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Review

Exploring the Potential of s-Triazine Derivatives as Novel Antifungal Agents: A Review

by
Haoyan Liao
1,†,
Menglu Liu
1,†,
Mengyuan Wang
2,
Dazhi Zhang
2,
Yumeng Hao
2,* and
Fei Xie
2,*
1
Student Bridge, College of Basic Medical Sciences, Naval Medical University, No. 800 Xiangyin Road, Shanghai 200433, China
2
Department of Organic Chemistry, School of Pharmacy, Naval Medical University, No. 325 Guohe Road, Shanghai 200433, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceuticals 2025, 18(5), 690; https://doi.org/10.3390/ph18050690
Submission received: 26 March 2025 / Revised: 2 May 2025 / Accepted: 5 May 2025 / Published: 7 May 2025
(This article belongs to the Collection Feature Review Collection in Medicinal Chemistry)
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Abstract

:
The growing incidence and prevalence of invasive fungal infections (IFIs) and the emergence of antimicrobial resistance compound clinical antifungal therapies. Given the significant threat posed by IFIs and the limits of the current antifungal agents, the search for novel, effective therapeutic options remains a compelling area of antifungal drug discovery. The s-triazine (1,3,5-triazine) scaffold, renowned for its structural versatility, ease of functionalization, and diverse biological profiles, has been extensively studied in medical chemistry. Driven by this privileged structure, several s-triazine derivatives have been synthesized through molecular hybridization and screened for their antifungal activities. Some of them demonstrated potent efficacy against pathogenic fungi, including Candida, Cryptococcus, and Aspergillus species. Structure–activity relationship (SAR) studies are also discussed whenever possible, underlying the essential substituents for their antifungal effect. This review provides a summary of recent advancements (2014–2024) in the development of antifungal agents featuring the s-triazine scaffold and highlights the antifungal activity of s-triazine derivatives, aiming to prompt further progress in this field.

Graphical Abstract

1. Introduction

The global incidence of life-threatening invasive fungal infections (IFIs) has increased significantly. It is estimated that over 6.5 million people have a life-threatening fungal infection worldwide, with approximately 2.5 million deaths each year [1,2], posing a significant impact on public health. Moreover, the incidence and prevalence of IFIs continue to be exacerbated by acquired immunodeficiency syndrome (AIDS), influenza, more recently by the COVID-19 outbreaks, and the emergence of multidrug resistance fungi [3,4]. Given the threat of fungal infection, the World Health Organization developed a fungal priority pathogens list (WHO FPPL, 2022) to help galvanize global action, which classified four fungal pathogens (Cryptococcus neoformans, Candida auris, Aspergillus fumigatus, and Candida albicans) as the “critical” group and a further fifteen fungal pathogens (including Candida glabrata, Candida parapsilosis, Candida krusei, Fusarium spp., and the Mucorales) as medium or high priority group [5]. Candida, Cryptococcus, and Aspergillus species are the primary opportunistic fungal pathogens, accounting for nearly 90% of deaths in IFIs [6]. Candida auris is characterized by a high level of multidrug resistance, with mortality rates as high as 72%, and has become an urgent healthcare threat [7].
Treatment of IFIs is highly challenging. Currently, only a few types of antifungal drugs are used in the clinic to treat IFIs: azoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, and oteseconazole), echinocandins (caspofungin, micafungin, and anidulafungin), polyene antibiotics (amphotericin B), antimetabolites (5-fluorocytosine), and triterpenoids (ibrexafungerp). However, issues with existing antifungal drugs include relatively narrow spectrums of activity, multiple and diverse drug–drug interactions, limitations to access worldwide, frequent acquired and innate drug resistance, etc. [8,9]. Therefore, there is an urgent need to develop new antifungal agents with novel chemical scaffolds.
The triazine ring is one of the most essential heterocyclic, pharmacologically active moieties in drug molecules. The planar, six-membered ring of triazine exists in three isomeric forms depending on the position of the nitrogen atom, namely 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine, known as s-triazine. Of these three isomers, the rigid symmetrical structure of s-triazine has received much attention in medicinal chemistry. It possesses diverse biological profiles such as antibacterial [10], antiviral [11], anticancer [12], antitubercular [13], anticonvulsant [14], etc. (Figure 1A). Moreover, many approved drugs available on the market (e.g., altretamine, enasidenib, almitrine, melarsoprol, and bemotrizinol) have an s-triazine moiety (Figure 1B), indicating its favorable safety and pharmacokinetic properties. Apart from their application in medicinal chemistry, s-triazine derivatives are also used as herbicides, insecticides, corrosion inhibitors, energetics, and new materials [15,16,17,18].
In addition, s-triazine is an ideal framework for constructing novel drug candidates due to the ease of synthesizing the s-triazine core from simple starting materials or the availability of cyanuric chloride or 2,4,6-trichloro-1,3,5-triazine (TCT, 1), alongside the ability to explore the chemical space within the core. Figure 2 presents a temperature-dependent selective replacement of the chlorine atoms in 1 with sequential nucleophilic substitutions (typically N-, O-, S- or P-nucleophiles) that allow the extensive preparation of mono-, di-, and tri-substituted s-triazine derivatives. The replacement of the first Cl atom was performed at 0 °C in the presence of a base such as Na2CO3, NaHCO3, triethylamine, diisopropylethylamine, etc., while the second one needs room temperature, and the third heating or reflux.
Although many reviews have reported the synthesis, structure–activity relationships (SARs) and the biological application of triazine derivatives, few of them focus on the antifungal properties of s-triazine compounds [19,20,21,22,23,24]. Given the grave need to develop new therapeutic options for the treatment of IFIs, we cover this review by highlighting recent studies of s-triazine derivatives as potential antifungal agents from publications between 2014–2024. This review not only attracts the attention of medicinal chemists but also provides insight into the antifungal drug development of s-triazine derivatives in future work.

