Research Advances on the Bioactivity of 1,2,3-Triazolium Salts

1,2,3-Triazolium salts have demonstrated significant potential in the fields of medicine and agriculture, exhibiting exceptional antibacterial, antifungal, anticancer, and antileishmanial properties. Moreover, these salts can be utilized as additives or components to produce nano- and fiber-based materials with antibacterial properties. In this review, we summarize several synthetic strategies to obtain 1,2,3-triazolium salts and the structures of 1,2,3-triazolium derivatives with biological activities in the domains of pharmaceuticals, pesticides, and functional materials. Additionally, the structure–activity relationship (SAR) of 1,2,3-triazolium salts with different biological activities has been analyzed. Finally, this review presents the potential applications and prospects of 1,2,3-triazolium salts in the fields of agriculture, medicine, and industrial synthesis.


Non-Selective Huisgen Reaction
The utilization and synthesis of 1,2,3-triazoles have experienced significant growth in recent decades [52]. The existence of triazoles has been recognized since the 1960s when Huisgen discovered the thermal cycloaddition reaction involving azides and alkynes (Scheme 1) [54]. Under high temperatures, the Huisgen 1,3-dipolar cycloaddition reaction between azides and terminal or internal alkynes leads to the formation of triazoles [54]. However, this method is limited due to its requirement for prolonged heating and its purification from the mixture of 1,4-and 1,5-regioisomers [52,55].

Selective Huisgen Reaction Mediated by Metal Catalysis
In 1974, Huisgen and coworkers found that Cu(I) cations could catalyze the cyclization reaction between an azide and an alkyne, leading to the formation of 1,2,3-triazoles [4]. They demonstrated that under catalytic conditions, the CuAAC reaction could selectively generate the 1,4-disubstituted isomer as the main product [4]. The key step in the Huisgen synthesis is the formation of a copper(I) acetylide intermediate from the alkyne and the copper catalyst [55][56][57]. This intermediate then reacts with the azide to generate a highly stable 1,2,3-triazole product. The reaction exhibits high regioselectivities under mild reaction conditions, giving the 1,4-disubstituted triazole product as the major isomer (Scheme 1) [55][56][57]. The selective Huisgen synthesis offers several advantages over traditional methods for triazole synthesis [55]. It proceeds rapidly, often achieving complete conversion within minutes to hours. It also tolerates a wide range of functional groups, enabling the incorporation of diverse molecular entities into the triazole scaffold. Additionally, the reaction can be performed in water or bio-orthogonal conditions, making it suitable for applications in biological systems [55].

Selective Huisgen Reaction Mediated by Metal Catalysis
In 1974, Huisgen and coworkers found that Cu(I) cations could catalyze the cyclization reaction between an azide and an alkyne, leading to the formation of 1,2,3-triazoles [4]. They demonstrated that under catalytic conditions, the CuAAC reaction could selectively generate the 1,4-disubstituted isomer as the main product [4]. The key step in the Huisgen synthesis is the formation of a copper(I) acetylide intermediate from the alkyne and the copper catalyst [55][56][57]. This intermediate then reacts with the azide to generate a highly stable 1,2,3-triazole product. The reaction exhibits high regioselectivities under mild reaction conditions, giving the 1,4disubstituted triazole product as the major isomer (Scheme 1) [55][56][57]. The selective Huisgen synthesis offers several advantages over traditional methods for triazole synthesis [55]. It proceeds rapidly, often achieving complete conversion within minutes to hours. It also tolerates a wide range of functional groups, enabling the incorporation of diverse molecular entities into the triazole scaffold. Additionally, the reaction can be performed in water or bio-orthogonal conditions, making it suitable for applications in biological systems [55].
In 2008, Fokin's group chose Ruthenium (II) as a catalyst to promote the reaction between a series of organic azides and terminal alkynes containing various functional groups. 1,5-disubstitued 1,2,3-triazole products were selectively generated at a high temperature (Scheme 1) [58]. Ru(II) catalysts possess advantages over copper catalysts due to their easy synthesis and air stability, which are suitable for ambient temperature cycloaddition reactions involving internal alkynes, aryl azides, and other thermally labile reactants [58]. Nonetheless, both catalysts exhibit excellent activities as well as chemo-and regio-selectivities. In addition to the CuAAC reaction, the new RuAAC process provides easier access to all 1H-1,2,3-triazole regioisomers [57,58].
The resulting alkylated product can be further converted into the various 1,2,3-triazolium salts through protonation or appropriate transformations [4,50]. For example, the anionic counterion X − of the triazolium salt can be easily exchanged by simply washing with excess inorganic salt or using an exchange resin [17] (Scheme 3).

Antibacterial Activities of 1,2,3-Triazolium Salts
Quaternary ammonium compounds (QACs) are a kind of cationic biocide with broad-spectrum antibacterial activity which are used in various fields from household cleaning and agriculture to medicine and industry [59]. QACs possess unique amphiphilic characteristics that allow them to disrupt the phospholipid bilayer of the cell membrane [59]. Consequently, they are often used as bactericides, such as benzalkonium chloride [60].
The resulting alkylated product can be further converted into the various 1,2,3triazolium salts through protonation or appropriate transformations [4,50]. For example, the anionic counterion X − of the triazolium salt can be easily exchanged by simply washing with excess inorganic salt or using an exchange resin [17] (Scheme 3). dition reactions involving internal alkynes, aryl azides, and other thermally labile reactants [58]. Nonetheless, both catalysts exhibit excellent activities as well as chemo-and regio-selectivities. In addition to the CuAAC reaction, the new RuAAC process provides easier access to all 1H-1,2,3-triazole regioisomers [57,58].
The resulting alkylated product can be further converted into the various 1,2,3-tria zolium salts through protonation or appropriate transformations [4,50]. For example, the anionic counterion X − of the triazolium salt can be easily exchanged by simply washing with excess inorganic salt or using an exchange resin [17] (Scheme 3).

