shown that the typical QAC hydrophobicity of long n-alkyl chains (Figure 1) could be redistributed into aryl and branched alkyl units where the antimicrobial potency could be preserved so long as a proper overall balance of substituent hydrophobicity was maintained.13 Because such compounds derive from a click chemistry approach for preparing the 1,2,3-triazole ring,14–17 substituent identity can be varied modularly and in good yield.

Fig. 1.

Fig. 1

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Representative structures of (A) benzalkonium chloride (major n-alkyl constituent), (B) cetylpyridinium chloride and (C) a 1,3,4-trisubstituted-1,2,3-triazolium bromide

Bioactive molecules that display visible wavelength emission can be useful for applications such as bioimaging, chemosensing and photodynamic therapy.18–20 Hence, the aim of this study was to develop triazolium salts that possess both antimicrobial and visible emission properties, and to examine how each desired property could be balanced through the variation of peripheral functional groups. Reported herein is the use of a click chemistry approach to incorporate a variety of arene-derived emission properties into bioactive triazolium QAC salts, where the impact of aryl group hydrophobicity can be counterbalanced in order to preserve antimicrobial potency.

Results and Discussion

Target compounds in this study were prepared using a click chemistry approach. As summarized in Scheme 1, organic azides (prepared from the Sandmeyer reaction of commercially available aryl amines with sodium azide) were reacted with terminal alkynes via the Sharpless-Meldal Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction to form 1,4-disubstituted-1,2,3-triazoles. Benzylation of the N3 group resulted in the desired 1,3,4-trisubsituted-1,2,3-triazolium bromide organic salts.13,21 N1 aryl group identity did not significantly impact reaction efficiency. The identity of each triazole analog prepared by this approach is summarized in Figure 2.

Scheme 1.

Scheme 1

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Preparation of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts

Fig. 2.

Fig. 2

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Identity of 1,4-disubstituted-1,2,3-triazole analogs

Substituent variations in this study were inspired by a previous report demonstrating that the antimicrobial potency of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts was highly sensitive to C4-alkyl chain length variations as well as N3-benzyl substituent identity.13 In that report it was shown that a decrease in hydrophobicity at one substituent location, such as a decrease in C4-alkyl chain length, could be counterbalanced by an increase in hydrophobicity at another substituent location, such as the incorporation of a 4-tert-butyl subunit within the N3-benzyl group.13 With the goal herein of examining whether the variation of N1-aryl units could be used to impart a variety of visible wavelength emission properties while maintaining significant antimicrobial activity, a twofold approach was taken in selecting analog iterations that might be useful for counterbalancing such corresponding changes in N1-arene hydrophobicity: (1) varying the C4-alkyl chain length for 2-fluorenyl analogs and (2) varying the N3 benzyl group identity for all analogs.

Antimicrobial activity was measured using microdilution minimum inhibitory concentration assays22–24 against exemplary Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis, Gram-negative bacteria Escherichia coli and Klebsiella aerogenes, and yeast Candida albicans and Saccharomyces cerevisiae. All neutral triazoles 1-7 and triazolium bromide salts 8-21 were initially evaluated using a 2-250 μM serial dilution, with analogs showing potency at 2 μM re-tested as a 0.2-25 μM serial dilution. None of the neutral triazoles 1-7 showed MIC potency at the concentrations studied.

A summary of MIC activity for triazolium bromide salts 8-21 is shown in Table 1 Similar to that observed previously for N1-phenyl analogs,13 the antimicrobial potency of N1-fluorenyl triazolium salts was highly sensitive to minor iterations in substituent identity and was maximized upon balancing overall hydrophobicity at these positions. Among analogs 8-13, it was observed that 8 (the least hydrophobic) and 13 (the most hydrophobic) displayed the lowest potency, with analogs 9 and 11 achieving a more ideal hydrophobic balance leading to improved MIC values against all organisms tested. Common QAC antiseptics benzalkonium chloride and cetylpyridinium chloride were included as controls in these assays.

Table 1.

Antimicrobial potency of 1,3,4-trisubstituted-1,2,3-triazolium bromide salts

graphic file with name nihms-1783364-t0008.jpg
Compound Identity Minimum Inhibitory Concentration (μM)
ID Ar R1 R2 Gram (+) Gram (−) Yeast
B. subt. S. epid. E. coli. K. aero. C. alb. S. cer.
8 2-fluor n-C4H9 H 4 4 >250 >250 125 125
9 2-fluor n-C8H17 H 0.4 0.8 16 32 8 16
10 2-fluor n-C12H25 H 0.8 0.8 >250 >250 16 4
11 2-fluor n-C4H9 t-Bu 2 0.8 16 >250 4 8
12 2-fluor n-C8H17 t-Bu 0.8 0.8 >250 >250 2 2
13 2-fluor n-C12H25 t-Bu 8 16 >250 >250 >250 250
14 1-naph n-C8H17 H 2 2 250 125 62 31
15 2-naph n-C8H17 H 2 2 16 8 4 2
16 2-anth n-C8H17 H 2 2 62 8 8 8
17 1-pyr n-C8H17 H 2 2 250 250 2 4
18 1-naph n-C8H17 t-Bu 2 2 16 8 4 2
19 2-naph n-C8H17 t-Bu 2 2 31 8 4 2
20 2-anth n-C8H17 t-Bu 4 2 >250 >250 2 2
21 1-pyr n-C8H17 t-Bu 2 2 >250 >250 16 8
Benzalkonium chloride 0.2 1 25 16 4 1
Cetylpyridinium chloride 1 4 62 62 62 12
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Importantly, it was shown that a peripheral subunit variation strategy could also be used to counterbalance the varying hydrophobicity imparted by the N1-aryl fluorophore units. For the less hydrophobic N3-benzyl series 9 and 14-17, both the smallest 1-naphthyl (14) and the largest 1-pyrenyl (17) analogs were the least potent against Gram-negative bacteria, with the intermediate sized aryl ring analogs showing optimal MIC values. (Assuming a membrane-destabilization mechanism, the outward extension of the 2-naphthyl unit relative to the 1-naphthyl unit is considered to behave as a “larger” subunit within the context of this bioactivity discussion.) This bioactivity trend among arene units was shifted by utilizing the more hydrophobic 4-tert-butylbenzyl substituent at N3, reflected in the series of 12 and 18-21 where the smaller sized arenes display maximum potency against Gram-negative bacteria and the largest analogs (2-anthracenyl (20) and 1-pyrenyl (21) show no Gram-negative MIC activity within the broad concentration range tested.