2. Methodology

A systematic literature search was performed in PubMed, SciFinder, Scopus, and Web of Science. A search on s-triazine derivatives with antifungal activity was conducted by using combinations of keywords, including “triazines”, “s-triazine”, “1,3,5-triazine”, “derivatives”, “compounds”, “agents”, “antimicrobial activity”, “antifungal activity”, “antifungal”, “fungi”, and “fungal”. Then, the literature was saved after being imported into Endnote, and duplicates were removed. Next, the literature was checked according to the following inclusion and exclusion criteria.
(a)
Inclusion: the literature (1) published between 2014 and 2024, (2) available in English or with an English abstract if published in another language, and (3) studies on pathogenic fungi.
(b)
Exclusion: the literature on (1) purely computational, structural, or in silico studies or (2) without full-text availability.

3. Antifungal Activities of s-Triazine Based Derivatives

In 2020, Patil et al. reported the synthesis of a series of s-triazine derivatives through a one-step reaction by mixing 2-cyanoguanidine with various substituted benzonitriles to yield fifteen 1,3,5-triazine-2,4-diamines derivatives (Figure 3) [25]. The antifungal activity of each compound was examined against two fungal strains: C. albicans and C. neoformans. Compound 2a, bearing a 4-Br substituted phenyl group, displayed moderate fungal growth inhibition (~25% at 32 µg/mL) against both fungi. Compound 2b, bearing a 4-ethyl substituted phenyl, showed the highest growth inhibition (~30% at 32 µg/mL) against C. neoformans. The SAR suggested that either electron-withdrawing or electron-donating group substitution on the aryl did not play any role in the antifungal profiles.
Mekheimer et al. (2022) synthesized and reported various N2-(tetrazol-5-yl)-6-substituted-5,6-dihydro-1,3,5-triazine-2,4-diamines through the microwave reaction of 5-amino-1,2,3,4-tetrazole, cyanamide, and aromatic or heteroaromatic aldehydes (Figure 4) [26]. These s-triazine-tetrazole analogs were subsequently screened for in vitro antimicrobial activity. Notably, compounds 3a–c demonstrated excellent antifungal efficacy against C. albicans with minimum inhibitory concentration (MIC) values of 1.475 × 10−8, 1.288 × 10−3, and 2.1851 × 10−4 µg/mL, respectively, which was significantly more efficacious than the reference fluconazole (MIC: 0.857 µg/mL). The replacement of the phenyl group with other aryl groups or a substitution on the benzene ring resulted in a loss of antifungal activity. Furthermore, compounds 3a–c exhibited good inhibition of Candida 14α-demethylase enzyme, with IC50 values of 7.451 ± 0.404, 25.066 ± 1.358, and 3.369 ± 0.183 µg/mL, respectively, as determined by a rapid fluorescence-based screening method. Molecular docking studies indicated that compounds 3a–c demonstrated good binding affinity to the human CYP51 protein (PDB code: 3LD6) and possessed acceptable ADME properties. Notably, effective antifungal drugs require fungal selectivity to avoid unwanted side effects. While inhibition of fungal CYP51 can be effective, inhibiting human CYP51 could generate toxicity. Therefore, it is necessary to consider the safety of these compounds in regard to mammalian cells.
Hybridization of different bioactive moieties into a single molecule have the potential to improve the efficacy, reduce toxicity, enhance the pharmacokinetic properties, and overcome drug resistance [27]. Dinari et al. in 2018 reported a series of s-triazine-quinazolinone hybrids (Figure 5) [28]. The synthesized compounds were screened for their in vitro antimicrobial activities. The trisubstituted s-triazine hydrazine intermediates 4a–f displayed moderate to weak inhibitory activity against C. albicans, with MICs ranging from 128 to 512 μg/mL. When a benzoxazinone moiety was added into the intermediates to afford target hybrids, 5a–f, their anti-C. albicans activity improved 1- to 2-fold. In general, the antifungal activity of s-triazine-quinazolinone hybrids was poor and substantially inferior to their antibacterial activity.
In 2023, Zala et al. synthesized twelve molecular hybrids of s-triazine with coumarin and s-triazine with benzothiazole (Figure 6) [29]. These compounds were evaluated for their in vitro antifungal activities against Trichoderma rubrum and C. albicans. The hybrid 6a (MIC: 100 μg/mL) was most effective against the T. rubrum strain and comparable to reference griseofulvin, whilst the remaining compounds had moderate activity, with MICs ranging from 500–1000 μg/mL. Compounds 6b–d gave MIC values of 250 μg/mL against the C. albicans strain, exhibiting a potency 2-fold greater than griseofulvin.
Sweta et al. (2014) synthesized clubbed coumarin and N-substituted piperazine s-triazine hybrids and tested their in vitro antifungal activity against C. albicans and Saccharomyces cerevisiae using the Kirby–Bauer disc diffusion method (Figure 7) [30]. The biological screening results indicated that compounds 7a (inhibition zone: 20 mm), 7b (inhibition zone: 19 mm), and 7d (inhibition zone: 24 mm) displayed considerable anti-C. albicans activities, which were comparable to fluconazole and nystatin. Compound 7c, bearing dibenzo [b,f]-thiazapine piperazine, showed a high inhibition effect against S. cerevisiae.
By fusion of triazine with other pharmacophoric fragments, Bhat et al. in 2019 prepared a series of 4-aminoquinoline-s-triazine derivatives (Figure 8) [31]. Compounds 8a–e were the most potent in this series against C. albicans with MIC = 8 μg/mL. For Aspergillus niger and A. fumigatus strains, all the tested compounds showed moderate activity with MICs ranging from 8–32 μg/mL.