Antibacterial Activities of 1,2,3-Triazolium Salts
Quaternary ammonium compounds (QACs) are a kind of cationic biocide with broad-spectrum antibacterial activity which are used in various fields from household cleaning and agriculture to medicine and industry [59]. QACs possess unique amphiphilic characteristics that allow them to disrupt the phospholipid bilayer of the cell membrane [59] Consequently, they are often used as bactericides, such as benzalkonium chloride [60].

Antibacterial Activities of 1,2,3-Triazolium Salts
Quaternary ammonium compounds (QACs) are a kind of cationic biocide with broadspectrum antibacterial activity which are used in various fields from household cleaning and agriculture to medicine and industry [59]. QACs possess unique amphiphilic characteristics that allow them to disrupt the phospholipid bilayer of the cell membrane [59]. Consequently, they are often used as bactericides, such as benzalkonium chloride [60].

Antibacterial Cationic Anthraquinone Analogs
Anthraquinone is the structural core of anthracycline and exhibits a wide rang biological activities [17]. It has played an important role in the discovery of new biolo and pharmaceutical therapeutic drugs [18]. The analogs of anthraquinone fused 1,2,3-triazolium units are called cationic anthraquinone analogs (CAAs), which have reported to possess good antibacterial activities [17][18][19]. These compounds are comp of several popular antibacterial scaffolds, including anthraquinone, triazolium, and Q cations.
In the same year, to clarify the effects of alkyl chain length on antibacterial activ they synthesized linear alkyl chain anthraquinone triazolium salts with different siz the N-3 position and tested their activities against drug-resistant bacteria [18]. The re showed that compounds 5a and 5b had broad activities against methicillin-resista aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), and the MIC va were both less than 8 µg/mL ( Figure 2). Later, they used the same method to obtain a series of anthraquinone triazolium containing different alkyl chains connecting to the N-1 and N-3 positions. They found compound 6 ( Figure 2) had the best inhibitory activities against S. aureus and Escher coli (E. coli), with MIC values of 0.25 to 2 µg/mL [17].
In 2017, they developed a series of dimeric cationic anthraquinone analogs with tibacterial activities [19]. The MIC values of compound 7 against G+ bacteria and Gteria were 1 to 16 µg/mL. In the following year, anthraquinone triazolium compou with different anions were also tested for antibacterial activities [20]. The MIC valu compound 8 with ¯O Tf anions against S. aureus and E. coli were 0.125 to 1 µg/mL. In a tion to the alkyl chain, the anthraquinone triazolium compounds connecting the Four years later, they synthesized more 1,3,4-trisubstituted-1,2,3-triazolium bromide salts via click reactions [15]. Compounds with 2-fluorenyl, 1-naphthyl, 2-naphthyl, 2anthracenyl, or 1-pyrenyl at the N-1 position of the triazolium salt exhibited emission properties and good antibacterial activities. Compound 2 showed similar inhibitory activities against G+ strains as compound 1, with MIC values of 0.4-0.8 µM (Figure 1).
In 2021, Sol and coworkers prepared a variety of 1,2,3-triazolium-containing phenolic ketone derivatives with moderate to good water solubility [14]. Among them, compound 3 exhibited good resistance to bacteria in the absence of light, and its antibacterial activity could be further increased under light irradiation through the light-induced activation of the highly conjugated R group. The MIC values of compound 3 against Staphylococcus aureus (S. aureus) CIP76. 25 and Staphylococcus epidermidis (S. epidermidis) CIP109.562 under light conditions were 0.39 µM and 0.78 µM, respectively ( Figure 1).

Antibacterial Cationic Anthraquinone Analogs
Anthraquinone is the structural core of anthracycline and exhibits a wide range of biological activities [17]. It has played an important role in the discovery of new biological and pharmaceutical therapeutic drugs [18]. The analogs of anthraquinone fused with 1,2,3-triazolium units are called cationic anthraquinone analogs (CAAs), which have been reported to possess good antibacterial activities [17][18][19]. These compounds are composed of several popular antibacterial scaffolds, including anthraquinone, triazolium, and QAC cations.
In the same year, to clarify the effects of alkyl chain length on antibacterial activities, they synthesized linear alkyl chain anthraquinone triazolium salts with different sizes at the N-3 position and tested their activities against drug-resistant bacteria [18]. The results showed that compounds 5a and 5b had broad activities against methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE), and the MIC values were both less than 8 µg/mL ( Figure 2).
Later, they used the same method to obtain a series of anthraquinone triazolium salts containing different alkyl chains connecting to the N-1 and N-3 positions. They found that compound 6 ( Figure 2) had the best inhibitory activities against S. aureus and Escherichia coli (E. coli), with MIC values of 0.25 to 2 µg/mL [17].

Antibacterial 1,2,3-Triazolium-Based Peptoid Oligomers
Amphiphilic cationic peptides with N-substituted glycine showed great prospects as antimicrobial peptide mimetics. In 2018, Faure and coworkers obtained a series of 1,2,3triazolium cationic amphiphilic peptide oligomers on a carrier [23]. Short hexamer 10 had a great inhibitory effect against G+ bacteria with MIC values of 6.3 µM and 3.1 µM against E. faecalis and S. aureus, respectively ( Figure 3). Furthermore, this hexamer was found to be non-hemolytic and non-cytotoxic to Hela cells. In 2021, they reported that the hexamer 11, which contains a triazolium cationic side chain, exhibited good inhibition activities against G+ strains, with a MIC value of 3.1 µM against S. aureus CIP 6525 [24]. This hexamer was the first peptide reported to have a preventive effect on biofilm formation in P. aeruginosa and E. faecalis at sub-MIC concentrations. The hemolytic assay demonstrated that Compound 11 had good selectivity and was neither hemolytic nor cytotoxic to Hela cells, even at high concentrations ( Figure 3).