Overall, among 14-21 activity against Gram-positive bacteria was largely consistent for all arene units, with yeast potency being only moderately influenced by such structural changes. Impacts on Gram-negative bacteria were more variable and generally showed the largest MIC values among the organisms studied. It is not uncommon for membrane-targeting QAC antimicrobials to show less potency against Gram-negative bacteria due to their outer membranes serving as a second barrier to overcome relative to the permeation of Gram-positive bacteria and yeast. It is noteworthy that the majority of the triazolium salts studied here did show significant bioactivity towards the model yeast organisms utilized in these assays, indicating that while the cationic charge of these triazolium salts may enhance their attraction to the negatively charged outer surfaces of prokaryotic organisms they nevertheless also show relatively strong bioactivity towards eukaryotic organisms. This general toxicity would support their more likely utility in antiseptic rather than antibiotic applications. In general, the most potent analogs of this triazolium salt series displayed antimicrobial properties equal to or exceeding that observed for the common commercial antiseptics benzalkonium chloride and cetylpyridinium chloride under these assay conditions.

The UV-visible absorption and emission properties of each triazole and triazolium bromide salt with N3-benzyl and C4-octyl substitution is shown in Figure 3. Comparing the absorbance bands of each neutral triazole compound with its analogous triazolium salt shows only minor differences, with slight red shifting and broadening of features upon salt formation. In contrast, major differences were observed in their emission spectra. Neutral triazoles largely matched the wavelengths and features of their constituent fluorescent arene rings, with modest Stokes shifts less than ~50 nm. In contrast, the emission signatures of the salts showed markedly broadened signals that were strongly red-shifted relative to their neutral counterpart, with Stokes shifts of ~150 nm. Such traits are indicative of emission from an excimer state, which are known to be concentration-dependent.25,26 It is therefore noteworthy that the observed salt emission signals persisted through serial dilution to the lower limit of spectrometer detection (0.1 μM), which was appreciably below the observed antimicrobial activity of these compounds.

Fig. 3.

Fig. 3

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Comparison of UV-visible absorbance and emission properties of 1-pyrenyl (A), 1-naphthyl (B), 2-naphthyl (C), 2-anthryl (D) and 1-pyrenyl (E) analogs as 25 μM acetonitrile solutions. Absorbance shown as solid lines, emission shown as dashed lines. Triazole compounds shown in blue, triazolium bromide salts shown in red. Emission intensity is normalized to the intensity of its corresponding absorbance band

As summarized in Figure 4, variation of the N1 aryl groups resulted in a family of triazolium salt analogs with emission signals spanning nearly 150 nm within the visible wavelengths. Represented within this family are blue (2-fluorenyl, 2-naphthyl, 1-naphthyl), green (1-pyrenyl) and yellow (2-anthracenyl) colored outputs. Emission properties were largely consistent upon varying solvents among acetonitrile, ethanol and 0.9% saline.

Fig. 4.

Fig. 4

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(A) Comparison of normalized spectroscopic emission properties for benzylated triazolium salts as 25 μM ethanol solutions. (B) Images of 25 μM ethanol solutions under long wave (365 nm) UV-lamp illumination

Single crystals of 10 suitable for XRD structural analysis were grown from slow evaporation of dichloromethane solutions. As shown in Figure 5, this characterization adds to the limited reported 1,2,3-triazolium salt structures that lack a bonded metal atom and possess either N3-benzyl 27,28 or C4-aryl subunits.29–31 This structure provides direct evidence of regioselective benzylation at the N3 position, and the equivalency of N1-N2 and N2-N3 bond lengths (1.327(3) and 1.325(3) Å, respectively) supports the delocalization of the cationic charge within the 1,2,3-triazolium ring.29 With a dihedral angle of only ~2°, the fluorene and triazolium rings are essentially coplanar.

Fig. 5.

Fig. 5

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Thermal ellipsoid plot of 10 shown at 25% probability

The crystal structure of 10 contained the 1,3,4-trisubsituted-1,2,3-triazolium cation, one bromide anion and one unit of water, as shown in Figure 5. Unlike a previous report showing hydrogen bonding between the C5-triazolium hydrogen atom and a chloride counterion,31 here the bromide is not directly bonded to the triazolium ion. The closest triazolium atom contact for bromide is exceedingly far at a distance of ~4.4 Å. Instead, the bromide is associated with the triazolium ion through an intervening unit of water, with hydrogen bonding observed between the C5-hydrogen atom and the oxygen atom of water (~2.2 Å), and between one of the hydrogen atoms of water and the bromide ion (~2.6 ); the bromide anion also has close contacts with a second neighboring water molecule (~2.7 Å), one of the benzylic hydrogen atoms (~2.7 Å) and one of the dodecyl chain α-carbon hydrogen atoms (~3.0 Å) (Figures S1 and S2).