In 2020, Masih et al. synthesized a series of s-triazine-dihydropyrimidine hybrids (Figure 9) [32]. All synthesized compounds were evaluated for their in vitro antifungal activities against C. albicans, C. glabrata, C. neoformans, and Aspergillus niger. These compounds exhibited mild to moderate antifungal activity against the four tested strains. Notably, most compounds demonstrated better inhibition of Candida spp. than C. neoformans and A. niger. Compared with the unsubstituted analogs, introduction of substituents at R/R1 position could enhance the antifungal activity. For instance, compound 9a exhibited no antifungal effect, whereas compound 9b displayed the best and broad-spectrum activity against the tested strains with an MIC of 1.25–5 µg/mL. Compounds 9c–f showed promising antifungal activity against C. albicans (MIC: 2.5–5 μg/mL). However, no clear SARs between the R and R1 substituents were observed.
Desai et al. (2016) reported multiple s-triazine based thiazole hybrids [33]. The antifungal activities of the synthesized compounds were investigated in C. albicans, A. niger, and A. clavatus (Figure 10). The -NO2 substituted aniline was determined as essential to increase pharmacological activity. For example, compounds 10a and 10b showed broad and excellent inhibition against three tested fungi. Compounds 10c and 10d possessed potent inhibition against C. albicans and A. niger, whose MIC values were lower or equal to that of griseofulvin.
A series of s-triazine-benzenesulfonamide hybrids were also evaluated for their antifungal activities against C. albicans, A. niger, and Aspergillus clavatus by Desai et al. in the year 2016 (Figure 11) [34]. All hybrids displayed better inhibitory activity against C. albicans than A. niger and A. clavatus. Among them, compounds 11a–d demonstrated mild antifungal activity (MIC: 250 μg/mL) against C. albicans, while the remaining compounds showed weak (MIC: 500–1000 μg/mL) or no activity against C. albicans. Additionally, 11b was identified as the most effective agent (MIC: 250 μg/mL) against A. niger, whereas it had no activity against A. clavatus. The SAR studies revealed that the antifungal activity of these s-triazine hybrids was significantly influenced by different R-substituents on the phenyl ring.
Similarly, s-triazine-bis-benzenesulfonamide hybrids 4-((4-chloro-6-((4-sulfamoylphenyl)amino)-1,3,5-triazin-2-yl)amino)-N-(pyrimidin-2-yl)benzenesulfonamide and 4,4′-((6-chloro-1,3,5-triazine-2,4-diyl)bis(azanediyl))bis(N-(pyrimidin-2-yl)benzenesulfonamide) were evaluated for in vitro antimicrobial activities against four bacterial strains and two fungal strains, A. niger and Schizophyllum commune, by Noureen and co-workers in 2022 (Figure 12) [35]. Compound 12a (inhibition zone: 20 ± 0.51 mm against A. niger) is more potent than 12b and fluconazole. In studies against S. commune, 12a (inhibition zone: 22 ± 0.65 mm) and 12b (inhibition zone: 25 ± 0.72 mm) displayed higher potency than sulfanilamide, sulfadiazine, sulfamethazine, and fluconazole. Moreover, the MIC values of the two compounds confirmed their antifungal activity. Cytotoxic studies indicated that compounds 12a and 12b had low hemolysis, suggesting a good safety profile.
In 2024, Mohamed-Ezzat et al. evaluated the potential of s-triazine sulfonamide conjugate as anti-microbial, antitumor, and anti-SARS-CoV-2 agents (Figure 13) [36]. Compounds 13a–c were the most active compounds against C. albicans, showing a zone of fungal inhibition with the values 12.3 ± 0.6 mm, 13.3 ± 0.6 mm, and 9.6 ± 0.6 mm, respectively. It is worth noting that replacement of pyrrolidine with piperidine or morpholine led to loss of anti-C. albicans potency. Additionally, 13a also demonstrated remarkable antiproliferative and antiviral potency.
In the same year, Kumawat et al. integrated multiple bioactive moieties such as adamantylamine, sulfamerazine, sulfadiazine, morpholine, thiazole, and piperazine into the s-triazine core (Figure 14) [37]. In vitro antifungal activity of these s-triazine hybrids was evaluated against Malassezia furfur. A total of 6 of 11 tested compounds revealed higher potency than ketoconazole. Notably, compound 14a exhibited the highest activity against M. furfur (MIC: 8.13 ± 0.27 µg/mL), followed by 14b (MIC: 9.34 ± 0.24 µg/mL) and 14c (MIC: 12.21 ± 0.25 µg/mL). Furthermore, 14a exhibited the highest antibacterial activity against Pseudomonas chlororaphis. In silico pharmacokinetic and ADME-T analysis of compounds 14a and 14b revealed favorable drug-like properties.
In another study, Shinde et al. (2021) synthesized a series of 4,6-dimethoxy-1,3,5-triazine and chalcone hybrids [38]. Antifungal activity testing was performed using four fungal strains (C. albicans, A. niger, Candida tropicalis, and C. glabrata) (Figure 15). Compound 15a demonstrated the highest activity against C. albicans (inhibition zone: 85 mm) and C. glabrata (inhibition zone: 82 mm), while 15b (inhibition zone: 85 mm) and 15c (inhibition zone: 81 mm) showed excellent antifungal activity, especially against A. niger and C. tropicalis, respectively. Generally, a fluorine substituent on the benzene ring of chalcones was more effective for antifungal activity.
Patel et al. in 2014 synthesized new thiazolidin-4-one fused s-triazine hybrids as potential antimicrobial and anticancer agents (Figure 16) [39]. The most active compounds, 16a and 16b, exhibited considerable activities (MIC: 3.12–25 μg/mL) against A. niger and C. albican, but they were less active than ketoconazole (MIC: 1.56 μg/mL). SAR studies suggested that both benzonitrile and nicotinonitrile were beneficial to increase the corresponding pharmacological activities.
Mewada et al. in 2018, developed four classes of s-triazine based derivatives that incorporated the methoxy, 4-aminobenzonitrile moieties with phenol, thiophenol, aniline, and piperazine/piperidine/morpholine to a triazine nucleus (Figure 17) [40]. Compounds 17a (MIC: 3.12 μg/mL against C. albicans), 17b (MIC: 3.12 μg/mL against A. clavatus), 17c (MIC: 3.12 μg/mL against A. niger), 17e (MIC: 3.12 μg/mL against A. clavatus), 17f (MIC: 3.12 μg/mL against C. albicans), and 17g (MIC: 3.12 μg/mL against A. niger) showed the best inhibition activities, respectively. The 3-Cl substituted phenol derivative 17d enhanced antifungal activity against A. niger and A. clavatus compared with the 3-Cl substituted thiophenol 17a. SAR studies indicated target compounds containing halogen-substituted thiophenol moiety exhibited better antifungal potency than other series.