Antibacterial Condensed-Heterocyclic 1,2,3-Triazolium Salts
In 1992, Yoshimura et al. synthesized a series of antibacterial compounds by transforming cephalosporins into heterocycles fused with triazolium [25]. Compound 12, which contains 1,2,3-triazolium cationic groups, showed effective antibacterial activities In 2017, they developed a series of dimeric cationic anthraquinone analogs with antibacterial activities [19]. The MIC values of compound 7 against G+ bacteria and Gbacteria were 1 to 16 µg/mL. In the following year, anthraquinone triazolium compounds with different anions were also tested for antibacterial activities [20]. The MIC values of compound 8 with -OTf anions against S. aureus and E. coli were 0.125 to 1 µg/mL. In addition to the alkyl chain, the anthraquinone triazolium compounds connecting the aryl group at the N-3 position also showed good inhibitory activities against MRSA. The MIC values of Compounds 9a and 9b against MRSA were 1 to 2 µg/mL ( Figure 2) [21].

Antibacterial 1,2,3-Triazolium-Based Peptoid Oligomers
Amphiphilic cationic peptides with N-substituted glycine showed great prospects as antimicrobial peptide mimetics. In 2018, Faure and coworkers obtained a series of 1,2,3-triazolium cationic amphiphilic peptide oligomers on a carrier [23]. Short hexamer 10 had a great inhibitory effect against G+ bacteria with MIC values of 6.3 µM and 3.1 µM against E. faecalis and S. aureus, respectively ( Figure 3). Furthermore, this hexamer was found to be non-hemolytic and non-cytotoxic to Hela cells.

Antibacterial 1,2,3-Triazolium-Based Peptoid Oligomers
Amphiphilic cationic peptides with N-substituted glycine showed great prospec antimicrobial peptide mimetics. In 2018, Faure and coworkers obtained a series of 1 triazolium cationic amphiphilic peptide oligomers on a carrier [23]. Short hexamer 10 a great inhibitory effect against G+ bacteria with MIC values of 6.3 µM and 3.1 µM aga E. faecalis and S. aureus, respectively ( Figure 3). Furthermore, this hexamer was foun be non-hemolytic and non-cytotoxic to Hela cells. In 2021, they reported that the hexamer 11, which contains a triazolium cationic chain, exhibited good inhibition activities against G+ strains, with a MIC value of 3.1 against S. aureus CIP 6525 [24]. This hexamer was the first peptide reported to have a ventive effect on biofilm formation in P. aeruginosa and E. faecalis at sub-MIC concen tions. The hemolytic assay demonstrated that Compound 11 had good selectivity and neither hemolytic nor cytotoxic to Hela cells, even at high concentrations ( Figure 3). In 2021, they reported that the hexamer 11, which contains a triazolium cationic side chain, exhibited good inhibition activities against G+ strains, with a MIC value of 3.1 µM against S. aureus CIP 6525 [24]. This hexamer was the first peptide reported to have a preventive effect on biofilm formation in P. aeruginosa and E. faecalis at sub-MIC concentrations. The hemolytic assay demonstrated that Compound 11 had good selectivity and was neither hemolytic nor cytotoxic to Hela cells, even at high concentrations ( Figure 3).
In 2015, Tejero et al. prepared polys (methyl methacrylate) using alkynyl alcohols and thiazole azide derivatives as raw materials [27]. The N-alkylation of the azole ring allowed the preparation of unipolar and polar polyelectrolytes with different amphiphilic properties, resulting in their antibacterial activity against various microorganisms. Compound 14, for example, showed significant antibacterial activities, with MIC values less than 10 µg/mL against P. aeruginosa, S. aureus, S. epidermidis, and MRSA ( Figure 5).  Recently, Wilson et al. synthesized a series of N,N'-disubstituted triazolium salts, and tested their antibacterial activity against several bacteria, including Enterococcus faecium (E. faecium), S. aureus, Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), Pseudomonas aeruginosa (P. aeruginosa) and E. faecium, which are common pathogens of hospital-acquired infections [26]. Those compounds exhibited potent antibacterial properties against all bacterial strains. Specifically, compound 13 exhibited a MIC value of ≤0.5 µg/mL (Figure 4).
In 2015, Tejero et al. prepared polys (methyl methacrylate) using alkynyl alcohols and thiazole azide derivatives as raw materials [27]. The N-alkylation of the azole ring allowed the preparation of unipolar and polar polyelectrolytes with different amphiphilic properties, resulting in their antibacterial activity against various microorganisms. Compound 14, for example, showed significant antibacterial activities, with MIC values less than 10 µg/mL against P. aeruginosa, S. aureus, S. epidermidis, and MRSA ( Figure 5).
In the same year, they also prepared a series of compounds with amphiphilic quaternary ammonium salts through controlled quaternization of triazolium side chains by polymethacrylates [28]. The MIC values of compound 15 against P. aeruginosa and S. aureus were 4 µg/mL at 100% quaternization. Meanwhile, compound 15 with 50% quaternization can also kill 100% of bacteria within 5 min at 2 × MIC. Interestingly, these polymers with a low degree of quaternization still exhibited strong and rapid bactericidal behavior, possibly due to the synergistic effect between the unquaternized heterocyclic and the quaternized heterocyclic ( Figure 5). tribution, cationic property, density, and chemical composition [27][28][29][30][31].
In 2015, Tejero et al. prepared polys (methyl methacrylate) using alkynyl alcohols and thiazole azide derivatives as raw materials [27]. The N-alkylation of the azole ring allowed the preparation of unipolar and polar polyelectrolytes with different amphiphilic properties, resulting in their antibacterial activity against various microorganisms. Compound 14, for example, showed significant antibacterial activities, with MIC values less than 10 µg/mL against P. aeruginosa, S. aureus, S. epidermidis, and MRSA ( Figure 5).  In 2017, Muñoz-Bonilla et al. prepared a cationic copolymer containing thiazole and triazole groups [29]. They blended it with commercial polystyrene by a simple spin coating method to obtain a series of contact-type active antibacterial films. These blended films exhibited significant microbicidal activity against both G+ and G-bacteria, as well as fungi. At 30% and 50% PS/copolymer content, the killing efficiency of the blended film 16 exceeded 99.99%. In 2018, the researchers reported that even a small amount (3~9 wt %) of PS/copolymer breath figure films prepared using the breath figures approach still had considerable antibacterial effects against G+ bacteria, such as S. aureus and C. parapsilonosis [30]. The breath figure film 16 was able to kill over 90% of the cells from both bacteria through surface contact ( Figure 5).
In 2018, Fernández-García and coworkers synthesized a series of copolymers with quaternary ammonium salt groups that exhibited contact active antibacterial properties [31]. These copolymers were made using quaternary ammonium salts and polyacrylonitrile as raw materials. Compound 17 has extremely strong bactericidal activities against S. aureus and P. aeruginosa, with cell-killing rates of over 99.99% ( Figure 5).