Crystal packing reflective of this compound’s amphiphilic nature was observed in its extended structure. Dodecyl chains associate intermolecularly through VDW forces, while the triazolium units show dimeric intermolecular π-stacking interactions (Figure S3). Figure 6 highlights the fluorene groups on two opposing structures of 10 having several π-π interactions ranging from ~3.7 to 3.8 Å. Additionally, a perpendicular molecule of 10 forms C-H⋯π interactions between the hydrogen atoms on its fluorene group with the noted π-stacked dimer. The combination of these two dominant interactions forms a dense, corrugated-like region of π-stacking in the extended structure. The ability to closely π-stack in such a dimerized cofacial manner, enabled by the essentially coplanar fluorene and triazolium subunits, supports the ability of these compounds to generate the proposed excimer-derived emission bands observed in solution that require such geometrical interactions.25,26

Fig. 6.

Fig. 6

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Intermolecular π-stacking interactions between fluorenyltriazolium units of 10 observed by XRD analysis. The dodecyl chain on the lower triazolium ring was cropped and the bromide ions, water molecules and all H’s except for the 3- and 4-positions of the fluorene ring removed for clarity

Conclusion

By incorporating a series of expanded arene units at the N1-position, a broad range of visible emission properties can be realized in 1,3,4-trisubstituted-1,2,3-triazolium salts while preserving their antimicrobial potency through counterbalancing peripheral substituent variations. Among the family of compounds studied are analogs with emission varying over a 200 nm range within the spectrum of visible wavelengths while displaying antimicrobial potency matching or exceeding that of common commercial QAC antiseptics. Structural features observed by XRD analysis support antiseptic bioactivity being driven by proposed amphiphilic membrane interactions and spectroscopic features deriving from proposed excimer emission. Similar to previous findings, the exact identity of the hydrophobic subunits within these organic salts was observed to be less impactful than the overall extent of hydrophobic content in regards to bioactivity. This tolerance towards the variation of emissive aryl units, facilitated by the click chemistry approach used to prepare such compounds and maintain a balance of overall hydrophobicity, establishes 1,3,4-trisubstituted-1,2,3-triazolium salts as an attractive motif to develop new tools for better understanding the mechanisms of antimicrobial resistance and realizing improved treatments to combat such pathogens.

Materials and Methods

Experimental

Terminal alkyne (GFS Chemicals), benzyl bromide and aminoarene reactants (Oakwood Chemical), all other reactants (Aldrich), reaction solvents (Fisher Scientific), and NMR solvents (Cambridge Isotopes) were used as purchased. 2-Azidofluorene,32 1-azidonaphthalene,33 2-azidonaphthalene,34 2-azidoanthracene35 and 1-azidopyrene were33 were prepared by Sandmeyer36 reaction as previously described. Microorganisms were prepared from freeze-dried samples purchased from ATCC (Bacillus subtilus (ATCC 6051), Staphylococcus epidermidis (ATCC 14990), Escherichia coli (ATCC 25922), Klebsiella aerogenes (ATCC 13048), Candida albicans (ATCC 90028) and Saccharomyces cerevisiae (ATCC 9763)). Mueller-Hinton broth and YM broth were purchased from Fisher Scientific and prepared as instructed.

NMR analyses were obtained on a 400 MHz Bruker Ascend system. HRMS analyses were acquired on a Bruker micrOTOF-Q III system using an elution of 0.1% formic acid in methanol. UV-visible absorbance measurements were acquired on an Agilent 8453 spectrophotometer, and data are reported as λmax = nm (log ε). UV-visible emission measurements were acquired on a Varian Cary Eclipse fluorescence spectrophotometer.

Synthesis

Preparation of 1,4-disubstuted-1,2,3-triazoles by CuAAC method

Organic azide (1.0 mmol), alkyne (1.0 mmol), CuSO4 (0.2 mmol), sodium ascorbate (0.4 mmol), tert-butanol (5 ml) and water (5 mL) were added to a 20 mL reaction vial and stirred rapidly at room temperature for 24 h. The reaction mixture was extracted with CH2Cl2 and 5% NH4OH (aq), and the organic layer separated and dried over MgSO4. Following gravity filtration, volatiles were removed via rotary evaporation and the residue air dried to give the desired triazole product.

4-Butyl-1-(9H-fluoren-2-yl)-1H-1,2,3-tricizole (1):

White solid, 67% yield, mp 128-129 °C, 1H NMR (400 MHz, CDC13): δ 7.96 (s, 1H), 7.90 (d, J = 8.2, 1H), 7.84 (d, J = 7.6, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.2, 1H), 7.60 (d, J = 7.3, 1H), 7.45 (t, J = 7.4, 1H), 7.38 (t, J = 7.4, 1H), 4.02 (s, 2H), 2.85 (t, J = 7.7, 2H), 1.75 (m, 2H), 1.46 (m, 2H), 1.00 (t, J = 7.3, 3H; 13C NMR (400 MHz, CDCl3): δ 149.1, 144.7, 143.5, 142.0, 140.5, 135.9, 127.4, 127.1, 125.2, 120.6, 120.2, 119.3, 119.0, 117.4, 37.0, 31.6, 25.4, 22.4, 13.9; HRMS (ESI) m/z: Calcd for C19N3H20 [M+H]+ 290.1652, found 290.1648; UV-vis (ACN): λ = 282 nm (4.34).