In a study by Singh et al. 2015, a series of 2,4,6-trisubstituted-s-triazine derivatives were synthesized and assessed for their antimicrobial activity (Figure 18) [41]. Compounds 18a–c demonstrated antifungal potency comparable to fluconazole. For example, 18b demonstrated the most significant antifungal activity against C. albicans (MIC = 3.125 μg/mL) and 18c was most active against C. tropicalis (MIC = 6.25 μg/mL), which was equipotent to fluconazole. Replacement of the N-aryl piperazine group (18b) with N-methyl (18a) made the compounds more active against C. tropicalis. Nevertheless, there was no clear SAR conclusion between the structures and antifungal activity.
A panel of s-triazine-based chalcone- and pyrimido[4,5-b][1,4]diazepine hybrids were developed by Moreno et al. in 2024 (Figure 19) [42]. The antifungal activity of these conjugates was evaluated against two yeasts C. albicans and Cryptococcus neoformans, three dermatophytes, Microsporum gypseum, Trichophyton rubrum, and Trichophyton mentagrophytes, and three filamentous fungi, A. fumigatus, A. niger, and A. flavus. Among them, the s-triazine-triazinyloxy-diazepine conjugate 19a showed moderate antifungal activity against T. rubrum (MIC: 62.5 μg/mL), and s-triazine fused triazinylamino-diazepine 19b displayed moderate potency against T. mentagrophytes and A. fumigatus (MIC: 62.5 μg/mL). Hybrid 19c showed marginal activity against T. rubrum and A. niger (MIC: 125 μg/mL), and 19d had the same activity against T. mentagrophytes with MIC = 125 µg/mL. A hemolytic assay and in silico toxicity prediction demonstrated that most of the synthesized compounds are safe. Thus, these s-triazine-based chalcone/diazepine hybrids offer an excellent framework for further optimization.
In 2023, Maliszewski et al. conducted an in vitro study to investigate the antifungal potential of novel 2,4,6-trisubstituted s-triazine derivatives, which contained amino acids or short peptide chains, 2-chloroethylpiperazine, and a methoxy group (Figure 20) [43]. The study evaluated the activity against yeasts (C. albicans), and filamentous fungi (A. fumigatus, A. flavus, Fusarium solani, and Penicillium citrinum) using the microbroth dilution method. Antifungal agents ketoconazole and nystatin served as positive controls. All compounds were more effective against C. albicans than other filamentous fungi. In particular, compounds 20a–c, which incorporated the -NH-PheOMe, -NH-Trp(Boc)-AlaOMe, and -NH-Asp(tBu)-AlaOMe functional groups, were more effective against C. albicans at a lower dose (MIC: 7.81–62.50 µg/mL) than ketoconazole and nystatin (MIC: 250 µg/mL). The studied compounds also showed broad-spectrum antibacterial effects.
Conrad et al. (2023) screened several classes of prohibitin inhibitors for antifungal activity studies (Figure 21) [44]. They identified that three melanogenin analogs 21a–c containing an s-triazine ring that inhibited C. albicans growth at a concentration of 16.08 µg/mL, and compound 21c completely blocked C. albicans growth. Compound 21c was further selected to determine the MIC by the microbroth dilution method. Various pathogenic fungal strains were tested, including C. albicans SC5314, SN250, DAY185, and DAY286, C. albicans clinical isolates MC99 and MC102, fluconazole-resistant C. albicans clinical isolate 3147, C. glabrata, C. tropicalis, C. parapsilosis, Candida dubliniensis, and S. cerevisiae. Compound 21c had broad spectrum antifungal activity with MICs ranging from 4–16 µg/mL. Viability analysis of C. albicans by flow cytometry demonstrated that 21c had fungicidal profiles with MIC of 8–16 µg/mL. Moreover, 21c inhibited C. albicans hyphal formation at sublethal concentrations (≥1 µg/mL). Although 21c targeted the inner mitochondrial integral membrane prohibitin proteins in human cancer cells, it did not impact C. albicans mitochondrial activity. The MIC of 21c in prohibitin mutant strains (phb1 or phb2 ∆/∆, phb1 ∆/∆-phb2 ∆/∆, and phb1 ∆/∆-phb2 ∆/∆-phb12 ∆/∆) corresponded to the wild-type parental strain, indicating a new fungal-specific mode of action.
Mena et al. (2022) screened 90 potential biological compounds from the JUNIA chemical library to assess their antifungal effects against C. albicans (Figure 22) [45]. One of the s-triazine based compounds, namely (Z)-N-(2-(4,6-dimethoxy-1,3,5-triazin-2-yl)vinyl)-4-methoxyaniline (22), displayed rapid fungicidal activity against C. albicans and was also effective against fluconazole-resistant or caspofungin-resistant clinical isolated C. albicans strains. Confocal microscopy revealed that compound 22 could modulate the C. albicans cell wall by reducing the thickness of the mannan, thereby affecting C. albicans virulence. In the Caenorhabditis elegans infection model, 22 prolonged the nematodes’ survival rate and increased the expression of immune related genes, such as lys-1, lys-7, cnc-4, and pmk-1, that promote nematodes against C. albicans infection. Overall, this study indicates that 22 represented a promising lead compound for the treatment of C. albicans infections. Possible target identification and synthetic study are under investigation.
In 2018, Dong et al. carried out a virtual screening of 287,000 compounds in the Specs 3D database for identifying secreted aspartic proteases 2 (SAP2, an important virulence factor) inhibitors of C. albicans (Figure 22) [46]. Seven compounds had an IC50 value lower than 100 μM. Among them, s-triazine based compound 23 showed certain SAP2 inhibitory activity (IC50 = 77.18 μM). Molecular docking revealed that the triazine core was located at the central part in the active site of C. albicans SAP2 (PDB ID: 1EAG). Three side chains attached to the core formed π–π and hydrophobic interactions with surrounding amino acid residues. Interestingly, 23 was inactive in the antifungal assay (MIC > 64 μg/mL), which is consistent with the action mode of virulence inhibitors (SAP2 gene not affecting the in vitro growth of C. albicans). To evaluate the antifungal potency of 23, a series of in vivo studies were performed. Notably, 23 exhibited potent in vivo efficacy in a mouse model of invasive candidiasis. Therefore, SAP2 inhibitors, by targeting fungal virulence factors, could be an effective way to develop new antifungal agents.