Antibacterial 1,2,3-Triazolium-Based Complex
In 2022, Muñoz-Bonilla and coworkers synthesized compound 18 via free radical polymerization and click reaction with a hydantoin moiety ( Figure 6). It underwent further N-alkylation and chlorination reactions to form triazolium salt polylactide-based fibers with antibacterial activity. Polylactide-based fiber 18 containing cationic triazolium and Nhaloamine groups showed good antibacterial activities against both G+ and G-bacteria [32].
To minimize the decreasing effect of ionic bactericidal compounds on the mechanical strength of dental composites, Yeganeh et al. (2017) prepared bactericidal dental nanocomposites containing 1,2,3-triazolium-based functionalized polyhedral oligomeric silsesquioxane (POSS) additives through thiol-one click polymerization. The addition of the triazolium cation resulted in increased bactericidal activity of complex 19 ( Figure 6) compared to similar compositions containing dimethyl aminoethyl methacrylate monomers (DMAEMA-BC). The inhibition rate (IR) of complex 19 against Streptococcus pyogenes (S. pyogenes) was above 60% [33].

Structure-Activity Relationship Analysis of Antibacterial 1,2,3-Triazolium
The cationic properties of triazolium salts are necessary for their antibacterial effi cacy. Compounds 1 and 2 have good antibacterial activity, whereas their parent 1,2,3-tri azole analogs have no significant antibacterial activity with a MIC value of ≥250 µM [13,14]. The phenolic ketone group in compound 3 is a nonpolar component, which can reduce the hydrophilicity of the triazolium group. There is a balance between the lipo philicity and hydrophilicity of compound 3, which supports good inhibitory activity against G+ bacteria [15]. However, compound 3 has poor activity against G-bacteria. It is caused by the presence of an outer layer of lipopolysaccharide that hinders the penetration of hydrophobic compounds [15]. Connecting a hydrophobic group at the N-3 and C-4 positions of 1,2,3-triazolium salts is beneficial to the resistance of G+ bacteria. However excessive increases in hydrophobicity (lipophilicity) will make it more difficult for com pounds to pass through bacterial cell membranes, resulting in decreased antibacterial ac tivity (Figure 7). Therefore, the maximum effectiveness of 1,2,3-triazolium salts against G-bacteria re quires the connection of a sufficient but not excessive hydrophobic group. Furthermore, a decrease in hydrophobicity at one substituent position can be compensated by an increase Compound 20, an antimicrobial polyurethane wound dressing film, was prepared through an N-alkylation reaction between 1,2,3-triazolium functional soybean oil (TSBO) and methyl iodide ( Figure 6). The introduction of 1,2,3-triazolium cation groups into the dressing skeleton increased their antibacterial activity against a range of bacteria. Appropriate concentrations of these cationic groups still maintained the membrane's good cytocompatibility with dermal fibroblast [34].