1-(9H-Fluoren-2-yl)-4-octyl-1H-1,2,3-triazole (2):

White solid, 73% yield, mp 133-134 °C, 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 1.0, 1H), 7.90 (d, J = 8.2, 1H), 7.84 (d, J = 7.4, 1H), 7.78 (s, 1H), 7.72 (dd, J1 = 8.2, J2 = 2.0, 1H), 7.61 (d, 7.4, 1H) 7.45 (t, J = 7.1, 1H), 7.38 (td, J1 = 7.4, J2 = 1.1, 1H), 4.02 (s, 2H), 2.8381 (t, J = 7.7, 2H), 1.76 (m, 2H), 1.32 (m, 10H), 0.91 (t, J = 7.0, 3H); 13C NMR (400 MHz, CDCl3): δ149.4, 144.9, 143.6, 142.2, 140.7, 136.1, 127.6, 127.3, 125.4, 120.8, 120.4, 119.5, 119.1, 117.7, 37.2, 32.1, 29.7, 29.6, 29.5, 29.4, 25.9, 22.9, 14.3; HRMS (ESI) m/z: Calcd for C23N3H28 [M+H]+ 346.2278, found 346.2257; UV-vis (ACN): λ = 281 nm (4.41).

4-Dodecyl-1-(9H-fluoren-2-yl)-1H-1,2,3-triazole (3):

White solid, 67% yield, mp 139-140 °C, 1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 1.2, 1H), 7.90 (d, J = 8.2, 1H), 7.85 (d, J = 7.4, 1H), 7.78 (s, 1H), 7.72 (dd, J1 = 8.2, J2 = 2.0, 1H), 7.61 (d, 7.4, 1H), 7.45 (t, J = 6.9, 1H), 7.38 (td, J1 = 7.4, J2 = 1.2, 1H), 4.02 (s, 2H), 2.84 (t, J = 7.6, 2H), 1.79 (m, 2H), 1.40 (m, 18H), 0.90 (t, J = 6.9, 3H); 13C NMR (400 MHz, CDCl3): δ 149.2, 144.7, 143.5, 142.0, 140.5, 136.0, 127.4, 127.1, 125.2, 120.6, 120.2, 119.3, 119.0, 117.5, 37.1, 31.9, 29.71, 29.69, 29.67, 29.6, 29.5, 29.44, 29.38, 29.3, 25.8, 22.7, 14.1; HRMS (ESI) m/z: Calcd for C26N3H36 [M+H]+ 402.2904, found 402.2911; UV-vis (ACN): λ = 282 nm (3.92).

1-(1-Naphthyl)-4-octyl-1H-1,2,3-triazole (4):

Brown oil, 57% yield, 1H NMR (400 MHz, CDCl3): δ 8.03 (m, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.69 (s, 1H), 7.66 (d, J = 8.12 Hz, 1H), 7.58 (m, 4H), 2.90 (t, J = 7.7 Hz, 2H), 1.82 (m, 2H), 1.48 (m, 2H), 1.35 (m, 8H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 148.8, 134.2, 134.1, 130.2, 128.7, 128.3, 127.8, 127.0, 125.0, 123.5, 122.5, 31.9, 29.54, 29.45, 29.4, 29.3, 25.8, 22.8, 14.2; HRMS (ESI) m/z: Calcd for C20N3H26 [M+H]+ 308.2121, found 308.2122; UV-vis (ACN): λ = 282 nm (3.90).

1-(2-Naphthyl)-4-octyl-1H-1,2,3-triazole (5):

Brown solid, 52% yield, mp 75-78 °C, 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.94 (m, 3H), 7.87 (s, 1H), 7.59 (m, 2H), 2.88 (t, J = 7.7 Hz, 2H), 1.79 (m, 2H), 1.46 (m, 2H), 1.33 (m, 8H), 0.91 (t, J = 6.9 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 149.4, 134.7, 133.3, 132.8, 129.9, 128.2, 127.9, 127.4, 126.8, 119.0, 118.9, 118.1, 31.9, 29.5, 29.4, 29.3, 29.2, 25.8, 22.7, 14.1; HRMS (ESI) m/z: Calcd for C20N3H26 [M+H]+ 308.2121, found 308.2128; UV-vis (ACN): λ = 284 nm (3.96).

1-(2-Anthryl)-4-octyl-1H-1,2,3-triazole (6):

White solid, 47% yield, mp 164-164 °C, 1H NMR (400 MHz, CDCl3): δ 8.51 (d, J = 3.5, 2H), 8.31 (s, 1H) 8.18 (d, J = 9.1, 1H), 8.06 (m, 2H), 7.95 (dd, J1 = 9.1, J2 = 1.7, 2H), 7.55 (m, 2H), 2.87 (bt, J = 7.1, 2H), 1.81 (bt, J = 7.2, 2H), 1.47 (bm, 2H), 1.34 (m, 8H), 0.92 (t, J = 6.8, 3H).; 13C NMR (400 MHz, CDCl3): δ 149.6, 134.3, 132.7, 132.3, 131.0, 130.73, 130.69, 128.5, 128.3, 127.1, 126.9, 126.4, 126.3, 119.3, 119.0, 117.9, 32.1, 29.7, 29.6, 29.53, 29.45, 26.0, 22.9, 14.3 ; HRMS (ESI) m/z: Calcd for C24N3H28 [M+H]+ 358.2278, found 358.2295; UV-vis (ACN): λ = 267 (4.57), 331 (3.69).