In 2020, Alhameed et al. presented the synthesis and biological assessment of 4,6-disubstituted s-triazin-2-yl amino acid derivatives (Figure 22) [47]. Among them, s-triazine with piperidine, glycine, and aniline derivatives (24a–c) showed the best inhibitory capacity at 50 µg per disc of 15 ± 0.2, 13 ± 0.1, and 14 ± 0.2 mm, respectively. The MIC and minimum fungicidal concentration (MFC) values of 24a–c against C. albicans ranged between 34.36–37.95 µM, and 68.72–75.90 µM, respectively. The SAR showed that piperidine is the key substitution for the antifungal activity. Additionally, non-substituted aniline appeared to be more active than chlorine and methoxy-substituted compounds. Docking studies revealed that these synthesized compounds were well accommodated in the binding site of C. albicans N-myristoyltransferase (NMT, PDB code: 1IYL), which could be used as potential NMT inhibitors to exert antifungal activity. Interestingly, all compounds were inactive against Gram-positive and Gram-negative bacteria.
Dongre et al. (2017) synthesized a series of 4,6-diethoxy-N-(4-(4,5-dihydro-5-phenylisoxazol-3yl)phenyl)-1,3,5-triazin-2-amines and screened for their in vitro antifungal activities against A. niger, A. flavus, Penicillium chrysogenum, and Fusarium moniliforme by the poison plate method (Figure 22) [48]. Most of the compounds inhibited fungal growth with compounds 25a–c identified as the most active.
Li et al. in 2019 investigated and reported the antifungal properties of a 2,4,6-triamine-substituted s-triazine derivative 26 (ENOblock) by a drug repurposing strategy (Figure 23) [49]. Compound 26 is the first reported non-substrate small-molecule inhibitor of human enolase [50]. As a homolog of human enolase, enolase 1 (Eno1) is also expressed in C. albicans and is essential for the growth and virulence of C. albicans [51]. Thus, the author first examined the antifungal activity of 26 against various fungal pathogens, including C. albicans, C. neoformans, C. krusei, C. tropicalis, C. glabrata, and C. parapsilosis. As expected, the MICs of 26 against these tested strains ranged from 8.0–64.0 µg/mL. The combination of 26 and fluconazole significantly reduced the MICs and exhibited a significant synergistic effect. Compound 26, alone or in combination with fluconazole, showed remarkable inhibitory effects on hyphal and biofilm formation of C. albicans SC5314. Importantly, the combination of 26 and fluconazole showed in vivo activity against C. albicans SC5314 in a murine model of systemic candidiasis. The author determined 26 could directly interact with CaEno1 and inhibited the transglutaminase activity of this enzyme (IC50 = 12.6 µM). Taken together, 26 was identified as a novel antifungal lead for further modification.
In 2022, Xie et al. then conducted a series of structural modifications of 26 (Figure 23) [52]. They designed and synthesized forty-two novel s-triazine derivatives by replacement of the ENOblock PEG-containing side chains. Among them, the series compounds containing a thiosemicarbazide moiety exhibited excellent synergistic activity with fluconazole against fluconazole-resistant C. albicans (combination MIC: 0.125–2.0 μg/mL, FICI: 0.127–0.25). Of particular note, compound 27 displayed activity against resistant C. albicans with MIC values 4.0 μg/mL and exhibited fungal-selective inhibitory effects on C. neoformans (MIC ≤ 0.125–0.5 μg/mL) and C. glabrata (MIC ≤ 0.125 μg/mL). It was concluded that the thiosemicarbazide moiety is an important pharmacophore for generating antifungal activity.
Furthermore, Xie and colleagues, in 2024, unified two amino-substituted moieties by 4-fluorophenylmethanamine, and replaced the PEG-amide containing side chains with a hydrazone moiety (Figure 23) [53]. Therefore, several triazine hydrazone derivatives have been synthesized. Out of all derivatives, compound 28 not only showed excellent in vitro synergy in combination with fluconazole (combination MIC: 0.25–2.0 μg/mL, FICI range: 0.094–0.38) but also had direct antifungal potency against fluconazole-resistant C. albicans and Candida auris (MIC: 1.0–16.0 μg/mL). The SAR studies revealed that ortho-hydroxyl-substituted triazine hydrazones are the key pharmacophore. Moreover, 28 (10 mg/kg) effectively reduced the kidney burden in C. albicans SC5314, therefore highlighting this compound as a promising antifungal candidate.
Haiba et al. (2019) designed and synthesized thirty-five new s-triazine derivatives based on the structure of the gyrase inhibitor Astrazeneca arylaminotriazine III, and the derivatives (29–32) were evaluated for their antibacterial and antifungal activities (Figure 24) [54]. Among them, 21 of 35 target compounds showed an inhibitory effect against C. albicans with MICs ranging from 25 to 100 μg/mL. The most active compound 29 displayed a lower MIC of 25 μg/mL compared to the reference clotrimazole (MIC: 12.5 μg/mL). Interestingly, it had no antibacterial activity against Staphylococcus aureus or Escherichia coli.
In 2023, Salaković et al. investigated eight symmetrical s-triazine derivatives characterized with the same N-alkane or N-cycloalkane substituent on the N2 and N4 position and evaluated them for their in vitro antifungal activity towards A. flavus (Figure 25) [55]. All analyzed compounds expressed significant antifungal activity, with compounds 33a–c containing an acyclic substituent, and 33d, containing cyclic substituents, possessed the highest inhibitory activities (inhibition zone: 20.3 ± 0.6 mm). The author also carried out a comparative molecular docking to analyze the compounds’ binding affinity on the enzymes of A. flavus.