Structure-Activity Relationship Analysis of Antibacterial 1,2,3-Triazolium
The cationic properties of triazolium salts are necessary for their antibacterial efficacy. Compounds 1 and 2 have good antibacterial activity, whereas their parent 1,2,3-triazole analogs have no significant antibacterial activity with a MIC value of ≥250 µM [13,14]. The phenolic ketone group in compound 3 is a nonpolar component, which can reduce the hydrophilicity of the triazolium group. There is a balance between the lipophilicity and hydrophilicity of compound 3, which supports good inhibitory activity against G+ bacteria [15]. However, compound 3 has poor activity against G-bacteria. It is caused by the presence of an outer layer of lipopolysaccharide that hinders the penetration of hydrophobic compounds [15]. Connecting a hydrophobic group at the N-3 and C-4 positions of 1,2,3triazolium salts is beneficial to the resistance of G+ bacteria. However, excessive increases in hydrophobicity (lipophilicity) will make it more difficult for compounds to pass through bacterial cell membranes, resulting in decreased antibacterial activity (Figure 7). against G+ bacteria [15]. However, compound 3 has poor activity against G-bacteria. It is caused by the presence of an outer layer of lipopolysaccharide that hinders the penetration of hydrophobic compounds [15]. Connecting a hydrophobic group at the N-3 and C-4 positions of 1,2,3-triazolium salts is beneficial to the resistance of G+ bacteria. However, excessive increases in hydrophobicity (lipophilicity) will make it more difficult for compounds to pass through bacterial cell membranes, resulting in decreased antibacterial activity (Figure 7). Therefore, the maximum effectiveness of 1,2,3-triazolium salts against G-bacteria requires the connection of a sufficient but not excessive hydrophobic group. Furthermore, a decrease in hydrophobicity at one substituent position can be compensated by an increase in hydrophobicity at other substituent positions. For example, connecting alkyl chains Therefore, the maximum effectiveness of 1,2,3-triazolium salts against G-bacteria requires the connection of a sufficient but not excessive hydrophobic group. Furthermore, a decrease in hydrophobicity at one substituent position can be compensated by an increase in hydrophobicity at other substituent positions. For example, connecting alkyl chains with different carbon chain lengths at different sites in compounds 5 and 6 maintains their antibacterial effectiveness by maintaining a balance in the overall hydrophobicity of the compounds [17,18].
In 2017, Guo et al. synthesized a series of compounds with the 1,2,3-triazolium groups. Compound 21 had a good inhibitory effect on the growth of the tested phytopathogens, with an inhibitory index of 82.56% at 1 mg/mL against Gibberella zeae (G. zeae) (Figure 8). This demonstrated that the introduction of 1,2,3-triazolium groups could improve the antifungal activity of inulin [5]. with different carbon chain lengths at different sites in compounds 5 and 6 maintains their antibacterial effectiveness by maintaining a balance in the overall hydrophobicity of the compounds [17,18].
In 2017, Guo et al. synthesized a series of compounds with the 1,2,3-triazolium groups. Compound 21 had a good inhibitory effect on the growth of the tested phytopathogens, with an inhibitory index of 82.56% at 1 mg/mL against Gibberella zeae (G. zeae) (Figure 8). This demonstrated that the introduction of 1,2,3-triazolium groups could improve the antifungal activity of inulin [5].

Antifungal 1,2,3-Triazolium-Based Chitosan Derivative
Chitosan is a promising biocompatible and biodegradable material with broad biological applications as a fungicidal and antibacterial agent. However, its poor solubility in both organic and aqueous solvents severely limit its application. To overcome this limitation, researchers have developed chitosan derivatives bearing the triazolium group, which possess important physical and chemical properties such as water solubility, chemical stability, and antifungal activity [9].

Antifungal 1,2,3-Triazolium-Based Chitosan Derivative
Chitosan is a promising biocompatible and biodegradable material with broad biological applications as a fungicidal and antibacterial agent. However, its poor solubility in both organic and aqueous solvents severely limit its application. To overcome this limitation, researchers have developed chitosan derivatives bearing the triazolium group, which possess important physical and chemical properties such as water solubility, chemical stability, and antifungal activity [9].
In 2018, Tan et al. synthesized several 1,2,3-triazolium chitosan derivatives and evaluated their biological activities. They found that the antifungal properties of the 1,2,3-triazolium-functionalized chitosan were significantly improved compared to those of 1,2,3triazole chitosan. Among the tested compounds, compound 25 showed a good inhibition rate of 98.44% at 1.0 mg/mL against C. lagenarium, followed by 79.16% and 67.56% against W. fusarium and F. oxysporum, respectively ( Figure 9). Notably, the cationic chitosan derivative 25 remained active against the tested fungi when the concentration of compound 25 was reduced to 0.5 mg/mL. In addition, the chitosan derivatives bearing the 1,2,3-triazolium group showed no cytotoxicity to cucumber seedlings [9].

Structure-Activity Relationship Analysis of Antifungal 1,2,3-Triazolium
Polysaccharide derivatives containing the triazolium group, such as compounds 21 [5,6], 22 [6], 23 [7], and 24 [8], exhibit higher inhibition rates against plant pathogenic fungi than their parent triazole analogs. This indicates that the triazolium group is the key active group. Cationic triazolium may form electrostatic interactions with anionic components on fungal cell walls. In comparison to starch derivatives containing 1,2,3triazole, the electrostatic interaction of 1,2,3-triazolium derivatives has a greater impact on microorganisms than the hydrogen bond interaction between 1,2,3-triazole analogs and targets. The length of alkyl groups is an important determinant of the antifungal activity of 1,2,3-triazolium functionalized starch derivatives, and their antifungal properties decrease as the side chain length increases. The possible reason for this is that longer alkyl groups tend to provide more electrons to the 1,2,3-triazolium moiety, resulting in a decrease in the positive charge density of the 1,2,3-triazolium moiety and leading to a decrease in antifungal performance. Furthermore, the introduction of pyridine and alkyl groups can enhance antifungal activity ( Figure 11).