4-Octyl-1-(1-pyrenyl)-1H-1,2,3-triazole (7):

Yellow solid, 52% yield, mp 92-93 °C, 1H NMR (400 MHz, CDCl3): δ 8.29 (q, J1 = 14.3, J2 = 6.4, 3H), 8.22 (d, J = 9.0, 1H), 8.17 (dd, J1 = 7.4, J2 = 1.4, 2H) 8.13 (d, J = 7.6, 1H), 8.09 (d, J = 8.0, 1H), 7.92 (d, J = 9.6, 1H), 7.82 (s, 1H), 2.96 (t, J = 7.7, 2H), 1.88 (m, 2H), 1.52 (m, 2H), 1.39 (m, 8H), 0.92 (t, J = 6.9, 3H); 13C NMR (400 MHz, CDCl3): δ 148.8, 132.2, 131.3, 130.9, 130.8, 129.6, 128.9, 127.1, 126.8, 126.4, 126.3, 126.1, 125.1, 124.8, 124.3, 124.0, 123.5, 121.4, 32.1, 29.7, 29.6, 29.5, 26.0, 22.9, 14.3; HRMS (ESI) m/z: Calcd for C26N3H28 [M+H]+ 382.2278, found 382.2260; UV-vis (ACN): λ = 265 nm (4.35), 276 nm (4.56), 327 nm (4.33), 341 nm (4.47).

Preparation of 1,3,4-trisubstuted-1,2,3-triazolium bromide salts

Triazole reactant (0.1 mmol), benzyl bromide reactant (0.5 mmol) and acetonitrile (5 mL) were added to a 20 mL reaction vial and stirred at 75 °C for 24 h. Products typically precipitated upon formation as the reaction proceeded. Acetonitrile was removed by evaporation and the remaining residue washed with three successive 10 mL portions of hexanes. Following each wash, undissolved material was separated by decanting or centrifugation, as applicable. Products were isolated upon air evaporation of any residual solvent.

3-Benzyl-4-butyl-1-(9H-fluoren-2-yl)-1H-1,2,3-triazolium bromide (8):

Tan solid, 87% yield, mp 218-220 °C, 1H NMR (400 MHz, CDCl3): δ 10.20 (s, 1H), 8.44 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.0 Hz, 1H), 7.6 (d, J = 7.4 Hz, 1H), 7.44 (m, 7H), 5.92 (s, 1H), 4.04 (s, 1H), 3.02 (t, J = 7.6 Hz, 2H), 1.79 (t, J = 6.7 Hz, 2H), 1.43 (m, 2H), 0.92 (t, J = 7.2, 3H); 13C NMR (400 MHz, CDCl3): δ 146.1, 145.5, 145.4, 144.2, 139.7, 133.1, 131.2, 130.0, 129.8, 128.5, 128.4, 128.2, 127.4, 125.5, 121.2, 121.0, 120.4, 118.4, 56.0, 37.3, 29.6, 24.1, 22.4, 13.7; HRMS (ESI) m/z: Calcd for C26N3H26 [M]+ 380.2121, found 380.2120; UV-vis (ACN): λ = 309 nm (4.28).

3-Benzyl-1-(9H-Fluoren-2-yl)-4-octyl-1H-1,2,3-triazolium bromide (9):

Tan solid, 74% yield, mp 141-143 °C, 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.45 (s, 1H), 8.18 (dd, J1 = 8.3 Hz, J2 = 2.1 Hz, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 6.9 Hz, 1H), 7.62 (d, J = 6.6, 1H), 7.45 (m, 7H), 5.93 (d, J = 8.4, 2H), 4.05 (d, J = 11.8, 2H), 3.03 (t, J = 7.9, 2H), 1.79 (m, 2H), 1.36 (m, 2H), 1.25 (m, 2H) 0.89 (t, J = 6.7, 3H); 13C NMR (400 MHz, CDCl3): δ 146.2, 145.31, 145.28, 144.2, 139.7, 133.1, 131.4, 129.9, 129.7, 128.44, 128.42, 128.0, 127.4, 125.4, 121.1, 120.9, 120.2, 118.1, 56.0, 37.2, 31.9, 29.32, 29.26, 29.1, 27.7, 24.4, 22.8, 14.2; HRMS (ESI) m/z: Calcd for C30N3H35 [M]+ 436.2747, found 436.2726; UV-vis (ACN): λ = 310 nm (4.30).

3-Benzyl-4-dodecyl-1-(9H-fluoren-2-yl)-1H-1,2,3-triazolium bromide (10):

Brown solid, 72% yield, mp 132-134°C, 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.45 (s, 1H), 8.18 (dd, J1 = 8.3 Hz, J2 = 2.1 Hz, 1H), 7.96 (d, J = 8.32 Hz, 1H), 7.85 (dd, J1 = 6.3 Hz, J2 = 1.3 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.44 (m, 7H), 5.93 (s, 1H), 4.06 (s, 1H), 3.03 (t, J = 7.9 Hz, 2H), 1.79 (m, 2H), 1.37 (m, 2H), 1.26 (m, 16H), 0.90 (t, J = 6.9, 3H); 13C NMR (400 MHz, CDCl3): δ146.2, 145.45, 145.42, 144.2, 139.7, 133.2, 131.4, 130.0, 129.8, 128.5, 128.4, 128.2, 127.4, 125.5, 121.2, 121.0, 120.3, 118.3, 56.0, 37.3, 32.1, 29.84, 29.82, 29.74, 29.65, 29.5, 29.4, 29.2, 27.8, 24.4, 22.9, 14.3; HRMS (ESI) m/z: Calcd for C34N3H42 [M]+ 492.3373, found 492.3372; UV-vis (ACN): λ = 309 nm (3.02).