Sharma et al. in 2017 reported the modification of amine-substituted s-triazine by incorporating different combinations of mono- or di-pyrazole, piperidine, benzylamine, aniline, and diethylamine moieties (Figure 26) [56]. The activity of the derivatives against C. albicans was tested by the agar-well diffusion method. The s-triazine bearing bis-pyrazole ring derivatives had no antifungal activity compared to mono-pyrazole. Among the mono-pyrazole compounds, the presence of the morpholine ring along with piperidine or diethylamine, like compounds 34a (inhibition zone: 9 mm) and 34b (inhibition zone: 8 mm), were good for anti-C. albicans activity.
Triazine derivatives with additional N or S donor atoms exhibit strong chelating abilities and provide potential binding sites for complexation with various metal ions, thereby causing considerable biological activity [57]. In 2020, Soliman et al. presented two novel zinc (II) pincer complexes, [Zn(BPT)(NO3)2] and [Zn(BPT)(H2O)Cl]ClO4, using a bis-pyrazolyl-s-triazine (35a, BPT) ligand (Figure 27) [58]. The ligand and its metal complexes were screened for in vitro antimicrobial activity against a panel of pathogenic strains. It was found that Zn(II) complexes exhibited broad-spectrum antimicrobial activity against the Gram positive (Bacillus subtilis, Bacillus cereus) and Gram-negative bacteria (E.coli, Pseudomonas aeruginosa, S. aureus), as well as the fungus C. albicans. Particularly, one complex, [Zn(BPT)(NO3)2], had the minimum inhibitory effect against C. albicans (MIC: 2.8 μmol/mL), which was superior to amoxicillin (MIC: 3.0 μmol/mL). In comparison with the related work, Refaat et al. (2022) reported two Zn(II) complexes, [Zn(BPT)(NCS)2] and [Zn(BPT)(Br)2], that showed either weak or no antifungal activity against C. albicans and A. fumigatus [59].
Using the same ligand (35a), Soliman et al. in 2020 and 2021 continuously developed a novel Co(II) complex, [Co(BPT)(NO3)2], and a novel Fe(III) pincer complex, [Fe(BPT)(CH3OH)Cl2], with respective MIC values of 3.2 μmol/mL and 6.2 μmol/mL against C. albicans [60,61]. In contrast, the Ni(II) complexes were inactive against C. albicans and A. niger [62]. In another work reported by Soliman et al. in 2020, similar Fe(III) complexes with mono- and bis-pyrazolyl s-triazine ligands (35b–d) showed good activity against C. albicans with MICs in the range of 18.8–37.5 µg/mL (Figure 27) [63]. In 2024, Yousri et al. synthesized Co(II), Mn(II), and Ni(II) complexes with the 35c ligand [64]. The three studied complexes have certain inhibitory against A. fumigatus and C. albicans. It was noted that the antimicrobial activities of these metal complexes depend not only on the metal ion but also on the structure of the s-triazine ligand.
Soliman et al. also reported Mn(II) complexes with a new s-triazine bis-Schiff base chelating ligand (36, L) in 2018 (Figure 28) [65]. Antimicrobial studies showed that the [MnL(H2O)2](NO3)2 complexes are the best as antifungal and antibacterial agents. Similar work by using different s-triazine Schiff bases as ligands to form metal complexes for antifungal was reported by Fathalla et al. in 2023 [66,67,68]. Al-Khodir et al. (2019) assessed the antimicrobial and anticancer activities of Ru(III) and Se(IV) complexes containing an s-triazine chelating ligand [69]. The results showed that all Se(IV) complexes have a higher activity against A. flavus and moderate activity against C. albicans compared to Ru(III) complexes and amphotericin B. The 6-chloro-N2-(4-chlorophenyl)-N4-(pyrimidin-2-yl)-1,3,5-triazine-2,4-diamine) ligand (37, Figure 28) with a Se(IV) complex introduced the most promising efficiency.
Martins et al. (2019) synthesized 2,4,6-tris(thiomorpholine)-1,3,5-triazine (38a, TMT), 2,4,6-tris(piperazine)-1,3,5-triazine (38b, PIPT), and their Sb(III) and Bi(III) complexes (Figure 28) [70]. The results from antimicrobial assays showed that the Sb(III) complexes, ([SbCl3(TMT)], [Sb3Cl9(TMT)2], and [Sb2Cl6(PIPT)].4H2O), had antifungal activity against S. aureus, C. albicans, C. tropicalis, and C. krusei with MICs in the range of 512–1024 µg/mL. Additionally, two free ligands (TMT, PIPT) and SbCl3 did not inhibit the growth of the evaluated microorganisms, suggesting that coordination of metal ions through s-triazine based ligands is a good strategy for the development of new antimicrobial agents.
Due to the branching capabilities of the s-triazine nucleus, many mono-, bi-, and tri-substituted compounds can be prepared by controlling the reaction conditions. In this regard, Bashiri et al. in 2020 synthesized a collection of tris-β-lactam 1,3,5-triazine hybrids (39) and investigated their potential biological activities (Figure 29) [71]. Although some hybrid molecules showed antiproliferative, antibacterial, and antioxidant properties, they were inactive against the two tested fungi (C. albicans and A. fumigates). Vembu et al. (2016) designed and synthesized a series of 2,4,6-tris(tetrazol-1-yl-(4-phenyl(3-arylpropene-1-on-1-yl))-1,3,5-triazines (dendrimers) [72]. Some compounds exhibited moderate fungicidal activities and were more active against C. albicans, S. cerevisiae, and Aspergillus spp. than fluconazole.
It is well known that Schiff bases (−NH−N=CH−) have numerous biological activities. In 2018, Ramadan et al. synthesized and reported a novel class of dimeric s-triazine hydrazide derivatives (40) using 1,2-diaminoethane, 1,4-diaminocycloalkane, 1,4-diaminobenzene, and 1,1’-biphenyl-4,4’-diamine as linkers (Figure 30) [73]. The synthesized compounds were investigated for their in vitro antimicrobial activity. Unfortunately, none of the dimeric s-triazine hydrazide showed anti-C. albicans activity. Also, Al-Rasheed et al. synthesized series of s-triazine based Schiff bases derivatives (41–43) (Figure 27) [74,75]. Some target compounds exhibited good antibacterial activity; however, none of them showed a specific effect against the tested fungi.
Al-Zaydi et al. (2017) synthesized a series of s-triazine based aminobenzoic acids and their methyl ester analogs (44a–e) (Figure 31) [76]. In vitro MIC antifungal results showed all the tested compounds have no inhibition activity against C. albicans (MIC > 200 μg/mL).