Structure-Activity Relationship Analysis of Antifungal 1,2,3-Triazolium
Polysaccharide derivatives containing the triazolium group, such as compounds 21 [5,6], 22 [6], 23 [7], and 24 [8], exhibit higher inhibition rates against plant pathogenic fungi than their parent triazole analogs. This indicates that the triazolium group is the key active group. Cationic triazolium may form electrostatic interactions with anionic components on fungal cell walls. In comparison to starch derivatives containing 1,2,3-triazole, the electrostatic interaction of 1,2,3-triazolium derivatives has a greater impact on microorganisms than the hydrogen bond interaction between 1,2,3-triazole analogs and targets. The length of alkyl groups is an important determinant of the antifungal activity of 1,2,3-triazolium functionalized starch derivatives, and their antifungal properties decrease as the side chain length increases. The possible reason for this is that longer alkyl groups tend to provide more electrons to the 1,2,3-triazolium moiety, resulting in a decrease in the positive charge density of the 1,2,3-triazolium moiety and leading to a decrease in antifungal performance. Furthermore, the introduction of pyridine and alkyl groups can enhance antifungal activity (Figure 11).
In 2016, Osmak et al. synthesized a series of novel anticancer 1-(2-pyridyl)-,4-(2pyridyl)-,1-(2-pyridyl)-and 4-(2-pyridyl)-3-methyl-1,2,3-triazolium salts, and triazole compounds. The triazolium salt compounds exhibited superior antitumor activities to the triazole compounds in several tumor cells. The cytotoxicity of compound 27 against tumor cells was significantly higher than that of normal cells, and the therapeutic index for lung cancer cells H460 was 7.69 ( Figure 12). The mechanism of compound 27 is to block cell mitosis during the G1 phase of the cell cycle. It does not bind to dsDNA but induces reactive oxygen species (ROS) in treated cells, further causing cell death [10].
Two years later, Silva et al. synthesized a series of 1,2,3-triazolium salt compounds with different substituents and tested their inhibitory activities on several cancer cells, including osteomyeloid leukemia HL-60, lymphoid leukemia JURKAT, breast cancer MCF-7 and colon cancer MCT-116. Compound 28 (Figure 12) demonstrated significant anticancer activity compared to other triazolium salts, with a half-maximal inhibitory concentration (IC50) value of 3.4 µM against HL-60 cell lines [36].
In 2016, Osmak et al. synthesized a series of novel anticancer 1-(2-pyridyl)-,4-(2pyridyl)-,1-(2-pyridyl)-and 4-(2-pyridyl)-3-methyl-1,2,3-triazolium salts, and triazole compounds. The triazolium salt compounds exhibited superior antitumor activities to the triazole compounds in several tumor cells. The cytotoxicity of compound 27 against tumor cells was significantly higher than that of normal cells, and the therapeutic index for lung cancer cells H460 was 7.69 ( Figure 12). The mechanism of compound 27 is to block cell mitosis during the G1 phase of the cell cycle. It does not bind to dsDNA but induces reactive oxygen species (ROS) in treated cells, further causing cell death [10]. In 2019, Antonenko et al. prepared carborane-triazolium cationic salt 30, which exhibited good anticancer activity against K562 cancer cell lines, with an IC50 value of 2.8 µM (Figure 12). Moreover, this boron-containing polyhedral triazolium cationic compound can carry protons through biological membranes, which has potential significance in designing anticancer drugs [11].
Further, they investigated the anticancer potential of compounds 32 [39] and 33 [20], and found promising activity against A549 cancer cell lines with IC50 values of 4.2 and 3.5 µg/mL, respectively ( Figure 13). Notably, compound 33 demonstrated remarkable selectivity towards A549 cancer cells relative to human lung normal cells, exhibiting a selectivity index (SI) of 15.09 [20].
In 2019, Antonenko et al. prepared carborane-triazolium cationic salt 30, which exhibited good anticancer activity against K562 cancer cell lines, with an IC 50 value of 2.8 µM (Figure 12). Moreover, this boron-containing polyhedral triazolium cationic compound can carry protons through biological membranes, which has potential significance in designing anticancer drugs [11]. In 2019, Antonenko et al. prepared carborane-triazolium cationic salt 30, which exhibited good anticancer activity against K562 cancer cell lines, with an IC50 value of 2.8 µM ( Figure 12). Moreover, this boron-containing polyhedral triazolium cationic compound can carry protons through biological membranes, which has potential significance in designing anticancer drugs [11].
Further, they investigated the anticancer potential of compounds 32 [39] and 33 [20], and found promising activity against A549 cancer cell lines with IC50 values of 4.2 and 3.5 µg/mL, respectively ( Figure 13). Notably, compound 33 demonstrated remarkable selectivity towards A549 cancer cells relative to human lung normal cells, exhibiting a selectivity index (SI) of 15.09 [20].

Anticancer Allobetulin 1,2,3-Triazolium Derivatives
In 2020, Dehaen and coworkers reported a series of allobetulin derivatives bearing 1,2,3-triazolium, which had better anticancer activities than the parent compound allobetulin and commercial anticancer drug of gefitinib. Compound 34a showed a good inhibitory effect on SGC-7901 cancer cells, with an IC 50

Anticancer 1,2,3-Triazolium Complex
In 2013, Riela et al. modified the external surface of halloysite with triazolium salts. This resulted in the production of a positively charged halloysite nanotube that was functionalized with triazolium salt 35 ( Figure 15). The nanotube is a drug-loading system that has the advantages of high drug encapsulation efficiency and strong controlled, and sustained release capabilities. By utilizing the drug-loading system, the water solubility of two anticancer drugs, curcumin and cardanol, was improved, which in turn overcame their limitations for clinical applications. Furthermore, the drug delivery system could synergize with the two anticancer drugs and enhance their anticancer activities [41,42].

Structure-Activity Relationship Analysis of Anticancer 1,2,3-Triazolium
Aryl substituents can regulate the cytotoxicity of 1,2,3-triazolium salts on tumor cells. Compound 27 with an electron-donating group (4-methoxyphenyl) has better anticancer activity compared to the compounds bearing electron-neutral groups (e.g., phenyl) or electron-withdrawing groups (e.g., 4-(trifluoromethyl)phenyl) [10]. Compounds 28 and 29 bearing decyl substituents at the N-1 positions exhibit strong cytotoxicity against cancer cells. Interestingly, there is no significant difference in the effect of different anionic forms of the same triazolium salts on anticancer activities [36,37]. In addition, the 1,2,3triazolium group is an effective mitochondrial targeting group [11,37]. Research studies suggest that 1,2,3-triazolium salts induce cancer cell apoptosis through mitochondrial apoptosis and cell cycle arrest pathways [11]. This may be due to the stronger mitochondrial electronic effect in cancer cells than in normal cells [37]. Furthermore, in complex living cell systems, the structure-activity relationship of 1,2,3-triazolium salt compounds is the result of a combination of stereoelectronic effects (Figure 16) [37].