4-Butyl-1-(9H-fluoren-2-yl)-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (11):

Tan solid, 94% yield, mp 181-182 °C, 1H NMR (400 MHz, CDCl3): δ 10.32 (s, 1H), 8.49 (s, 1H), 8.20 (dd, J1 = 8.3 Hz, J2 = 1.7 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 6.8 Hz, 1H), 7.62 (dd, J1 = 6.2 Hz, J2 = 0.9 Hz, 1H), 7.46 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 5.84 (s, 1H), 4.08 (s, 1H), 3.03 (t, J = 7.9 Hz, 2H), 1.80 (m, 2H), 1.43 (m, 2H), 1.34 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 153.4, 146.0, 145.4, 145.3, 144.2, 139.7, 133.2, 128.5, 128.30, 128.26, 128.2, 127.4, 126.7, 125.5, 121.2, 121.0, 120.2, 118.2, 55.8, 37.3, 35.0, 31.4, 29.6, 24.1, 22.4, 13.7; HRMS (ESI) m/z: Calcd for C30N3H34 [M]+ 436.2747, found 436.2732; UV-vis (ACN): λ = 310 nm (4.32).

1-(9H-Fluoren-2-yl)-4-octyl-3-{[p-(tert-butyl)phenyl]metliyl}-1H-1,2,3-triazolium bromide (12):

Tan solid, 75% yield, mp 167-168 °C, 1H NMR (400 MHz, CDCl3): δ 10.30 (s, 1H), 8.49 (s, 1H), 8.20 (dd, J1 = 8.3 Hz, J2 = 2.1 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 6.6 Hz, 1H), 7.47 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 5.83 (s, 2H), 4.09 (s, 2H), 3.03 (t, J = 7.9 Hz, 2H), 1.81 (m, 2H), 1.39 (m, 2H), 1.35 (s, 9H), 1.26 (m, 8H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ153.2, 146.0, 145.24, 145.15, 144.1, 139.7, 133.1, 128.38, 128.36, 128.2, 128.0, 127.3, 126.6, 125.4, 121.1, 120.9, 120.2, 118.0, 55.7, 37.2, 34.9, 31.9, 31.3, 29.3, 29.2, 29.1, 27.7, 24.3, 22.7, 14.2; HRMS (ESI) m/z: Calcd for C34N3H42 [M]+ 492.3373, found 492.3352; UV-vis (ACN): λ = 310 nm (4.29).

4-Dodecyl-1-(9H-fluoren-2-yl)-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (13):

Brown solid, 91% yield, mp 159-160 °C, 1H NMR (400 MHz, CDCl3): δ 10.29 (s, 1H), 8.49 (s, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 6.3 Hz, 1H), 7.46 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 5.84 (s, 2H), 4.08 (s, 2H), 3.03 (t, J = 7.8 Hz, 2H), 1.80 (m, 2H), 1.38 (m, 2H), 1.35 (s, 9H), 1.27 (m, 16H), 0.90 (t, J = 6.9 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 153.3, 146.0, 145.3, 145.2, 144.2, 139.7, 133.2, 128.39, 128.38, 128.2, 128.1, 127.4, 126.6, 125.4, 121.1, 120.9, 120.2, 118.1, 55.8, 37.2, 34.9, 32.1, 31.3, 29.8, 29.7, 29.6, 29.5, 29.4, 29.2, 27.8, 24.4, 22.8, 14.3 ; HRMS (ESI) m/z: Calcd for C38N3H50 [M]+ 548.3999, found 548.3978; UV-vis (ACN): λ = 310 nm (4.27).

3-Benzyl-1-(1-naphthyl)-4-octyl-1H-1,2,3-triazolium bromide (14):

Tan solid, 81% yield, mp 79-80 °C, 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.18 (d, J = 8.28, 1H), 8.06 (d, J = 8.3, 2H), 7.79 (d, J = 7.7, 1H), 7.70 (m, 3H), 7.48 (s, 5H), 6.11 (s, 2H), 3.19 (t, J = 7.9, 2H), 1.75 (t, J = 7.6, 2H), 1.41 (m, 2H), 1.25 (m, 10H), 0.89 (t, J = 6.8, 3H); 13C NMR (400 MHz, CDCl3): δ 146.3, 134.2, 133.0, 131.4, 131.3, 131.0, 129.9, 129.8, 129.5, 128.9, 128.8, 128.0, 127.1, 125.4, 125.3, 121.4, 56.6, 31.9, 29.3, 29.23, 29.20, 27.5, 24.6, 22.8, 14.2; HRMS (ESI) m/z: Calcd for C27N3H32 [M]+ 398.2591, found 398.2587; UV-vis (ACN): λ = 290 nm (3.76).

3-Benzyl-1-(2-naphthyl)-4-octyl-1H-1,2,3-triazolium bromide (15):

Orange solid, 87% yield, mp 104-106 °C, 1H NMR (400 MHz, CDC13): δ 10.29 (br s, 1H), 9.04 (br s, 1H), 8.21 (br s, 2H), 7.98 (br s, 1H), 7.89 (br d, J = 6.2 Hz, 1H), 7.64 (br s, 2H), 7.47 (br s, 5H), 5.97 (br s, 2H), 3.07 (br s, 2H), 1.88 (br s, 2H), 1.40 (br s, 2H), 1.24 (br m, 12 H), 0.89 (t, J = 5.7 Hz, 3H); 13C NMR (400 MHz, CDCl3): δ 146.7, 134.1, 132.9, 132.0, 131.5, 131.39, 131.37, 130.3, 130.0, 129.9, 129.8, 128.9, 128.32, 128.25, 122.8, 119.2, 59.7, 32.0, 30.1, 29.7, 29.5, 29.1, 27.3, 22.9, 14.4; HRMS (ESI) m/z: Calcd for C27N3H32 [M]+ 398.2596, found 398.2584; UV-vis (ACN): λ = 257 nm (4.36), 289 nm (3.94).