4. Discussion

Presently, limited anti-IFIs drugs are available in clinical settings. Of those available, there are three predominant classes: azoles, polyenes, and echinocandins. Azoles, including triazole and tetrazole, are fungal lanosterol 14α-demethylase (CYP51, encoded by the erg11) inhibitors, which disrupt cell membrane integrity and thereby block fungal cell growth. Azoles are widely used due to their broad-spectrum activity, particularly against Candida, Cryptococcus, and Aspergillus. However, azoles also inhibit cytochrome P450 enzymes and are fungistatic, which leads to hepatotoxicity, drug–drug interactions, and severe drug resistance. Amphotericin B (AmB) is a clinically used polyene that binds to the cell membrane ergosterol, leading to cell death. Although AmB is the earliest-used drug and remains the “gold standard” for treating IFIs, it has severe toxicity due to the similarity between ergosterol and cholesterol in mammalian cell membranes. This side effect and low oral bioavailability curb its clinical application. Echinocandins inhibit fungal growth by targeting β-(1,3)-glucan synthesis, which is an essential component of the fungal cell wall. These agents display excellent fungicidal activity against various Candida species and are commended as first-line drugs in patients suffering from invasive Candida infection. The primary drawbacks of echinocandins include poor oral bioavailability, ineffectiveness against Cryptococcus species, and emerging resistance in non-C. albicans. Remarkably, each antifungal drug class has significant therapeutic limitations, ranging from toxicity to drug resistance. Therefore, discovering novel antifungal agents with new chemical scaffolds is urgently needed.
This review covers the advancement of s-triazine and its derivatives with potential antifungal activities against fungal strains, and SARs are also analyzed briefly. As an essential class of the heterocyclic compound, the triazine ring is a six-membered benzene structure with three carbons replaced by nitrogen. Among the three isomeric forms of triazine, s-triazine occupies a key position in medicinal chemistry because of its wide applications and high biological activities. As one of the primary starting materials, cyanuric chloride can afford numerous s-triazine derivatives (mono-substituted, di-substituted, and tri-substituted), taking advantage of its low cost and easy manipulation via multiple nucleophilic substitution reaction. This lies in further conjugating with active pharmacophores of the s-triazine core through molecular hybridization. Some general conclusions could be obtained based on the SARs from the above-mentioned s-triazine derivatives:
  • Substituents on the s-triazine core with tetrazole, pyridine, pyrimidine, morpholine, piperazine, piperidine, coumarin, chalcone, and quinoline are favored for improving their antifungal activity against Candida, Cryptococcus, and Aspergillus species.
  • Halogen atoms, especially fluorine, chlorine, and bromine, are present in the s-triazine derivatives’ chemical structures, which suggests the significant importance of halogen bonding in interactions with corresponding targets.
  • Tri-substituted s-triazine derivatives are generally more active than di-substituted and mono-substituted, possibly due to the introduction of more pharmacophore fragments.
On the other hand, triazines are more often used in studies of antibacterial, antitumor, antiviral, and other fields. Due to the lack of in-depth antifungal mechanisms and target studies, most of the s-triazine derivatives mentioned in the text are obtained based on phenotypic screening or via medicinal chemistry driven SARs studies, not by structure-based drug design or target-based drug discovery. Therefore, further pharmacology experiments are warranted to investigate the corresponding mechanism/targets of s-triazine antifungal compounds. Moreover, applying s-triazine derivatives in clinical practice still faces significant challenges. Promising compounds need further evaluation, including a susceptibility test against other fungal species, safety evaluation (e.g., hemolytic activity or cytotoxicity against mammalian cell lines), unraveling mechanisms of action (e.g., enzyme inhibition, cell membrane/wall disruption), and a deeper understanding of pharmacokinetic/pharmacodynamic (PK/PD) properties, as well as in vivo efficacy studies.

5. Conclusions

Fungal infections have posed a heavy burden on the world health system. The current treatment of fungal disease is compounded by its efficacy, toxic side effects, bioavailability, and emergence as a drug-resistant fungi. s-Triazine displays a broad spectrum of pharmacological activities, acting as a versatile scaffold for drug design and development. Several s-triazine derivatives have recently been reported for their antifungal activities, and some exhibited promising in vitro and in vivo potency against drug-sensitive and drug-resistant fungal pathogens. This review covers the recent advances of s-triazine compounds as potential antifungal agents, and the effect of different substituents installed on the s-triazine core is also discussed. More synthesis and SAR studies will bring new perspectives for further optimization of s-triazine compounds.

6. Future Prospects

The synthesis of s-triazine derivatives will continue to be a research focus. Nevertheless, it should be noted that most of the above-mentioned studies lack comprehensive evaluation or do not determine the exact antifungal mechanism of the s-triazine derivatives. There still remains adequate room for exploring s-triazine compounds and their underlying antifungal activity. For example, by carrying out structure-based drug design (SBDD), computer-aided drug design (CADD), and even the proteolysis-targeting chimeras (PROTAC) technique, chemists can further construct multifunctional s-triazine derivatives that possess multi-targeting, membrane-targeting, protein–protein interactions, inhibition, anti-virulence, and/or anti-drug efflux characteristics. As such, s-triazine/s-triazine derivatives are promising chemical entities for antifungal activity screening, and sufficient effort should be devoted to exploring their potential. Based on more systematic studies, novel s-triazine antifungal candidates with a broad-spectrum, higher activities, and a lower toxicity are worth expecting in future drug discovery.

Author Contributions

H.L. and M.L. contributed to the literature review and manuscript drafting. H.L. wrote the manuscript and prepared the illustrative figures. M.W. and D.Z. conceived the figures and revised the contents. Y.H. and F.X. conceived the manuscript topic and structure, supervised its writing, and reviewed all contents thoroughly. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by the National Natural Science Foundation of China (No. 82304302), the Naval Key Discipline Professional Project (No. 2024-HJZDXK-JS-08), the Naval Medical University Young Research Fellowship Grant (2024QN013), and the Naval Medical University Undergraduates’ Innovation and Practice Training Programs (FH2024212).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