Anticancer 1,2,3-Triazolium Complex
In 2013, Riela et al. modified the external surface of halloysite with triazolium salts. This resulted in the production of a positively charged halloysite nanotube that was functionalized with triazolium salt 35 ( Figure 15). The nanotube is a drug-loading system that has the advantages of high drug encapsulation efficiency and strong controlled, and sustained release capabilities. By utilizing the drug-loading system, the water solubility of two anticancer drugs, curcumin and cardanol, was improved, which in turn overcame their limitations for clinical applications. Furthermore, the drug delivery system could synergize with the two anticancer drugs and enhance their anticancer activities [41,42].

Anticancer 1,2,3-Triazolium Complex
In 2013, Riela et al. modified the external surface of halloysite with triazolium salts. This resulted in the production of a positively charged halloysite nanotube that was functionalized with triazolium salt 35 ( Figure 15). The nanotube is a drug-loading system that has the advantages of high drug encapsulation efficiency and strong controlled, and sustained release capabilities. By utilizing the drug-loading system, the water solubility of two anticancer drugs, curcumin and cardanol, was improved, which in turn overcame their limitations for clinical applications. Furthermore, the drug delivery system could synergize with the two anticancer drugs and enhance their anticancer activities [41,42].

Structure-Activity Relationship Analysis of Anticancer 1,2,3-Triazolium
Aryl substituents can regulate the cytotoxicity of 1,2,3-triazolium salts on tumor cells. Compound 27 with an electron-donating group (4-methoxyphenyl) has better anticancer activity compared to the compounds bearing electron-neutral groups (e.g., phenyl) or electron-withdrawing groups (e.g., 4-(trifluoromethyl)phenyl) [10]. Compounds 28 and 29 bearing decyl substituents at the N-1 positions exhibit strong cytotoxicity against cancer cells. Interestingly, there is no significant difference in the effect of different anionic forms of the same triazolium salts on anticancer activities [36,37]. In addition, the 1,2,3triazolium group is an effective mitochondrial targeting group [11,37]. Research studies suggest that 1,2,3-triazolium salts induce cancer cell apoptosis through mitochondrial apoptosis and cell cycle arrest pathways [11]. This may be due to the stronger mitochondrial electronic effect in cancer cells than in normal cells [37]. Furthermore, in complex living cell systems, the structure-activity relationship of 1,2,3-triazolium salt compounds is the result of a combination of stereoelectronic effects (Figure 16) [37].

Structure-Activity Relationship Analysis of Anticancer 1,2,3-Triazolium
Aryl substituents can regulate the cytotoxicity of 1,2,3-triazolium salts on tumor cells. Compound 27 with an electron-donating group (4-methoxyphenyl) has better anticancer activity compared to the compounds bearing electron-neutral groups (e.g., phenyl) or electron-withdrawing groups (e.g., 4-(trifluoromethyl)phenyl) [10]. Compounds 28 and 29 bearing decyl substituents at the N-1 positions exhibit strong cytotoxicity against cancer cells. Interestingly, there is no significant difference in the effect of different anionic forms of the same triazolium salts on anticancer activities [36,37]. In addition, the 1,2,3-triazolium group is an effective mitochondrial targeting group [11,37]. Research studies suggest that 1,2,3-triazolium salts induce cancer cell apoptosis through mitochondrial apoptosis and cell cycle arrest pathways [11]. This may be due to the stronger mitochondrial electronic effect in cancer cells than in normal cells [37]. Furthermore, in complex living cell systems, the structure-activity relationship of 1,2,3-triazolium salt compounds is the result of a combination of stereoelectronic effects ( Figure 16) [37].  Figure 16. The summarized structure-activity relationship of anticancer 1,2,3-triazolium.

Antileishmanial Other 1,2,3-Triazolium Salts
In 2022, Velázquez and colleagues reported that 1,2,3-triazolium salts exhibited higher antileishmanial activity in intracellular amastigotes than their parent triazoles. Compound 39, which had a biphenylethyl substituent on the triazolium cation group, exhibited an EC 50 (half maximal effective concentration) value of 4.8 µM against L. infantum axenic amastig-otes ( Figure 18). It also showed good selectivity between Leishmania and macrophages, with an SI above 10.3. In addition, compound 39 significantly decreased the content of low molecular weight mercaptans in intracellular amastigotes of L. infantum, and LiTryR may be the main target of this new compound [45]. content of low molecular weight mercaptans in intracellular amastigotes of L. infantum, and LiTryR may be the main target of this new compound [45].

Structure-Activity Relationship Analysis of Antileishmanial 1,2,3-Triazolium
Compounds 36, 37, and 38 bearing 10-carbon side chains at the N-1 position and a methyl group at the N-3 position exhibit good antileishmanial activities [12,43,44]. The long carbon chain at the N-1 position of these compounds is beneficial to their antileishmanial activities. The analogs of compound 38 containing 12, 14, or 16 carbon atoms in the alkyl side chain exhibit better antileishmanial activities, but the long carbon chain also leads to strong toxicity against macrophages [12]. Furthermore, those 1,2,3-triazolium salts bearing a propyl group on the N-3 position exhibit a strong toxic effect on macrophages, regardless of the length of the side chain [12]. It is worth noting that the 1,2,3triazolium group is crucial for enhancing the antileishmanial activities of the compounds, since compounds 37 and 38 exhibit higher antileishmanial activities than their parent triazole [12,44]. Different anion types of the compounds have certain effects on antileishmanial activities and selectivity. For example, compound 36 contained acetic acid anions and was 5.5 times more active against promastigotes of L. amazonensis than analogs containing iodine anions and exhibits highly selective biological activity ( Figure 19) [43].