1-(2-Anthryl)-3-benzyl-4-octyl-1H-1,2,3-triazolium bromide (16):

Yellow solid, 95% yield, 132-133 °C, 1H NMR (400 MHz, CDCl3): δ 10.58 (s, 1H), 9.28 (s, 1H), 8.76 (s, 1H), 8.40 (s, 1H), 8.06 (m, 4H), 7.57 (m, 2H), 7.48 (m, 3H), 7.41 (m, 2H), 5.95 (bs, 2H), 3.01 (m, 2H), 1.84 (bs, 2H), 1.36 (bs, 2H), 1.25 (m, 8H), 0.89 (t, J = 6.9, 3H); 13C NMR (400 MHz, CDCl3): δ 146.1, 133.0, 132.5, 131.2, 131.1, 130.8, 129.8, 129.7, 129.6, 129.1, 128.6, 128.5, 128.4, 128.2, 126.9, 126.7, 126.6, 121.7, 116.7, 56.4, 31.7, 29.3, 29.2, 29.0, 27.7, 24.7, 22.6, 14.1; HRMS (ESI) m/z: Calcd for C31N3H34 [M]+ 448.2747, found 448.2728; UV-vis (ACN): λ = 258 nm (4.56), 301 nm (4.15).

3-Benzyl-4-octyl-1-(1-pyrenyl)-1H-1,2,3-triazolium bromide (17):

Yellow solid, 94% yield, mp 143-144 °C, 1H NMR (400 MHz, CDCl3): δ 8.92 (s, 1H), 8.42 (d, J = 8.0, 1H), 8.34 (m, 4H), 8.27 (d, J = 9.0, 1H), 8.16 (m, 2H), 8.08 (d, J = 9.1, 1H), 7.51 (m, 5H), 6.19 (s, 2H), 3.24 (bm, 2H), 1.44 (bm, 2H), 1.30 (m, 13H), 0.90 (t, 3H); 13C NMR (400 MHz, CDCl3): δ 146.2, 133.5, 131.4, 131.33, 131.26, 130.7, 130.2, 130.0, 129.7, 129.6, 128.7, 127.19, 127.16, 127.1, 126.8, 126.7, 125.3, 124.9, 124.5, 123.5, 123.4, 119.9, 56.6, 31.7, 29.2, 29.11, 29.09, 27.5, 24.6, 22.6, 14.1; HRMS (ESI) m/z: Calcd for C33N3H34 [M]+ 472.2753, found 472.2747; UV-vis (ACN): λ = 266 nm (4.25), 276 nm (4.43), 343 nm (4.36).

1-(1-Naphthyl)-4-octyl-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (18):

Brown oil, 83% yield, 1H NMR (400 MHz, CDCl3): δ 8.86 (bs, 1H), 8.10 (d, J = 7.9, 1H), 7.98 (d, J = 7.2, 2H), 7.70 (bs, 1H), 7.64 (bs, 3H), 7.44 (d, J = 7.2, 2H), 7.33 (d, J = 7.0, 2H), 5.93 (bs, 2H), 3.02 (bs, 2H), 1.66 (bs, 2H), 1.31 (bs, 11H), 1.21 (m, 8H), 0.85 (t, J = 6.7, 3H); 13C NMR (400 MHz, CDCl3): δ 152.9, 145.8, 134.0, 132.8, 131.6, 130.9, 129.2, 128.8, 128.6, 128.1, 127.7, 126.9, 126.4, 126.0, 125.3, 122.7, 56.1, 34.6, 31.7, 31.1, 29.3, 29.1, 29.0, 27.7, 24.4, 22.5, 14.0; HRMS (ESI) m/z: Calcd for C31N3H40 [M]+ 454.3217, found 454.3209; UV-vis (ACN): λ = 290 nm (3.72).

1-(2-Naphthyl)-4-octyl-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (19):

Tan solid, 66% yield, 131-133 °C, 1H NMR (400 MHz, CDCl3): δ 10.49 (bs, 1H), 9.06 (bs, 1H), 8.20 (bt, J = 8.3, 2H), 8.09 (d, J = 8.7, 1H), 7.96 (t, J = 4.7, 1H), 7.68 (t, J = 4.2, 2H), 7.50 (d, J = 8.1, 2H), 7.32 (d, J = 8.2, 2H) 5.84 (bs, 2H), 3.02 (bs, 2H), 1.85 (bs, 2H), 1.41 (bs, 2H), 1.35 (s, 9H), 1.27 (m, 8H), 0.90 (t, J = 6.8, 3H); 13C NMR (400 MHz, CDCl3): δ 153.4, 146.2, 134.2, 133.0, 132.0, 130.8, 129.7, 128.8, 128.7, 128.28, 128.25, 128.2, 128.0, 126.7, 121.3, 117.8, 56.2, 35.0, 31.9, 31.3, 29.4, 29.3, 29.2, 27.9, 24.8, 22.8, 14.3; HRMS (ESI) m/z: Calcd for C31N3H40 [M]+ 454.3217, found 454.3202; UV-vis (ACN): λ = 257 nm (4.37), 289 nm (3.96).