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Pharmaceuticals 18 00690 g001
Figure 1. (A) Three isomers of triazine and the wide range pharmacological activities of s-triazine. (B) Some commercial drugs containing the s-triazine ring.
Figure 1. (A) Three isomers of triazine and the wide range pharmacological activities of s-triazine. (B) Some commercial drugs containing the s-triazine ring.
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Pharmaceuticals 18 00690 g002
Figure 2. General synthesis routine of a substituted s-triazine from cyanuric chloride.
Figure 2. General synthesis routine of a substituted s-triazine from cyanuric chloride.
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Pharmaceuticals 18 00690 g003
Figure 3. Chemical structures of the s-triazine derivatives 2a,b.
Figure 3. Chemical structures of the s-triazine derivatives 2a,b.
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Figure 4. Chemical structures of the s-triazine derivatives 3a–c.
Figure 4. Chemical structures of the s-triazine derivatives 3a–c.
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Figure 5. Chemical structures of the s-triazine derivatives 4a–f and 5a–f.
Figure 5. Chemical structures of the s-triazine derivatives 4a–f and 5a–f.
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Figure 6. Chemical structures of the s-triazine derivatives 6a–d.
Figure 6. Chemical structures of the s-triazine derivatives 6a–d.
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Figure 7. Chemical structures and antifungal activities of the s-triazine derivatives 7a–d.
Figure 7. Chemical structures and antifungal activities of the s-triazine derivatives 7a–d.
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Pharmaceuticals 18 00690 g008
Figure 8. Chemical structures and antifungal activities of the s-triazine derivatives 8a–e.
Figure 8. Chemical structures and antifungal activities of the s-triazine derivatives 8a–e.
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Pharmaceuticals 18 00690 g009
Figure 9. Chemical structures and antifungal activities of the s-triazine derivatives 9a–f.
Figure 9. Chemical structures and antifungal activities of the s-triazine derivatives 9a–f.
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Pharmaceuticals 18 00690 g010
Figure 10. Chemical structures and antifungal activities of the s-triazine derivatives 10a–e.
Figure 10. Chemical structures and antifungal activities of the s-triazine derivatives 10a–e.
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Pharmaceuticals 18 00690 g011
Figure 11. Chemical structures of the s-triazine derivatives 11a–d.
Figure 11. Chemical structures of the s-triazine derivatives 11a–d.
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Figure 12. Chemical structures and antifungal activities of the s-triazine derivatives 12a,b.
Figure 12. Chemical structures and antifungal activities of the s-triazine derivatives 12a,b.
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Pharmaceuticals 18 00690 g013
Figure 13. Chemical structures of the s-triazine derivatives 13a–c.
Figure 13. Chemical structures of the s-triazine derivatives 13a–c.
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Figure 14. Chemical structures of the s-triazine derivatives 14a–c.
Figure 14. Chemical structures of the s-triazine derivatives 14a–c.
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Figure 15. Chemical structures and antifungal activities of the s-triazine derivatives 15a–c.
Figure 15. Chemical structures and antifungal activities of the s-triazine derivatives 15a–c.
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Figure 16. Chemical structures of the s-triazine derivatives 16a,b.
Figure 16. Chemical structures of the s-triazine derivatives 16a,b.
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Figure 17. Chemical structures and antifungal activities of the s-triazine derivatives 17a–g.
Figure 17. Chemical structures and antifungal activities of the s-triazine derivatives 17a–g.
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Figure 18. Chemical structures and antifungal activities of the s-triazine derivatives 18a–c.
Figure 18. Chemical structures and antifungal activities of the s-triazine derivatives 18a–c.
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Figure 19. Chemical structures of the s-triazine derivatives 19a–d.
Figure 19. Chemical structures of the s-triazine derivatives 19a–d.
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Figure 20. Chemical structures of the s-triazine derivatives 20a–c.
Figure 20. Chemical structures of the s-triazine derivatives 20a–c.
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Figure 21. Chemical structures of the s-triazine derivatives 21a–c.
Figure 21. Chemical structures of the s-triazine derivatives 21a–c.
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Figure 22. Chemical structures of the s-triazine derivatives 22–25.
Figure 22. Chemical structures of the s-triazine derivatives 22–25.
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Figure 23. Design strategies and chemical structures of the s-triazine derivatives 26–28.
Figure 23. Design strategies and chemical structures of the s-triazine derivatives 26–28.
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Figure 24. Design strategies and chemical structures of the s-triazine derivative 29–32.
Figure 24. Design strategies and chemical structures of the s-triazine derivative 29–32.
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Figure 25. Chemical structures of the s-triazine derivatives 33a–d.
Figure 25. Chemical structures of the s-triazine derivatives 33a–d.
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Figure 26. Chemical structures of the s-triazine derivatives 34a,b.
Figure 26. Chemical structures of the s-triazine derivatives 34a,b.
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Figure 27. Chemical structures of the s-triazine derivatives 35a–d.
Figure 27. Chemical structures of the s-triazine derivatives 35a–d.
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Figure 28. Chemical structures of the s-triazine derivatives 36–38.
Figure 28. Chemical structures of the s-triazine derivatives 36–38.
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Figure 29. Chemical structures of the s-triazine derivatives 39.
Figure 29. Chemical structures of the s-triazine derivatives 39.
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Figure 30. Chemical structures of the s-triazine derivatives 40–43.
Figure 30. Chemical structures of the s-triazine derivatives 40–43.
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Figure 31. Chemical structures of the s-triazine derivatives 44a–e.
Figure 31. Chemical structures of the s-triazine derivatives 44a–e.
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Liao, H.; Liu, M.; Wang, M.; Zhang, D.; Hao, Y.; Xie, F. Exploring the Potential of s-Triazine Derivatives as Novel Antifungal Agents: A Review. Pharmaceuticals 2025, 18, 690. https://doi.org/10.3390/ph18050690

AMA Style

Liao H, Liu M, Wang M, Zhang D, Hao Y, Xie F. Exploring the Potential of s-Triazine Derivatives as Novel Antifungal Agents: A Review. Pharmaceuticals. 2025; 18(5):690. https://doi.org/10.3390/ph18050690

Chicago/Turabian Style

Liao, Haoyan, Menglu Liu, Mengyuan Wang, Dazhi Zhang, Yumeng Hao, and Fei Xie. 2025. "Exploring the Potential of s-Triazine Derivatives as Novel Antifungal Agents: A Review" Pharmaceuticals 18, no. 5: 690. https://doi.org/10.3390/ph18050690

APA Style

Liao, H., Liu, M., Wang, M., Zhang, D., Hao, Y., & Xie, F. (2025). Exploring the Potential of s-Triazine Derivatives as Novel Antifungal Agents: A Review. Pharmaceuticals, 18(5), 690. https://doi.org/10.3390/ph18050690

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