Conclusions
In summary, 1,2,3-triazolium salts can be directly synthesized in three steps, including CuAAC, N-alkylation, and salt metathesis. A broad scope of 1,2,3-triazolium derivatives bearing various substituents and substitution patterns can be achieved through these approaches. In addition to their impressive applications as ionic liquids (ILs), catalysts, and metal ligands. 1,2,3-triazolium salts exhibit a broad range of biological activities, such  [12,43,44]. The long carbon chain at the N-1 position of these compounds is beneficial to their antileishmanial activities. The analogs of compound 38 containing 12, 14, or 16 carbon atoms in the alkyl side chain exhibit better antileishmanial activities, but the long carbon chain also leads to strong toxicity against macrophages [12]. Furthermore, those 1,2,3-triazolium salts bearing a propyl group on the N-3 position exhibit a strong toxic effect on macrophages, regardless of the length of the side chain [12]. It is worth noting that the 1,2,3-triazolium group is crucial for enhancing the antileishmanial activities of the compounds, since compounds 37 and 38 exhibit higher antileishmanial activities than their parent triazole [12,44]. Different anion types of the compounds have certain effects on antileishmanial activities and selectivity. For example, compound 36 contained acetic acid anions and was 5.5 times more active against promastigotes of L. amazonensis than analogs containing iodine anions and exhibits highly selective biological activity ( Figure 19) [43]. content of low molecular weight mercaptans in intracellular amastigotes of L. infantum, and LiTryR may be the main target of this new compound [45].

Structure-Activity Relationship Analysis of Antileishmanial 1,2,3-Triazolium
Compounds 36, 37, and 38 bearing 10-carbon side chains at the N-1 position and a methyl group at the N-3 position exhibit good antileishmanial activities [12,43,44]. The long carbon chain at the N-1 position of these compounds is beneficial to their antileishmanial activities. The analogs of compound 38 containing 12, 14, or 16 carbon atoms in the alkyl side chain exhibit better antileishmanial activities, but the long carbon chain also leads to strong toxicity against macrophages [12]. Furthermore, those 1,2,3-triazolium salts bearing a propyl group on the N-3 position exhibit a strong toxic effect on macrophages, regardless of the length of the side chain [12]. It is worth noting that the 1,2,3triazolium group is crucial for enhancing the antileishmanial activities of the compounds, since compounds 37 and 38 exhibit higher antileishmanial activities than their parent triazole [12,44]. Different anion types of the compounds have certain effects on antileishmanial activities and selectivity. For example, compound 36 contained acetic acid anions and was 5.5 times more active against promastigotes of L. amazonensis than analogs containing iodine anions and exhibits highly selective biological activity ( Figure 19) [43].

Conclusions
In summary, 1,2,3-triazolium salts can be directly synthesized in three steps, including CuAAC, N-alkylation, and salt metathesis. A broad scope of 1,2,3-triazolium derivatives bearing various substituents and substitution patterns can be achieved through these approaches. In addition to their impressive applications as ionic liquids (ILs), catalysts, and metal ligands. 1,2,3-triazolium salts exhibit a broad range of biological activities, such Figure 19. The summarized structure-activity relationship of antileishmanial 1,2,3-triazolium.

Conclusions
In summary, 1,2,3-triazolium salts can be directly synthesized in three steps, including CuAAC, N-alkylation, and salt metathesis. A broad scope of 1,2,3-triazolium derivatives bearing various substituents and substitution patterns can be achieved through these approaches. In addition to their impressive applications as ionic liquids (ILs), catalysts, and metal ligands. 1,2,3-triazolium salts exhibit a broad range of biological activities, such as antibacterial, antifungal, anticancer and antileishmanial properties. They are valuable in the development of pesticides and pharmaceuticals. Incorporating 1,2,3-triazolium groups into polymer materials via simple synthetic methods can generate antibacterial properties. The utilization of such materials can address the issue of microbial contamination in medical devices or specialized antibacterial environments. Additionally, 1,2,3-triazolium can be incorporated with nanomaterials, such as compounds 19 and 35, imparting strong hydrophilicity to enhance the ductility of nanomaterials and antibacterial properties. The incorporation of 1,2,3-triazolium salt compounds into anticancer drug carriers can bring additional possibilities. Modifying halloysite nanotubes with triazolium salts can yield positively charged anticancer drug carriers possessing improved encapsulation efficiency, controllable release ability, increased water solubility, and thus enhanced anticancer activity. These polymer derivatives can not only be employed to generate antibacterial films through polymerization, but can also be used as additives or components in fibers and nanomaterials.
Based on the structure-activity relationship of 1,2,3-triazolium salt derivatives, it is believed that substituents at N-1 and N-3 positions play critical roles in biological activities. The lip/water balance of 1,2,3-triazolium salts is critical to their high biological activity and selectivity. Additionally, 1,2,3-triazolium derivatives may have multiple action modes, and electrostatic interactions with anionic components on the cell membrane are among the most important. Compared with the parent triazole, 1,2,3-triazolium salts have superior biological activities and water solubility, and are promising in the development of new drugs for drug-resistant pathogens. Currently, the biological activities of 1,2,3triazolium salts are receiving increasing attention from researchers. More precise and reliable data are required to elucidate the possible action mechanism of triazolium salts, providing a theoretical basis for their design and synthesis. Overall, 1,2,3-triazolium salts have promising development prospects in the fields of agriculture, medicine, and industrial production.