1-(2-Anthryl)-4-octyl-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (20):

Brown solid, 89% yield, mp 169-171 °C, 1H NMR (400 MHz, CDCl3): δ 10.63 (s, 1H), 9.34 (s, 1H), 8.81 (s, 1H), 8.45 (s, 1H), 8.15 (d, J = 8.8, 1H), 8.05 (m, 3H), 7.58 (m, 3H), 7.49 (d, J = 8.0, 2H), 7.32 (d, J = 8.2, 2H), 5.86 (s, 2H), 3.01 (bs, 2H), 1.85 (bs, 2H), 1.38 (bs, 1H), 1.34 (s, 9H), 1.28 (m, 8H), 0.90 (t, J = 6.9, 3H); 13C NMR (400 MHz, CDCl3): δ 153.2, 146.0, 132.9, 132.5, 131.21, 131.19, 130.8, 129.8, 129.0, 128.6, 128.33. 128.31, 128.29, 126.9, 126.7, 126.6, 121.5, 116.8, 56.1, 34.9, 31.9, 31.3, 29.4, 29.3, 29.2, 27.8, 24.6, 22.7, 14.2; HRMS (ESI) m/z: Calcd for C35N3H42 [M]+ 504.3373, found 504.3356; UV-vis (ACN): λ = 258 nm (4.73), 300 nm (4.31).

4-Octyl-1-(1-pyrenyl)-3-{[p-(tert-butyl)phenyl]methyl}-1H-1,2,3-triazolium bromide (21):

Yellow solid, 83% yield, mp 150-152 °C, 1H NMR (400 MHz, CDCl3): δ 8.96 (s, 1H), 8.44 (m, 1H), 8.35 (m, 3H), 8.28 (d, J = 8.9, 1H), 8.16 (m, 2H), 8.10 (m, 1H), 7.52 (d, J = 7.8, 2H), 7.45 (d, J = 8.0, 2H), 6.12 (s, 2H), 3.27 (bs, 2H), 1.81 (bs, 2H), 1.45 (bs, 2H), 1.36 (s, 9H), 1.28 (m, 8H), 0.90 (t, J = 6.7, 3H); 13C NMR (400 MHz, CDCl3): δ 153.1, 146.1, 133.4, 131.6, 131.2, 130.7, 130.1, 129.9, 128.6, 128.4, 127.2, 127.11, 127.06, 126.8, 126.7, 126.5, 125.2, 125.0, 124.4, 123.7, 123.3, 120.3, 56.4, 34.8, 31.8, 31.2, 29.4, 29.19, 29.15, 27.7, 24.7, 22.6, 14.1;; HRMS (ESI) m/z: Calcd for C37N3H42 [M]+ 528.3379, found 528.3383; UV-vis (ACN): λ = 266 nm (4.18), 276 nm (4.34), 343 nm (4.26).

Minimum Inhibitory Concentration Assays

Inoculum were prepared following standard microdilution assay procedures22–24 using Mueller-Hinton broth for all bacteria and YM broth for yeast. Each triazole and triazolium bromide compound was prepared as a 10 mM solution in DMSO. 10 μL of each DMSO stock solution was diluted into 190 μL broth and a 1:1 serial dilution was performed in a 96 well plate. Addition of 100 μL inoculum to each well resulted in a range of 250, 120, 62, 31, 16, 8, 4 and 2 μM concentrations for each MIC assay. Plates were incubated for 20 h (bacteria) and 24 h (yeast) at 37 °C then examined by eye for cloudiness indicating microbial growth. The most dilute member within a serial dilution that remained transparent after 24 h was defined as the minimum inhibitory concentration (MIC) value for that compound/organism combination. Assays were performed in triplicate. Any compounds displaying activity at the minimum 2 μM concentration of the original assay were tested again at a 10-fold dilution using the same microdilution procedure with a 1 mM DMSO stock solution.

XRD Analysis

Crystals of 10 were grown from slow evaporation of a CH2Cl2 solution. Crystals were mounted on MiTeGen Microloop with non-drying immersion oil. The crystals were then optically aligned on the Rigaku SCX-Mini diffractometer using a digital camera. Initial matrix images were collected to determine the unit cell, validity and proper exposure time. Three hemispheres (where φ= 0.0, 120.0 and 240.0) of data were collected with each consisting 180 images each with 1.00° widths and a 1.00° step. CrysAlis PRO 1.171.39.46 was used to integration, scaling and absorption correction.37 The structure was refined using SHELXT Intrinsic Phasing38 and SHELXL.39 Olex2 was used as a graphical interface.40 Images for the above compounds generated using CrystalMaker® version 10.4.3: a crystal and molecular structures program for Mac and Windows (CrystalMaker Software Ltd, Oxford, England, www.crystalmaker.com).41 Crystallographic information for the obtained structure is summarized in Supporting Information Table S1, along with atomic coordinates and additional structural information provided in Tables S2–S7.

Supplementary Material

1783364_sup_info

Acknowledgements

This publication was made possible by grants from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH), and its contents are the sole responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Footnotes

Appendix. Supplementary Material

Copies of 1H and 13C NMR spectra for all newly reported compounds and crystallographic information for the SC-XRD analysis of compound 10 are included. Crystallographic data for the structure presented in this paper has been deposited with the Cambridge Crystallographic Data Centre as #2102273. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax: +44-(0)1223-336033 or despoit@ccdc.cam.ac.uk).

Conflict of Interest

The authors declare that they have no conflict of interest.

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